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Information on EC 2.7.1.91 - sphingosine kinase and Organism(s) Homo sapiens and UniProt Accession Q9NRA0
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2.7.1.91 sphingosine kinaseIUBMB Comments
The enzyme is involved in the production of sphingolipid metabolites. It phosphorylates various sphingoid long-chain bases, such as sphingosine, D-erythro-dihydrosphingosine (sphinganine), phytosphingosine (4-hydroxysphinganine), 4-hydroxy-8-sphingenine, 4,8-sphingadienine and D-threo-dihydrosphingosine and L-threo-dihydrosphingosine. The exact substrate range depends on the species.
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Word Map
- 2.7.1.91
- sphingosine-1-phosphate
- 1-phosphate
- sphingolipids
- ceramide
- endothelial
- sirnas
- necrosis
- agonist
- metastasis
- artery
- erk
- phospholipase
- fingolimod
- fibrosis
- lymphocyte
-
protein-coupled
- sphingomyelinase
- tnf
- pulmonary
- leukemia
- sphingomyelin
-
anti-apoptotic
-
s1p-induced
- stat3
- pertussis
- mapks
-
pro-apoptotic
-
mitogen
- sclerosis
- pkc
-
rheostat
-
signal-regulated
- caspase-3
-
pro-survival
-
platelet-derived
- lysophospholipids
-
cardioprotective
- phytosphingosine
- drug development
- lymphopenia
-
egress
- glucosylceramide
- medicine
- fumonisins
-
s1p-mediated
- dihydroceramide
-
mitogenesis
-
pdgf-induced
-
ceramide-induced
-
lysophosphatidic
- fcepsilonri
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
sphk1, sphingosine kinase, sphk2, sphingosine kinase 1, sphingosine kinase-1, sphingosine kinase 2, sphk-1, sphingosine kinase-2, sphk1a, sphingosine kinase type 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
sphingosine kinase 2
-
SPHK2
dihydrosphingosine kinase
-
-
-
-
kinase, dihydrosphingosine (phosphorylating)
-
-
-
-
kinase, sphingosine (phosphorylating)
-
-
-
-
SK
SK1
sphinganine kinase
sphingoid base kinase
-
-
-
-
sphingosine kinase 1
sphingosine kinase-1
SPHK
SPHK1
additional information
SK
-
-
-
-
sphinganine kinase
-
sphingosine kinase 1
-
sphingosine kinase-1
is a substrate for the cysteine protease cathepsin B
SPHK
-
-
-
-
SPHK1
-
additional information
-
the enzyme belongs to the subfamily of diacylglyceride kinases DAGKs
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism, the catalytic domain contains the C1-C5 sequence stretches and the ATP-binding site
-
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
Lys103 is important in catalysis
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:sphingoid base 1-phosphotransferase
The enzyme is involved in the production of sphingolipid metabolites. It phosphorylates various sphingoid long-chain bases, such as sphingosine, D-erythro-dihydrosphingosine (sphinganine), phytosphingosine (4-hydroxysphinganine), 4-hydroxy-8-sphingenine, 4,8-sphingadienine and D-threo-dihydrosphingosine and L-threo-dihydrosphingosine. The exact substrate range depends on the species.
CAS REGISTRY NUMBER
COMMENTARY
50864-48-7
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine
ADP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine 1-phosphate
-
-
-
?
ATP + biotinyl-D-erythro-sphingosine
ADP + biotinyl-D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
-
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
immunomodulatory drug, high activity with isozyme SPHK2, 7fold lower activity with isozyme SPHK1
-
-
?
ATP + sphingosine-fluorescin
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
-
approximately 20% the activity of sphingosine at isoformSPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutan-1-ol
ADP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutyl dihydrogen phosphate
-
isoform SPHK2 is 6fold more efficient than SPHK1 in phosphorylating
product is a nanomolar agonist of sphingosine 1-phsphate receptor 1, whereas the (2S)-enantiomer is much weaker
-
?
ATP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol
ADP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-yl dihydrogen phosphate
-
no substrate for SPHK1, phosphorylated by SPHK2 at low rates
product is a potent agonist of sphingosine 1-phsphate receptor 1
-
?
ATP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol
ADP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol 3-phosphate
-
isozyme SPHK2, 10fold lower activity with isozyme SPHK1
-
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
-
good substrate of isoform SPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
-
moderate activity at isoform SPHK2, it is the only alcohol in the series to have significant activity at isoform SPHK1
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine
ADP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine 1-phosphate
-
-
-
?
ATP + biotinyl-D-erythro-sphingosine
ADP + biotinyl-D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-(+)-erythro-sphinganine
ADP + D-(+)-erythro-sphinganine 1-phosphate
-
-
-
-
?
ATP + DL-erythro-dihydrosphingosine
ADP + DL-erythro-dihydrosphingosine 1-phosphate
-
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
-
isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + fluorescein-labeled sphingosine
ADP + fluorescein-labeled sphingosine 1-phosphate
-
-
-
-
?
ATP + L-(-)-threo-sphinganine
ADP + L-(-)-threo-sphinganine 1-phosphate
-
-
-
-
?
ATP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine
ADP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine 1-phosphate
-
-
-
-
?
ATP + sphingosine-fluorescin
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
2fold higher activity with isozyme SPHK1 compared to isozyme SPHK2
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
SK2 has a higher substrate affinity to sphinganine than to sphingosine
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
nucleotide binding in the cleft between the N-terminal domain and C-terminal domain
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
immunomodulatory drug, high activity with isozyme SPHK2, 7fold lower activity with isozyme SPHK1
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
-
FTY720 is stereoselectively phosphorylated to the active principle (S)-FTY720-phosphate which binds to four of the five known sphingosine-1-phosphate receptors. The introduction of a second stereocenter in the amino alcohol head group of FTY720-like compounds has a strong effect on the phosphorylation efficiency and selectivity by SPHKs and on transiently decreasing peripheral lymphocyte counts in vivo
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
-
isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
involved in signal transduction in the nucleus
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
2fold higher activity with isozyme SPHK1 compared to isozyme SPHK2
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
additional information
?
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
?
additional information
?
-
-
FYT720 is no substrate of isozymes SphK1 and SphK2
-
-
?
additional information
?
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
no activity with ceramide, the 2 isozymes interact with a number of proteins, overview
-
-
?
additional information
?
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
?
additional information
?
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
involved in signal transduction in the nucleus
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
-
binding site of SPHK1: involves Gly82, nucleotide binding also involved the SGDGX17-21K motif in the C2-region
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mg2+
Mn2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
-
-
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
-
-
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
-
-
(2S)-2-(3-[6-[(3-bromophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 35% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(3-chlorophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 46% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-bromophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 49% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-chlorophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 56% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-cyanophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 43% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-methylphenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 94% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[([1,1'-biphenyl]-4-yl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 51% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[2-([1,1'-biphenyl]-4-yl)-2-oxoethoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 77% residual activity at 0.001 mM
-
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
-
(2S)-2-[3-(6-butoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 69% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 65% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[2-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 47% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[3-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 34% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[4-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 30% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[[3-(trifluoromethyl)phenyl]methoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform isoform SphK2 shows 81% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[[4-(trifluoromethyl)phenyl]methoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5091592, isoform SphK2 shows 42% residual activity at 0.001 mM
-
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
(2S)-2-[3-[4-(octyloxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLM6031434, the inhibitor is 23fold selective for isoform SphK2 over SphK1 with 51% inhibition of isoform SphK2 at 0.0003 mM
-
(2S)-2-[3-[4-(octyloxy)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
8% inhibition of isoform SphK2 at 0.001 mM
-
(2S)-2-[3-[6-(2-methoxyethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 87% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 74% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(benzyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 97% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(cyclopentylmethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 57% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(heptyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 83% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
(2S)-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5081308, isoform SphK2 shows 51% residual activity at 0.001 mM
-
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression
(2S,3S)-3-hydroxy-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5121314, isoform SphK2 shows 53% residual activity at 0.001 mM
-
(2S,3S)-3-hydroxy-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5111312, isoform SphK2 shows 46% residual activity at 0.001 mM
-
(3S)-1-([4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl]methyl)pyrrolidin-3-ol
-
-
(3S)-N-[(1S)-1-[4-[5-(2-cyclohexylethyl)-1,2,4-oxadiazol-3-yl]phenyl]propyl]-3-hydroxy-L-prolinamide
-
-
(4-dodecylphenyl)[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(4-dodecylphenyl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(E)-3-(3-(4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)-6-methoxyquinolin-2(1H)-one
-
-
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(E)-6-methoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
-
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
-
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
-
(S)-2-((3-(4-((4-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(2-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
35% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(2-chloro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
40% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3,5-dimethyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
23% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-(pyridin-4-yl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
8% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
SLM6071469, the inhibitor is 73fold selective for isoform SphK2 over SphK1 with 65% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-allyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
59% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-bromo-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
24% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
33% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(3-ethyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
42% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-fluoro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
23% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(3-methoxy-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
15% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
3% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-nitro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
33% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(4'-fluoro-6-((4-(trifluoromethyl)benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
31% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
2% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(4?-(trifluoromethyl)-6-((4-(trifluoromethyl)-benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
12% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(6-((4-(trifluoromethyl)benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
28% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
-
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
-
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
-
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
-
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium chloride
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
-
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
-
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
-
1-(3-(4-((4-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
-
1-methyl-1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[[4-(4-tert-butylphenoxy)-3-fluorophenyl]methyl]pyrrolidin-3-ol
-
-
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
3-(((4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)amino)methyl)-6,7-dimethoxyquinolin-2(1H)-one
-
-
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
-
-
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
selective inhibition of isoform SK2
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
inhibits both isoforms SK1 and SK2
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6-[5-[(2S)-1-carbamimidoylpyrrolidin-2-yl]-1,2,4-oxadiazol-3-yl]naphthalen-2-yl 4-methylbenzene-1-sulfonate
isoform SphK2 shows 89% residual activity at 0.001 mM
-
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
-
N-cyclohexyl-N-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetamide
-
SG-12
i.e. (2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol, potent and selective isoform SphK2 inhibitor
-
SLM6031434
the inhibitor is 23fold selective for isoform SphK2 over SphK1 with 51% inhibition of isoform SphK2 at 0.0003 mM
-
SLM6071469
i.e. (S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide. The inhibitor is 73fold selective for isoform SphK2 over SphK1 with 65% inhibition of isoform SphK2 at 0.0003 mM
-
(1S)-1-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol
i.e. ZINC19691372
-
(1S,3R)-1-(3,4-dihydroxyphenyl)-2,3,4,9-tetrahydro-1H-b-carboline-3-carboxylic acid
i.e. ZINC00095976
-
(2R)-1-[5-methoxy-2-([[2-(methylsulfanyl)ethyl]amino]methyl)phenoxy]-3-(4-methylpiperazin-1-yl)propan-2-ol
i.e. ZINC20254629
-
(2R)-2-amino-4-(4-octylphenyl)butan-1-ol
-
i.e. (R)-2-amino-4-(4-octylphenyl)butan-1-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S)-2-[[(4-octylphenyl)amino]methyl]pyrrolidin-3-ol
-
inhibition of isoform Sk1
(2R,3S)-3-amino-4-morpholin-4-yl-1-phenylbutan-2-ol
-
i.e. (2R,3S)-3-amino-4-morpholino-1-phenylbutan-2-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
potent, water-soluble, isoenzyme-specific inhibitor of SphK1. The inhibitor decreases growth and survival of human leukemia U937 and Jurkat cells, and enhances apoptosis and cleavage of Bcl-2. Lethality of SK1-I is reversed by caspase inhibitors and by expression of Bcl-2. The specific inhibitor of SphK1 warrants attention as potential addition to the therapeutic armamentarium in leukemia
(2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
i.e. SK1-I, BML-258, isotype-specific SphK1 inhibitor. Treatment suppresses growth of LN229 and U373 glioblastoma cell lines and nonestablished human GBM6 cells. SK1-I also enhances glioblastoma multiforma cell death and inhibits their migration and invasion. Sk1-I enhances the survival of mice harboring LN229 intracranial tumors. SK1-I rapidly reduces phosphorylation of Akt but has no significant effect on activation of extracellular signal-regulated kinase 1/2
(2S)-1-(1,3-benzodioxol-5-yloxy)-3-[benzyl(2-hydroxyethyl)amino]propan-2-ol
i.e. ZINC03253280
-
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
-
-
(2S)-1-(azepan-1-yl)-3-(1,3-benzodioxol-5-yloxy)propan-2-ol
i.e. ZINC02686881
-
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
-
-
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
-
-
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
-
(2S)-2-[[(2R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl]amino]butanedioic acid
i.e. ZINC02707482
-
(2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3R)-2-amino-N-(4-octylphenyl)-3-hydroxybutanamide
-
inhibition of isoform Sk1
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression
(2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(3aR,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid
i.e. ZINC05033974
-
(3R,4R,5S)-2-(6-amino-9H-purin-9-yl)-5-methyltetrahydrofuran-3,4-diol
i.e. ZINC17005625
-
(3S)-1-([4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl]methyl)pyrrolidin-3-ol
-
-
(3S)-N-[(1S)-1-[4-[5-(2-cyclohexylethyl)-1,2,4-oxadiazol-3-yl]phenyl]propyl]-3-hydroxy-L-prolinamide
-
-
(4-dodecylphenyl)[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(4-dodecylphenyl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(4R)-4-(4-hydroxy-3-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol
i.e. ZINC01719191
-
(E)-3-(3-(4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)-6-methoxyquinolin-2(1H)-one
-
-
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(E)-6-methoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
-
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
-
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
-
(S)-2-((3-(4-((4-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
-
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
-
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
-
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
-
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
-
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
-
1-(3-(4-((4-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(4-octylphenethyl)piperidin-4-ol
a selective inhibitor of isozyme SK1, structure-activity relationship profile
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
-
1-methyl-1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[[4-(4-tert-butylphenoxy)-3-fluorophenyl]methyl]pyrrolidin-3-ol
-
-
2-(4-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-N-(prop-2-en-1-yl)hydrazinecarbothioamide
i.e. ZINC12651592
-
2-(4-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-N-phenylhydrazinecarbothioamide
i.e. ZINC19419587
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
2-[(1R)-1-amino-2-methylpropyl]-6-hydroxypyrimidin-4(3H)-one
i.e. ZINC82450359
-
2-[(2S)-2-aminobutan-2-yl]-6-hydroxypyrimidin-4(3H)-one
i.e. ZINC82450459
-
2-[(2S)-4-[(2-aminopyrimidin-5-yl)methyl]-1-[(2-methylphenyl)methyl]piperazin-2-yl]ethan-1-ol
i.e. ZINC19759036
-
3-(((4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)amino)methyl)-6,7-dimethoxyquinolin-2(1H)-one
-
-
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
-
-
3-O-sulfogalactosylceramide
-
endogenous glycolipid sulfatide, binds to and inhibits the activity of isoform Sphk2 and the closely related ceramide kinase Cerk, but not isoform Sphk1. The lipid binding domain is mapped to the N-terminus of Sphk2, residues 1-175, a region of sequence that is absent in Sphk1, but aligns with a pleckstrin homology domain in Cerk
4-[5-[(1S)-6-hydroperoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-6-hydroxy-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]benzoic acid
i.e. ZINC16995081
-
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
inhibits both isoforms SK1 and SK2
5-([(3S)-3-(2-hydroxyethyl)-4-[(6-methylpyridin-2-yl)methyl]piperazin-1-yl]methyl)-2-methoxyphenol
i.e. ZINC19792941
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5-[[2-(3-methylphenyl)hydrazinyl]methylidene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
i.e. ZINC00221579
-
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6-hydroxy-5-[2-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]pentyl]-2-methylpyrimidin-4(3H)-one
i.e. ZINC18996465
-
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
-
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulphate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
Melatonin
-
melatonin decreases enzymic activity in PC-3 cells during hypoxia. In addition, Melatonin inhibits the stability of hypoxia inducible factor 1alpha in a time- and concentration-dependent manner and suppresses AKT/glycogen synthase kinase-3beta signaling pathway
N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
selective inhibition of isoform SK1
N-cyclohexyl-N-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetamide
-
N-[(1R)-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1R)-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((R)-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S)-1-methyl-3-phenylpropyl]hexadecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3R)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(morpholin-4-ylmethyl)-3-phenylpropyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-1-morpholino-4-phenylbutan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
phosphatidylinositol 4,5-bisphosphate
-
0.01 mM, isoform SphK2, 60% of initial activity, isoform SphK1, 90% of initial activity
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
-
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
-
-
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
potent and selective isoform SphK2 inhibitor
-
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
-
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
potent and selective isoform SphK2 inhibitor
-
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5011416, isoform SphK2 shows 64% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5091592, isoform SphK2 shows 42% residual activity at 0.001 mM
-
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
potent and selective isoform SphK2 inhibitor
-
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
specific inhibitor for isoform SphK2
-
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
66% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
52% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
67% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
60% inhibition of isoform SphK2 at 0.0003 mM
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
a dual SphK1/2 inhibitor
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
-
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione, isoform SphK2-selective inhibitor
-
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione, potent and selective isoform SphK2 inhibitor
-
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
potent and selective isoform SphK2 inhibitor
-
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
-
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
-
(S)-FTY720 vinylphosphonate
uncompetitive with sphingosine and is a mixed inhibitor with respect to ATP
(S)-FTY720 vinylphosphonate
uncompetitive, binds to a putative allosteric site in the enzyme contingent on formation of the enzyme-sphingosine complex. (S)-FTY720 vinylphosphonate binding to and stabilization of the allosteric site might enhance the autoinhibitory effect on the enzymic activity
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
i.e. SKi, or SKI-II. Mixed inhibitor of sphingosine and ATP binding. N-terminal 86 amino-acid isoform variant SK1b shows reduced sensitivity to proteasomal degradation induced by 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole in comparison to isoform SK1a
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
a dual SphK1/2 inhibitor
2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole
0.001-0.008 mM, specific inhibition
B-5354c
-
SphK1 inhibitor, induces apoptosis in a caspase-dependent manner by tilting the ceramide/sphingosine 1-phosphate rheostat toward ceramide. Pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
DL-threo-dihydrosphingosine
-
treatment of Jurkat and U-937 cells induces apoptosis and produces dramatic increases in SphK1 expression, the latter being a result of apoptotic stress
docetaxel
-
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
FTY720
i.e. fingolimod, competitive with sphingosine and uncompetitive with ATP
N,N-dimethylsphingosine
-
decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
N,N-dimethylsphingosine
-
inhibition of both isoforms Sphk1 and Sphk2. Treatment of Jurkat and U-937 cells results ina large increase in expression of SphK1 concomitant with induction of apoptosis
PF-543
potent, selective, sphingosine-competitive isoform SphK1 inhibitor
SKI-II
-
isoform Sk1-specific inhibitor. Treatment markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
SKI-II
highly selective and non ATP-competitive, enzyme binding structure, overview
SKI-II
i.e. 4-[[4-(4-chlorophenyl)thiazol-2-yl]amino]phenol, isoform SphK1-selective inhibitor
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-(4-methylphenethyl)piperidin-4-amine, 1-(4-octylphenethyl)piperidin-4-amine, 1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, and 1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, while potential inhibitors 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, [(2S)-1-[2-(4-octylphenyl)ethyl]pyrrolidin-2-yl]methanol, and (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone are slightly activating
-
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-(4-methylphenethyl)piperidin-4-amine, 1-(4-octylphenethyl)piperidin-4-amine, 1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, and 1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, while potential inhibitors 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, [(2S)-1-[2-(4-octylphenyl)ethyl]pyrrolidin-2-yl]methanol, and (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone are slightly activating
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
additional information
-
inhibitors of isozyme SphK2 are cytotoxic, overview, inhibitory potency of the synthetic sphingosine analogues on isozymes SphK1 and SphK2, overview
-
additional information
-
isoform Sphk2 binds to phosphatidylinositol monophosphates but not to abundant cellular phospholipids
-
additional information
-
short-term androgen removal induces a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that is not observed in the hormone-insensitive PC-3 cells. The addition of dihydrotestosterone to androgen-deprived LNCaP cells re-establishes cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 can markedly impede the effects of dihydrotestosterone
-
additional information
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-(4-methylphenethyl)piperidin-4-amine, 1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium, and 1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium, while potential inhibitors (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone, 4-octyl-N-(pyridin-4-ylmethyl)benzamide, N-(4-hydroxyphenyl)-4-octylbenzamide, 4-(4-octyl-1H-1,2,3-triazol-1-yl)phenol, and 2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethanol are slightly activating
-
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-(4-methylphenethyl)piperidin-4-amine, 1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium, and 1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium, while potential inhibitors (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone, 4-octyl-N-(pyridin-4-ylmethyl)benzamide, N-(4-hydroxyphenyl)-4-octylbenzamide, 4-(4-octyl-1H-1,2,3-triazol-1-yl)phenol, and 2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethanol are slightly activating
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-(3-[6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 104% activity at 0.001 mM
-
(2S)-2-[3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 106% activity at 0.001 mM
-
(2S)-2-[3-[6-(2-methoxyethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 118% activity at 0.001 mM
-
(2S)-2-[3-[6-(2-oxo-2-phenylethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 103% activity at 0.001 mM
-
(2S)-2-[3-[6-(3-methoxypropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 109% activity at 0.001 mM
-
11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid
-
treatment markedly augments SK activity in HUVECs. At the concentration of 1 mM, 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid increases SK activity by 110% and the maximal effect on SK activation is observed at 20 min after 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid addition. Inhibition of SK by a specific inhibitor, SKI-II, markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-Epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
12-O-tetradecanoylphorbol-13-acetate
50 nM, maximum increase in activity after 24 h
camptothecin
0.003 mM camptothecin induces marked elevation of SPHK activity, reaching a maximal level with approximately 250% of the control untreated cells at 36 h
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulfate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
heregulin
-
heregulin stimulates SphK1 activity only in filamin A-expressing A7 melanoma cells but not in filamin A-deficient cells and induces its translocation and colocalization with filamin A at lamellipodia. SphK1 is required for heregulin-induced migration, lamellipodia formation, activation of PAK1, and subsequent filamin A phosphorylation. Sphingosine 1-phosphate directly stimulates PAK1 kinase. Heregulin also induces colocalization of S1P1, the promotility sphingosine 1-phosphate receptor, but not S1P2, with SphK1 and filamin A at membrane ruffles
-
N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide
-
i.e. K6PC-5, induces intracellular Ca2+ concentration oscillations in HaCaT cells. The K6PC-5-induced intracellular Ca2+ oscillations are dependent on thapsigargin-sensitive Ca2+ stores and Ca2+ entry, but independent of the classical phospholipase C-mediated pathway. K6PC-5 enhances the expression of involucrin and filaggrin, specific differentiation-associated marker proteins in HaCaT cells, whereas transfection of SphK1 siRNA blocks the increase of involucrin
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
thrombin
-
stimulation of the lung epithelial cell line A-549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine 1-phosphate, abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin. PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells is also dependent on SPHK1
-
phosphatidic acid
-
0.01 mM, isoform SphK2, 102% of initial activity, isoform SphK1, 265% of initial activity
additional information
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
-
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
not stimulated by phosphatidylcholine or phosphatidylethanolamine
-
additional information
not stimulated by phosphatidylcholine or phosphatidylethanolamine
-
additional information
SPHK2 is not activated by transforming growth factor beta1
-
additional information
SPHK2 is not activated by transforming growth factor beta1
-
additional information
-
SPHK2 is not activated by transforming growth factor beta1
-
additional information
-
selective activation mechanism of isozymes, overview, isozyme SPHK2 is activated by high ionic strength
-
additional information
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
-
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
-
under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0076
sphingosine
in 50 mM HEPES, pH 7.4, 10 mM KCl, 15 mM MgCl2, 0.1% Triton X-100, 20% glycerol, 2 mM orthovanadate, 2 mM dithiothreitol, 10 mM NaF, and 1 mM deoxypyridoxine
0.02
ATP
recombinant wild-type enzyme, pH and temperature not specified in the publication
0.0255
ATP
recombinant mutant D81N enzyme, pH and temperature not specified in the publication
0.0628
ATP
pH and temperature not specified in the publication, mutant E180Q
0.071
ATP
pH and temperature not specified in the publication, mutant G113A
0.073
ATP
pH and temperature not specified in the publication, mutant K27A
0.0774
ATP
pH and temperature not specified in the publication, mutant D176N
0.078
ATP
pH and temperature not specified in the publication, mutant K29A
0.0884
ATP
pH and temperature not specified in the publication, mutant D178N
0.09
ATP
pH and temperature not specified in the publication, mutant G26A
0.092
ATP
pH and temperature not specified in the publication, mutant K103R
0.0947
ATP
pH and temperature not specified in the publication, mutant E182Q
0.124
ATP
pH and temperature not specified in the publication, mutant S79A
3.8
ATP
pH and temperature not specified in the publication, mutant G82A
0.00247
D-erythro-sphingosine
pH and temperature not specified in the publication, deletion mutant DELTA364-384
0.0102
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant E182Q
0.014
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K103R
0.018
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G26A
0.019
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K29A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G113A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K27A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant S79A
0.022
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G82A
0.0257
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant E180Q
0.0366
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant D176N
0.108
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant D178N
1
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 10 microM 3-O-sulfogalactosylceramide
1.7
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 25 microM 3-O-sulfogalactosylceramide
3.6
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 4 microM 3-O-sulfogalactosylceramide
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
-
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
-
simple quantitative radio-assay
-
additional information
additional information
-
assay for measurement of intracellular levels of free sphingoid bases
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
-
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
additional information
additional information
kinetic values of wild-type and mutant enzymes, overview
-
additional information
additional information
kinetic values of wild-type and mutant enzymes, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0065
ATP
recombinant mutant D81N enzyme, pH and temperature not specified in the publication
0.0427
ATP
recombinant wild-type enzyme, pH and temperature not specified in the publication
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0015
(2S)-1-(3-dodecylbenzoyl)pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0042
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.003
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00009
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000089
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.00037
(2S)-2-[3-[4-(octyloxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.00102 - 0.0038
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
0.00098
(2S)-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.014
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
pH not specified in the publication, temperature not specified in the publication
0.00098
(2S,3S)-3-hydroxy-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0009
(2S,3S)-3-hydroxy-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
-
0.044
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.083
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.096
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.09
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
pH and temperature not specified in the publication
0.094
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
pH and temperature not specified in the publication
0.000197
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000089
(S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000186
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000192
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000201
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.096
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
pH and temperature not specified in the publication
0.098
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.042
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.085
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
pH and temperature not specified in the publication
0.075
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.091
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.095
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.1
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.08
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.1
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.09
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.056
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.095
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.099
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
pH and temperature not specified in the publication
0.006
1-carbamimidoyl-N-(3-dodecylphenyl)cyclopropane-1-carboxamide
isoform SphK2, pH and temperature not specified in the publication
-
0.09
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
pH and temperature not specified in the publication
0.0103
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0141
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0117
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0099
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.006
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.008
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.011
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.043
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0102
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0081
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0034
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0012
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0079
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH not specified in the publication, temperature not specified in the publication
0.0093
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.0042
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.00002
Amgen 82
isoform SphK2, pH and temperature not specified in the publication
-
0.092
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.07
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.065
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.09
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.008
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
isoform SphK2, at pH 8.0 and 25°C
-
0.0005
N-(1-carbamimidoylcyclopropyl)-3-dodecylbenzamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0109
N-(1-carbamimidoylcyclopropyl)-4-dodecylbenzamide
isoform SphK2, pH and temperature not specified in the publication
-
0.016
SLP-120701
IC50 above 100 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.0014
SLR080811
isoform SphK2, pH and temperature not specified in the publication
0.02
VPC94075
isoform SphK2, pH and temperature not specified in the publication
-
0.000125
(2S)-1-(3-dodecylbenzoyl)pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.000047
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.000075
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00012
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
isoform SphK1, at pH 8.0 and 25°C
-
0.0065
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK1, at pH 8.0 and 25°C
-
0.016
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
pH not specified in the publication, temperature not specified in the publication
0.093
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.1
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.088
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.078
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
pH and temperature not specified in the publication
0.07
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
pH and temperature not specified in the publication
0.092
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
pH and temperature not specified in the publication
0.088
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.096
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.094
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
pH and temperature not specified in the publication
0.012
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.1
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.09
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.095
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.077
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.094
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.098
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.091
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.075
1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)guanidine
pH and temperature not specified in the publication
0.088
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
pH and temperature not specified in the publication
0.0003
1-carbamimidoyl-N-(3-dodecylphenyl)cyclopropane-1-carboxamide
isoform SphK1, pH and temperature not specified in the publication
-
0.098
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
pH and temperature not specified in the publication
0.0001
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00004
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00098
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00007
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00044
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00032
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0025
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.055
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0004
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0002
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.003
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0016
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0031
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.069
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.096
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.098
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.084
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.06
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
isoform SphK1, at pH 8.0 and 25°C
-
0.0002
N-(1-carbamimidoylcyclopropyl)-3-dodecylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0046
N-(1-carbamimidoylcyclopropyl)-4-dodecylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.00028
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
pH not specified in the publication, temperature not specified in the publication
0.055
N-[(2S)-1-amino-1-iminopropan-2-yl]-3-octylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.055
VPC94075
isoform SphK1, pH and temperature not specified in the publication
-
0.00102
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0038
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
isoform SphK2, at pH 8.0 and 25°C
-
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
isoform SphK2, pH and temperature not specified in the publication
-
0.016
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH not specified in the publication, temperature not specified in the publication
0.017
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH 7.4, 30°C, competitive inhibition
0.048
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH 7.4, 30°C, uncompetitive inhibition
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00002
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
Homo sapiens
isoform SphK2, pH and temperature not specified in the publication
-
0.00028
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.0071
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.000234
(S)-2-((3-(4-((4-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000359
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000391
(S)-2-((3-(4-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000266
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.00064
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000452
(S)-2-((3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000687
(S)-2-((3-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000254
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000248
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000396
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000909
(S)-2-(3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000269
1-(3-(4-((4-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000717
1-(3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000261
1-(3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.0182
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0156
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0139
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0089
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
100
CB5468139
Homo sapiens
IC50 above 100 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.01
SLP7111228
Homo sapiens
IC50 above 0.01 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
0.00043
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
Homo sapiens
-
pH 7.5, 22°C
0.000062
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
Homo sapiens
-
pH 7.5, 22°C
0.0282
(E)-3-(3-(4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)-6-methoxyquinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0141
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0031
(E)-6-methoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0591
3-(((4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)amino)methyl)-6,7-dimethoxyquinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0107
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0439
4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenol
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0157
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0187
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0079
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.002
CB5468139
Homo sapiens
IC50 above 0.01 mM, isoform SphK1, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
Homo sapiens
IC50 below 0.0000017 mM, isoform SphK1, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
Homo sapiens
IC50 below 0.0000017 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
Homo sapiens
IC50 below 0.0000017 mM, isoform SphK2, at pH 8.0 and 25°C
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 8.5
-
pH 6: about 55% of maximum activity, pH 8.5: about 40% of maximum activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
671269, 672377, 673342, 674084, 674380, 674810, 760267, 760268, 760460, 760683, 761036, 761596, 761682
SwissProt
isozyme SPHK2; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
higher activity of isozyme SPHK1, low activity of isozyme SPHK2
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
higher activity of isozyme SPHK1, low activity of isozyme SPHK2
-
in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
additional information
-
SPHK2 is expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of rheumatiod patients. In the cultured synovial fibroblasts from these patients, SPHK2 is more highly expressed than that in the human macrophage cell line, THP-1 and human dermal fibroblasts. SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of the cultured synovial fibroblasts
-
sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells
-
in the cultured synovial fibroblasts from rheumatoid arthritis patients, SPHK2 is more highly expressed than in the human macrophage cell line, THP-1 and human dermal fibroblasts
-
epidermal growth factor regulates plasminogen activator inhibitor-1 by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells
-
N,N-dimethyl-D-erythro-sphingosine induces apoptotic cell death via modulation of mitochondrial membrane potential, c-Jun N-terminal protein kinase, p38 MAP kinase, extracellular signal-regulated kinase, and Akt kinase, but not through inhibition of sphingosine kinase or protein -kinase C in U937 cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
isozyme SK2 possess (and isozyme SK1 lacks) nuclear localization R88-R93 and export signal sequences L380-L389 that help to define subcellular localization and function
-
SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
isozyme SphK1 is mostly in the cytoplasm and migrates to the plasma membrane upon phosphorylation
-
deleting the N-terminal domain with residues 1-175 reduces Sphk2 membrane localisation in cells
-
SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
isozyme SphK1 is mostly in the cytoplasm and migrates to the plasma membrane upon phosphorylation
additional information
isozyme hSK1 lacks the nuclear localization R88-R93 and export signal sequences, in contrast to isozyme hSK2. Threonine 54 and asparagine 89 are required for the specific increase in affinity of hSK1 with vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol. Mutants T54A and N89A lose selective binding to POPC/POPS over POPC/POPG, whereas the S168A mutant maintain the selectivity shown by WT
-
additional information
isozyme hSK1 lacks the nuclear localization R88-R93 and export signal sequences, in contrast to isozyme hSK2. Threonine 54 and asparagine 89 are required for the specific increase in affinity of hSK1 with vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol. Mutants T54A and N89A lose selective binding to POPC/POPS over POPC/POPG, whereas the S168A mutant maintain the selectivity shown by WT
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
dysregulation of the sphingosine-1-phosphate pathway is linked to a number of immune system disorders
metabolism
the interconversion of sphingosine and sphingosine1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
physiological function
malfunction
metabolism
the interconversion of sphingosine and sphingosine 1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
physiological function
additional information
physiological function
isozymes sphingosine kinases 1 and 2 (SK1 and SK2) generate the bioactive lipid mediator sphingosine 1-phosphate and as such play a significant role in cell fate and in human health and disease, SK1 and SK2 have overlapping, yet in some cases opposing, effects, overview. D-erythro-Sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2. Isozyme SphK2 can localize in the nucleus to inhibit DNA synthesis and regulate HDAC1/2 activity
physiological function
sphingosine-1-phosphate is a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase and plays a crucial role in natural killer cell proliferation, migration, and cytotoxicity
malfunction
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme
malfunction
dysregulation of the sphingosine-1-phosphate pathway is linked to a number of immune system disorders
malfunction
loss of sphingosine kinase 1 potentiates induction of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted, also known as CCL5) in HeLa cells stimulated with TNF-alpha despite RANTES induction being highly dependent on the NF-kappaB pathway. Analysis of the mechanism by which SK1 regulates RANTES induction, overview. Loss of SK1 strongly upregulates RANTES independently of effects on NF-kappaB activation, while loss of SK2 does not affect NF-kappaB pathway activation
malfunction
sphingosine kinase-1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell infiltration
physiological function
-
adenovirus-mediated SPK1 gene transfer to rat mesothelial cells increases the cellular SPK1 activity, and leads to enhanced migration. Median adhesion scores are significantly lower in the transfected group than in controls in both rat caecum and rat uterine horn models
physiological function
-
cell lines sensitive to daunorubicin show increased ceramide content, while cell lines resistant to daunorubicin do not when treated with low doses of drug. Upon daunorubicin treatment, sphinganine 1-phosphate decreases more in the sensitive cell lines than in the resistant cell lines. A sphinganine kinase inhibitor recovers the daunorubicin sensitivity of daunorubicin resistant cells. The modulation of isoform Sk1 gene expression by overexpression or using siRNA affects the daunorubicin sensitivity of cell lines
physiological function
-
depletion of isoform Sk1 by siRNA or inhibitors leads to accelerated connective tissue growth factor CTGF induction, mediated by sphingosine 1-phosphate
physiological function
-
endothelial cells overepressing isoform Sk1 show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption
physiological function
-
filamin A links SphK1 and S1P1 receptor to locally influence the dynamics of actin cytoskeletal structures by orchestrating the concerted actions of of SphK1, FLNa, and PAK1, each of which requires and/or regulates the actions of the others, at lamellipodia to promote cell movement
physiological function
-
HUVEC cells with 3- to 5fold overexpression of isoform SK1 show an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells show constitutive activation, and a more augmented vascular cell adhesion molecule VCAM-1 and E selectin response to TNF compared with empty vector control cells
physiological function
-
isoform Sk1 activity is causally associated with endocrine resistance in MCF-7 cells. Enforced overexpression of Sk1 results in enhanced cell proliferation and resistance to tamoxifen-induced cell growth arrest and apoptosis. Tamoxifen-resistant cells exhibit higher levels of Sk1 expression and activity. Inhibition of Sk1 by pharmaceutical inhibitors or the dominant-negative mutant G82D restores the antiproliferative and proapoptotic effect of tamoxifen. Silencing of isoform Sk1, but not Sk2, expression by siRNA also restores the tamoxifen responsiveness in the resistant cells
physiological function
-
isoform Sk1 interacts with four-and-a-half LIM only protein FHL-2. Overexpression of FHL-2 in endothelial cells inhibits VEGF-induced Sk1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. Overexpression of FHL-2 has no effect on sphinganine 1-phosphate induced Akt phosphorylation. VEGF stimulation decreases the binding of FHL-2 and Sk1. Depletion of FHL-2 by siRNA increases endothelial cell migration accompanied with Sk1 and Akt activation
physiological function
-
knockdown of SK1 expression by specific siRNA inhibits 11,12-epoxyeicosatrienoic acid-induced endothelial cell proliferation and migration, whereas SK2 siRNA knockdown is without effect
physiological function
-
overexpression of isoform Sk1 in ML-1 cells results in increased expression of sphingosine 1-phosphate, which can be attenuated by inhibiting Sk1 activity and an ATP-binding cassette transporter. Overexpression of Sk1 enhances serum-induced migration of ML-1 cells. Inhibition of protein kinase Calpha attenuates migration in Sk1 overexpressing cells. Overexpressing cells show an impaired adhesion, slower cell growth, and up-regulation of ERK1/2 phosphorylation
physiological function
-
overexpression of SK1 results in inhibition of permeability similar to that seen for Ang-1, which rapidly and transiently stimulates SK1 activity and phosphorylation, and induces an increase in intracellular sphingosine 1-phosphate concentration. Knockdown of SK1 by siRNA blocks Ang-1-mediated inhibition of permeability. Transfection with S225A, a nonphosphorylatable mutant of SK1, inhibits basal leakiness, and both S225A and a dominant-negative SK1 mutant remove the capacity of Ang-1 to inhibit endotheial cell permeability. These effects are independent of extracellular sphingosine 1-phosphate
physiological function
-
short-term androgen removal induces a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that is not observed in the hormone-insensitive PC-3 cells. The addition of dihydrotestosterone to androgen-deprived LNCaP cells re-establishes cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 can markedly impede the effects of dihydrotestosterone. Long-term removal of androgen support in LNCaP and C4-2B cells results in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which is characterized by the acquisition of a neuroendocrine-like cell phenotype. Inhibition of the PI3K/Akt pathway by negatively impacting SphK1 activity can prevent neuroendocrine differentiation in both cell models, an event that can be mimicked by SphK1 inhibitors
physiological function
-
SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1alpha levels is mediated by the Akt/glycogen synthase kinase-3beta signaling pathway that prevents its von Hippel-Lindau proteinmediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1A and its transcriptional activity in several human cancer cell lineages from prostate, brain, breast, kidney, and lung, suggesting a canonical pathway
physiological function
-
SphK1 enforced expression in PC-3 and LNCaP cells shifts the lipid biostat toward prosurvival sphingosine 1-phosphate and protects against B-5354cinduced apoptosis
physiological function
-
SphK1 siRNA reduces both the SphK1 mRNA and the protein levels by 70% and has no effect on SphK2 expression. The SphK2 siRNA is equally specific but somewhat less efficient at reducing SphK2 expression. Decreasing SphK1expression significantly decreases both TGFbeta-induced chemotactic migration and invasion, whereas decreasing SphK2 expression inhibits chemotactic migration less effectively and has no effect on chemotactic invasion. Decreased expression of SphKs also inhibits TGFbeta activation of ERK1/2. TGFbeta activation of sphingosine kinases and formation of sphinmgosine 1-phosphate contribute to non-Smad signaling
physiological function
-
stimulation of the lung epithelial cell line A-549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine 1-phosphate, abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin. PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells is also dependent on SPHK1
physiological function
-
the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors is comparable. Tumor-associated macrophages from SphK2-deficient tumors display a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206
physiological function
-
under basal conditions, SK1, integrin alphaVbeta3 and CD31 exist as a heterotrimeric complex. Under conditions that affect endothelial cell survival such as loss of contact with the extracellular matrix or growth factor activation, more of this heterotrimeric complex forms. Increased heterotrimeric complex formation requires SK1 phosphorylation at serine 225 for, activation of integrin alphaVbeta3, and endothelial cell survival signals, including Bcl-X and nuclear factor-B pathways. beta3-Integrin depletion confirms the requirement for this heterotrimeric complex in SK1-mediated endothelial cell survival
physiological function
-
under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium. Knockdown of Sk2 by siRNA releives chemoresistance of A-450 cells under hypoxia and conditioned medium obtained from Sk2 knock-down cells is only partly protective, while conditioned medium of cells with normal levels of Sk2, incubated for 24 h under hypoxia, protects naive A-549 cells from etoposide-induced cell death
physiological function
-
application of siRNA-SPHK1 and sphingosine kinase inhibitor effectively blocks the expression of hypoxia inducible factor 1alpha, phospho-AKT and vascular endothelial growth factor production in PC-3 cells under hypoxia
physiological function
expression of isoform SK1 artificially targeted to the endoplasmic reticulum or without targeting signal, but surprisingly not plasma membrane-targeted SK1, results in a dramatic increase in the phosphorylation of dihydrosphingosine. Knockdown of endogenous SK1 diminishes both dihydrosphingosine-1-phosphate and sphinganine 1-phosphate levels. Sphinganine 1-phosphate produced at the plasma membrane is degraded to the same extent as that produced in the endoplasmic reticulum indicating that there is an efficient mechanism for the transport of sphinganine 1-phosphate. Sphinganine 1-phosphate degradation is primarily driven by lyase cleavage of sphinganine 1-phosphate
physiological function
-
mice with kidney-specific overexpression of enhanced green fluorescent protein fused to isoform SK1 have significantly improved renal function with lower plasma creatinine, renal necrosis, apoptosis, and inflammation. Overexpression of the fusion protein cultured human proximal tubule cells protects against peroxide-induced necrosis. Selective overexpression of the construct leads to increased HSP27 mRNA and protein expression in vivo and in vitro. Functional protection as well as induction of HSP27 with the construct overexpression in vivo is blocked with sphingosine-1-phosphate-1 receptor-1 antagonism
physiological function
isozymes sphingosine kinases 1 and 2 (SK1 and SK2) generate the bioactive lipid mediator sphingosine 1-phosphate and as such play a significant role in cell fate and in human health and disease, SK1 and SK2 have overlapping, yet in some cases opposing, effects, overview. D-erythro-Sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
lipid kinase sphingosine kinase 1 catalyzes the conversion of sphingosine to sphingosine-1-phosphate, which plays a role in lymphocyte trafficking, angiogenesis, and response to apoptotic stimuli. As a central enzyme in modulating the sphingosine-1-phosphate levels in cells, the enzyme is an important regulator for diverse cellular functions
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2
physiological function
sphingosine kinase 1 produces the pro-survival sphingolipid sphingosine 1-phosphate and is implicated in inflammation, proliferation, and angiogenesis. The enzyme is required for activation of p38 MAPK, but is not required for transcriptional NF-kappaB activity following TNF treatment. But nuclear translocation of NF-kappaB subunits does not require enzyme SK1
physiological function
sphingosine-1-phosphate is a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase and plays a crucial role in natural killer cell proliferation, migration, and cytotoxicity
physiological function
sphingosine kinase-1 is a key regulator of anti-tumor immunity. Increased expression of the enzyme in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-programmed cell death protein-1
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
-
modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SPHK2_HUMAN
654
0
69217
Swiss-Prot
other Location (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
43000
additional information
lesser amounts of immunoreactive protein migrate in the 45-48 kDa range
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
relationship to diacylglyceride kinases, NAD+ kinases and 6-phosphofructokinases
additional information
-
structure analysis of the 2 isozymes, schematic map, the enzyme contains 5 sequences stretches C1-C5 typical for lipid kinases, but the enzyme does not contain distinct domains for catalysis or substrate binding, overview
additional information
-
isoform Sk1 interacts with four-and-a-half LIM only protein FHL-2. Overexpression of FHL-2 in endothelial cells inhibits VEGF-induced Sk1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. Overexpression of FHL-2 has no effect on sphinganine 1-phosphate induced Akt phosphorylation. VEGF stimulation decreases the binding of FHL-2 and Sk1. Depletion of FHL-2 by siRNA increases endothelial cell migration accompanied with Sk1 and Akt activation
additional information
-
isoform SK1 interacts with subunit 7 of cytosolic chaperonin CCT, i.e. chaperonin containing t-complex polypeptide, also called TRiC for TCP-1 ring complex, a hexadecameric chaperonin that binds unfolded polypeptides. Other CCT/TRiC subunits also associate with SK1 in HEK293T cell lysates in an ATP-sensitive manner. CCT/TRiC binds specifically to newly translated SK1. Depletion of functional CCT/TRiC through the use of RNA interference in HeLa cells or temperature sensitive CCT mutants reduces cellular SK1 activity
additional information
oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
additional information
the SphK1 structure reveals a two-domain architecture in which its catalytic site is located in the cleft between the two domains and a hydrophobic lipid-binding pocket is buried in the C-terminal domain, structure comparisons with Staphylococcus aureus DgkB, PDB ID 2QVL, and Archaeoglobus fulgidus NAD kinase, PDB ID 1ZOZ
additional information
-
the SphK1 structure reveals a two-domain architecture in which its catalytic site is located in the cleft between the two domains and a hydrophobic lipid-binding pocket is buried in the C-terminal domain, structure comparisons with Staphylococcus aureus DgkB, PDB ID 2QVL, and Archaeoglobus fulgidus NAD kinase, PDB ID 1ZOZ
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
isozyme SPHK1 is phosphorylated at Ser225 by extracellular signal-regulated kinases 1 and 2, i.e. ERK1 and 2, and by cyclin dependent kinase 2, i.e. CDK2, recombinant isozyme SPHK1 in HEK293 cells is phosphorylated by ERK1 after stimulation with TNF-alpha, mechanism, overview, phosphorylation activates the enzyme by up to 14fold
phosphoprotein
isozyme SphK1 migrates to the plasma membrane upon phosphorylation
phosphoprotein
phosphorylation of S225 results in a 14fold increase in SK1 activity arising from a 13.6fold increase in kcat
phosphoprotein
the enzyme is phosphorylated and activated mainly by proline-rich receptor-like protein kinase 2
phosphoprotein
the translocation and activity of isoform SphK1 are regulated by its phosphorylation of Ser225
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
homology modeling based of Staphylococcus aureus diacylglycerol kinase, PDB entry 2QV7, and docking of substrate sphinganine 1-phosphatre to the model con taining bound ADP
homology modeling based of Staphylococcus aureus diacylglycerol kinase, PDB entry 2QV7, and docking of substrate sphinganine 1-phosphatre to the model con taining bound ADP
purified recombinant truncated enzyme comprising residues 9-364, in apo-form and in complex with inhibitor SKI-II, and with inhibitor SKI-II and ADP, sitting drop vapour diffusion method, mixing of 0.001 ml of 10 mg/ml protein in 50 mM Tris-HCl, pH 8.5, 300 mM NaCl, 0.5 M GdnHCl, 10% glycerol, 0.1% Tween 20, and 10 mM DTT, and for complex crystals with a 3fold excess of inhibitor, and ATP/ADP, with 0.001 ml of well solution containing 1.0-1.4 M ammonium sulfate, 0.3-1.3 M NaCl, and 0.1 M Bis-Tris, pH 6.0, 16°C, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution, molecular replacement
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G212E
site-directed mutagenesis, the mutant is catalytically inactive
G212E/L218A
site-directed mutagenesis, the mutant is catalytically inactive
L218A
site-directed mutagenesis, the mutant shows about 38% of wild-type activity
S351A
site-directed mutagenesis, the mutant shows about 115% of wild-type activity
S401A
site-directed mutagenesis, the mutant shows about 109% of wild-type activity
S430A
site-directed mutagenesis, the mutant shows about 124% of wild-type activity
S441A
site-directed mutagenesis, the mutant shows about 35% of wild-type activity
T578A
site-directed mutagenesis, the mutant shows about 56% of wild-type activity
V327A/L328Q
site-directed mutagenesis, the mutant shows about 75% of wild-type activity
D176N
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
D176N/D178N
site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type
D176N/E180Q
site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type
D81A
site-directed mutagenesis, the mutant shows essentially no activity for phosphoryl transfer and ADP formation
D81N
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
D89A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane
E180Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
E182Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
F197A
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
F197A/L198Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
F303H
G111A
site-directed mutagenesis, the mutant is catalytically inactive
G111D
site-directed mutagenesis, the mutant is catalytically inactive
G113A
G113D
site-directed mutagenesis, the mutant is catalytically inactive
G26A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
G26D
site-directed mutagenesis, the mutant is catalytically inactive
G80A
site-directed mutagenesis, the mutant is catalytically inactive
G80D
site-directed mutagenesis, the mutant is catalytically inactive
G82A
site-directed mutagenesis, the mutant shows a 44.7fold increase in Km compared to the wild-type
G82D
H122A
the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 60%
K103A
site-directed mutagenesis, the mutant is catalytically inactive
K103R
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
K27A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
K29A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
L134Q
L147Q
L153Q
L187Q
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
L194Q
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
L198Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
L200Q
N121E
the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 20%
N89A
site-directed mutagenesis, the mutant loses 50% activity compared to the wild-type, and loses selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol
R185A/R186A
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
R56A/R57A/H59A/R61A
the mutations of isoform SphK1 reduce the phorbol 12-myristate 13-acetate- and ceramide 1-phosphate-induced translocation of isoform SphK1 to the plasma membrane, however, the capacity of ceramide 1-phosphate to bind with and activate isoform SphK1 is not affected by the mutations
S168A
site-directed mutagenesis, the mutant maintains the selectivity of selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol, as shown by the wild-type
S225A
S225D
site-directed mutagenesis, mutation of S225 to aspartic and glutamic acids, mimicing serine phosphorylation, does not alter SK1 activity but maintains preferred binding of SK1 to plasma membrane over nuclear membrane
S225E
site-directed mutagenesis, mutation of S225 to aspartic and glutamic acids, mimicing serine phosphorylation, does not alter SK1 activity but maintains preferred binding of SK1 to plasma membrane over nuclear membrane
S79A
site-directed mutagenesis, the mutant shows a 1.5fold increase in Km compared to the wild-type
S79D
site-directed mutagenesis, the mutant is catalytically inactive
T54A
T74A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane
V290N
additional information
F303H
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
F303H
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
G113A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
G82D
-
dominant-negative SK1 mutant, removes the capacity of Ang-1 to inhibit endothelial cell permeability
G82D
-
dominant-negative SK1mutant, displays substantially attenuated 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation, migration, and tube formation in vitro and Matrigel plug angiogenesis in vivo
G82D
-
over-expression inhibits the TNF-induced vascular cell adhesion molecule VCAM-1 and E selectin and inhibits PMN adhesion
G82D
site-directed mutagenesis, the mutant is catalytically inactive
L134Q
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
L147Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
L147Q
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
L153Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
L153Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
L200Q
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
L200Q
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
S225A
the mutation prevents ERK1/2-mediated phosphorylation and membrane localization of SK1
S225A
-
transfection with S225A, a nonphosphorylatable mutant of SK1, inhibits basal leakiness, and both S225A and a dominant-negative SK1 mutant remove the capacity of Ang-1 to inhibit endothelial cell permeability
S225A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane, the mutant shows 39% reduced activity compared to the wild-type
T54A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
T54A
site-directed mutagenesis, the mutant loses selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol
T54A
site-directed mutagenesis, the mutant shows 55% reduced activity compared to the wild-type
V290N
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
additional information
construction of catalytically inactive deletion mutants DELTA1226 and DELTA226-619
additional information
construction of catalytically inactive deletion mutants DELTA1226 and DELTA226-619
additional information
deletion mutants in highly conserved regions, truncation mutants
additional information
-
deletion mutants in highly conserved regions, truncation mutants
additional information
-
isoform SphK2 contains a lipid binding domain at the N-terminal residues 1-175, a region of sequence that is absent in Sphk1. Deleting the N-terminal domain reduces Sphk2 membrane localisation in cells
additional information
-
deletion of 21 amino acids from the COOH-terminus of isoform SphK1, expression of residues 1-363, results in about 2.2fold increase in catalytic activity relative to wild-type SphK1, which is independent of the phosphorylation state of Serine 225 and stimulation by phorbol-12,13-myristic acid. HEK-293 cells stably expressing the truncated protein exhibit enhanced cell growth under serum-deprived cell culture conditions. A further truncated mutant, residues 1-315, displays about 20% of wild-type activity
additional information
construction of an N- and C-terminally truncated enzyme form comprising residues 9-364 of full-length 368 residues, the mutant is catalytically active
additional information
-
construction of an N- and C-terminally truncated enzyme form comprising residues 9-364 of full-length 368 residues, the mutant is catalytically active
additional information
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme. Deletion of 21 residues from the C-terminus (hSK1DELTA364-384) results in a protein that is constitutively and 2.2times more active than the wild-type. No significant change enzyme affinity for ATP but a slightly higher Vmax of 1.3fold are observed. Construction of mutations in domain 4 focusing primarily on SPH and calcium-calmodulin/CIB1 interactions
additional information
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme. Deletion of 21 residues from the C-terminus (hSK1DELTA364-384) results in a protein that is constitutively and 2.2times more active than the wild-type. No significant change enzyme affinity for ATP but a slightly higher Vmax of 1.3fold are observed. Construction of mutations in domain 4 focusing primarily on SPH and calcium-calmodulin/CIB1 interactions
additional information
enzyme knockdown in HeLa cells using siRNA cell treatment. Enzyme knockdown significantly enhances RANTES induction in response to TNF with no statistically significant effect on unstimulated levels. RANTES induction is highly NF-kappaB-dependent as shown using NF-kappaB inhibitor BAY 11-7082
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His6-tagged wild-type and mutant enzymes from High Five cells by nickel affinity chromatography, the tag is cleaved by TEV protease, followed by anion and cation exchange chromatographies, and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene sphK2, sequence comparison of human isozymes sphingosine kinases 1 and 2
isozymes SPHK1 and SPHK2, several splicing variants are differently active, expression in HEK293 cells as EGFP-fusion proteins
expression in HEK-293 cell
expression of FLAG-tagged isozyme in HEK293 cells, expression of His-tagged isozyme in Sf9 insect cells via baculovirus infection system
gene sphK1, sequence comparison of human isozymes sphingosine kinases 1 and 2
isoform SphK1 is expressed in Saccharomyces cerevisiae strain CGY32
isozymes SPHK1 and SPHK2, DNA and amino acid sequence determination and analysis
-
isozymes SPHK1 and SPHK2, several splicing variants are differently active, expression in HEK293 cells as EGFP-fusion proteins
recombinant expression of N-terminally His6-tagged wild-type and mutant enzymes in High Five cells using the baculovirus transfection method
transient expression in murine C2C12 myoblasts in the cytosolic fraction, in Golgi-enriched and endosome/plasma membrane fraction of transfected cells, the over-expressed SphK1 is localized at plasma membrane, as well as at internal membranes, SphK1 partially colocalized with caveolin-1, known to be an integral plasma membrane protein, secretion of extracellularly produced sphingosine 1-phosphate
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
knockdown of isoform SK2 expression results in overexpression of isoform SK1 in several cell lines. Treatment with inhibitor (2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression. Treatment with inhibitor 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole increases mRNAs for both isoforms SK1 and SK2 by about 4fold
hypoxia increases SK1 mRNA levels, protein expression, and enzyme activity, followed by intracellular sphingosine 1-phosphate production and sphingosine 1-phosphate release. Knockdown of hypoxia-inducible factor HIF-2 by small interfering RNA abolishes the induction of SK1 and the production of extracellular shpingosine 1-phosphate after CoCl2 treatment, whereas HIF-1 small interfering RNA results in an increase of HIF-2 and of SK1 protein levels. HIF-2 binds the SK1 promoter
-
in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed. Inhibitor N,N-dimethylsphingosine decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
-
knockdown of isoform SK2 expression results in overexpression of isoform SK1 in several cell lines. Treatment with inhibitor (2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression. Treatment with inhibitor 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole increases mRNAs for both isoforms SK1 and SK2 by about 4fold
long-term removal of androgen support in LNCaP and C4-2B cells results in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which is characterized by the acquisition of a neuroendocrine-like cell phenotype
-
sphingosine kinase-1 transcript levels are higher in human primary melanomas as compared to nevi
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
-
the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells. IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines, it does not affect SphK2 expression. The IL-1-induced SphK1 up-regulation can be blocked by the inhibition of c-Jun N-terminal kinase, the overexpression of the dominant-negative c-Jun(TAM67), and the down-regulation of c-Jun expression by small interference RNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated via a novel AP-1 element located within the first intron of the sphk1 gene
-
transforming growth factor TGF-beta2 activates the promoter of isoform Sk1, resulting in upregulation of its mRNa and protein expression
-
treatment with inhibitors N,N-dimethylsphingosine or DL-threo-dihydrosphingosine or with doxorubicin leads to increase in expression as a result of apoptotic stress. The caspase inhibitor ZVAD reduces not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of sphingosine 1-phosphate
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
involved in signal transduction by TRAF2, tumor necrosis factor-alpha receptor-associated factor 2
medicine
-
isozyme SPHK1 is a potential therapeutic target in the treatment of inflammatory and autoimmune diseases
medicine
-
89% of human colon cancer samples tested stain positively for SphK1, whereas normal colon mucosa has negative or weak staining. Adenomas have higher expression of SphK1 versus normal mucosa, and colon cancers with metastasis have higher expression of SphK1 than those without metastasis
medicine
-
adenovirus-mediated SPK1 gene transfer promotes recovery of the surgically damaged mesothelial cell layer and prevents postoperative peritoneal adhesion formation
medicine
-
isoform Sk1 expression is increased in the podocytes of kidney sections of patients with diabetic nephropathy
medicine
isoform SphK1 protein and mRNA levels are higher in clinical tissue samples of patients with non-Hodgkin lymphomas than in reactive lymphoid hyperplasias, with a clear trend towards increasng levels with increasing clinicla grade
medicine
-
levels of SPHK1mRNA and protein are higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level is up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 65.7% of patients reveals high level of SPHK1protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 are found in patients at different clinical stages. Patients with higher SPHK1expression have shorter overall survival time, whereas those with lower SPHK1 expression survive longer
medicine
-
patients with breast cancer that express higher CerS2 or 4 mRNA levels tend to show no changes in sphingosine kinase 1 levels, and likewise patients that express no change in CerS2 or CerS4 mRNA levels tend to express higher levels of sphingosine kinase 1. Results suggest an important role for the CerS genes in breast cancer etiology or diagnosis
medicine
-
pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
medicine
-
sphingosine analogue FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of cultured synovial fibroblasts
medicine
-
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
medicine
-
SPHK1in astrocytoma cell lines is elevated at both mRNA and protein levels, and the SPHK1 mRNA and protein are significantly up-regulated by up to 6.8- and 40fold, respectively, in primary astrocytomas compared with those in the adjacent noncancerous brain tissues. 41.2% of paraffin-embedded archival astrocytoma biopsies exhibit high expression of SPHK1. The up-regulation of SPHK1 is significantly correlated with the histologic grade of astrocytoma and patients with high SPHK1 level exhibit shorter survival time
medicine
-
synthesis of shingosine kinase substrates as sphingosine 1-phosphate receptor prodrugs, with varying activities at the five sphingosine 1-phosphate receptors
medicine
-
the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors is comparable. Tumor-associated macrophages from SphK2-deficient tumors display a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206
medicine
-
the synovial fluid levels of sphingosine 1-phosphate are significantly higher in patients with rheumatoid arthritis than in those with osteoarthritis. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in rheumatoid arthritis
medicine
the expression level and properties of N-terminal 86 amino-acid isoform variant of sphingosine kinase 1, SK1b, in prostate cancer cells reduce its sensitivity to proteasomal degradation induced by 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole in comparison to isoform SK1a. The reduced sensitivity of SK1b to proteasomal degradation in response to 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole results in specific changes in ceramide and S1P levels that lead to apoptosis of androgen-sensitive but not androgen-independent LNCaP prostate cancer cells
medicine
sphingosine kinase-1 expression inversely correlates with survival after immune checkpoint inhibitor (ICI) therapy in melanoma tumors. Downregulation of sphingosine kinase-1 improves the efficacy of ICI therapy in various cancer models
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Stoffel, W.; Heimann, G.; Hellenbroich, B.
Sphingosine kinase in blood platelets
Hoppe-Seyler's Z. Physiol. Chem.
354
562-566
1973
Homo sapiens, Sus scrofa
Stoffel, W.; Hellenbroich, B.; Heimann, G.
Properties and specificities of sphingosine kinase from blood platelets
Hoppe-Seyler's Z. Physiol. Chem.
354
1311-1316
1973
Homo sapiens, Sus scrofa
Pitson, S.M.; D'Andrea R.J.; Vandeleur, L.; Moretti, P.A.; Xia, P.; Gamble, J.R.; Vadas, M.A.; Wattenberg, B.W.
Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes
Biochem. J.
350
429-441
2000
Homo sapiens (Q9NYA1), Homo sapiens
Xia, P.; Wang, L.; Moretti, P.A.B.; Albanese, N.; Chai, F.; Pitson, S.M.; D'Andrea, R.J.; Gamble, J.R.; Vadas, M.A.
Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-a signaling
J. Biol. Chem.
277
7996-8003
2002
Homo sapiens (Q9NYA1)
Pitson, S.M.; Moretti, P.A.B.; Zebol, J.R.; Zareie, R.; Derian, C.K.; Darrow, A.L.; Qi, J.; D'Andrea, R.J.; Bagley, C.J.; Vadas, M.A.; Wattenberg, B.W.
The nucleotide-binding site of human sphingosine kinase 1
J. Biol. Chem.
277
49545-49553
2002
Homo sapiens (Q9NYA1), Homo sapiens
Liu, H.; Sugiura, M.; Nava, V.E.; Edsall, L.C.; Kono, K.; Poulton, S.; Milstien, S.; Kohama, T.; Spiegel, S.
Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform
J. Biol. Chem.
275
19513-19520
2000
Mus musculus (Q9JIA7), Mus musculus, Homo sapiens (Q9NRA0), Homo sapiens
Kleuser, B.; Maceyka, M.; Milstien, S.; Spiegel, S.
Stimulation of nuclear sphingosine kinase activity by platelet-derived growth factor
FEBS Lett.
503
85-90
2001
Homo sapiens
Murate, T.; Banno, Y.; Koizumi, K.T.; Watanabe, K.; Mori, N.; Wada, A.; Igarashi, Y.; Takagi, A.; Kojima, T.; Asano, H.; Akao, Y.; Yoshida, S.; Saito, H.; Nozawa, Y.
Cell type-specific localization of sphingosine kinase 1a in human tissues
J. Histochem. Cytochem.
49
845-855
2001
Homo sapiens
Melendez, A.J.; Carlos-Dias, E.; Gosink, M.; Allen, J.M.; Takacs, L.
Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution
Gene
251
19-26
2000
Homo sapiens
Olivera, A.; Rosenthal, J.; Spiegel, S.
Sphingosine kinase from Swiss 3T3 fibroblasts: a convenient assay for the measurement of intracellular levels of free sphingoid bases
Anal. Biochem.
223
306-312
1994
Homo sapiens
Kono, K.; Sugiura, M.; Kohama, T.
Inhibition of recombinant sphingosine kinases by novel inhibitors of microbial origin, F-12509A and B-5354c
J. Antibiot.
55
99-103
2002
Homo sapiens
Nava, V.E.; Lacana, E.; Poulton, S.; Liu, H.; Sugiura, M.; Kono, K.; Milstien, S.; Kohama, T.; Spiegel, S.
Functional characterization of human sphingosine kinase-1
FEBS Lett.
473
81-84
2000
Homo sapiens
Labesse, G.; Douguet, D.; Assairi, L.; Gilles, A.M.
Diacylglyceride kinases, sphingosine kinases and NAD kinases: distant relatives of 6-phosphofructokinases
Trends Biochem. Sci.
27
273-275
2002
Homo sapiens
Pitson, S.M.; Moretti, P.A.B.; Zebol, J.R.; Vadas, M.A.; D'Andrea, R.J.; Wattenberg, B.W.
A point mutant of human sphingosine kinase 1 with increased catalytic activity
FEBS Lett.
509
169-173
2001
Homo sapiens
Roberts, J.L.; Moretti, P.A.B.; Darrow, A.L.; Derian, C.K.; Vadas, M.A.; Pitson, S.M.
An assay for sphingosine kinase activity using biotinylated sphingosine and streptavidin-coated membranes
Anal. Biochem.
331
122-129
2004
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Meacci, E.; Cencetti, F.; Donati, C.; Nuti, F.; Becciolini, L.; Bruni, P.
Sphingosine kinase activity is required for sphingosine-mediated phospholipase D activation in C2C12 myoblasts
Biochem. J.
381
655-663
2004
Homo sapiens
Kim, J.W.; Kim, Y.W.; Inagaki, Y.; Hwang, Y.A.; Mitsutake, S.; Ryu, Y.W.; Lee, W.K.; Ha, H.J.; Park, C.S.; Igarashi, Y.
Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases
Bioorg. Med. Chem.
13
3475-3485
2005
Homo sapiens
Kee, T.H.; Vit, P.; Melendez, A.J.
Sphingosine kinase signalling in immune cells
Clin. Exp. Pharmacol. Physiol.
32
153-161
2005
Arabidopsis thaliana, Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Tetrahymena pyriformis
Baumruker, T.; Bornancin, F.; Billich, A.
The role of sphingosine and ceramide kinases in inflammatory responses
Immunol. Lett.
96
175-185
2005
Homo sapiens, Mus musculus
Billich, A.; Bornancin, F.; Devay, P.; Mechtcheriakova, D.; Urtz, N.; Baumruker, T.
Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases
J. Biol. Chem.
278
47408-47415
2003
Mus musculus (O88885), Mus musculus (Q9JIA7), Mus musculus, Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Kono, Y.; Nishiuma, T.; Nishimura, Y.; Kotani, Y.; Okada, T.; Nakamura, S.; Yokoyama, M.
Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1
Am. J. Respir. Cell Mol. Biol.
37
395-404
2007
Mus musculus (Q8CI15), Mus musculus, Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Cuvillier, O.
Sphingosine kinase-1 - a potential therapeutic target in cancer
Anticancer Drugs
18
105-110
2007
Homo sapiens (Q9NYA1)
Akao, Y.; Banno, Y.; Nakagawa, Y.; Hasegawa, N.; Kim, T.J.; Murate, T.; Igarashi, Y.; Nozawa, Y.
High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation
Biochem. Biophys. Res. Commun.
342
1284-1290
2006
Homo sapiens (Q9NYA1), Homo sapiens
Huwiler, A.; Doell, F.; Ren, S.; Klawitter, S.; Greening, A.; Roemer, I.; Bubnova, S.; Reinsberg, L.; Pfeilschifter, J.
Histamine increases sphingosine kinase-1 expression and activity in the human arterial endothelial cell line EA.hy 926 by a PKC-alpha-dependent mechanism
Biochim. Biophys. Acta
1761
367-376
2006
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Francy, J.M.; Nag, A.; Conroy, E.J.; Hengst, J.A.; Yun, J.K.
Sphingosine kinase 1 expression is regulated by signalling through PI3K, AKT2, and mTOR in human coronary artery smooth muscle cells
Biochim. Biophys. Acta
1769
253-265
2007
Homo sapiens (Q9NYA1), Homo sapiens
Ma, M.M.; Chen, J.L.; Wang, G.G.; Wang, H.; Lu, Y.; Li, J.F.; Yi, J.; Yuan,Y.J.; Zhang, Q.W.; Mi, J.; Wang, L.Sh.; Duan, H.F.; Wu, C.T.
: Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice
Diabetologia
50
891-900
2007
Homo sapiens (Q9NYA1), Homo sapiens
Doell, F.; Pfeilschifter, J.; Huwiler, A.
Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration
Endocr. Relat. Cancer
14
325-335
2007
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Taha, T.A.; El-Alwani, M.; Hannun, Y.A.; Obeid, L.M.
Sphingosine kinase-1 is cleaved by cathepsin B in vitro: Identification of the initial cleavage sites for the protease
FEBS Lett.
580
6047-6054
2006
Mus musculus (Q8CI15), Rattus norvegicus (Q91V26), Homo sapiens (Q9NYA1)
Leclerq, T.M.; Pitson, S.M
Cellular signalling by sphingosine kinase and sphingosine 1-phosphate
IUBMB Life
58
467-472
2006
Mus musculus (Q8CI15), Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Taha, T.A.; Hannun, Y.A.; Obeid, L.M.
Sphingosine kinase: biochemical and cellular regulation and role in disease
J. Biochem. Mol. Biol.
39
113-131
2006
Rattus norvegicus (Q91V26), Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Don, A.S.; Martinez-Lamenca, C.; Webb, W.R.; Proia, R.L.; Roberts, E.; Rosen, H.
Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues
J. Biol. Chem.
282
15833-15842
2007
Homo sapiens (Q9NRA0)
Kusner, D.J.; Thompson, C.R.; Melrose, N.A.; Pitson, S.M.; Obeid, L.M.; Iyer, S.S.
The localization and activity of sphingosine kinase 1 are coordinately regulated with actin cytoskeletal dynamics in macrophages
J. Biol. Chem.
282
23147-23162
2007
Mus musculus (Q8CI15), Homo sapiens (Q9NYA1)
Radeff-Huang, J.; Seasholtz, T.M.; Chang, J.W.; Smith, J.M.; Walsh, C.T.; Brown, J.H.
Tumor necrosis factor-alpha-stimulated cell proliferation is mediated through sphingosine kinase-dependent Akt activation and cyclin D expression
J. Biol. Chem.
282
863-870
2007
Homo sapiens
Zhi, L.; Leung, B.P.; Melendez, A.J.
Sphingosine kinase 1 regulates pro inflammatory responses triggered by TNFalpha in primary human monocytes
J. Cell. Physiol.
208
109-115
2006
Homo sapiens (Q9NYA1), Homo sapiens
Kohno, M.; Momoi, M.; Oo, M.L.; Paik, J.H.; Lee, Y.M.; Venkataraman, K.; Ai, Y.; Ristimaki, A.OP.; Fyrst, H.; Sano, H.; Rosenberg, D.; Saba, J.D.; Proia, R.L.; Hla1, T.
Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation
Mol. Cell. Biol.
26
7211-7223
2006
Mus musculus (Q8CI15), Homo sapiens (Q9NYA1)
Paugh, S.W.; Paugh, B.S.; Rahmani, M.; Kapitonov, D.; Almenara, J.A.; Kordula, T.; Milstien, S.; Adams, J.K.; Zipkin, R.E.; Grant, S.; Spiegel, S.
A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia
Blood
112
1382-1391
2008
Homo sapiens
Paugh, B.S.; Paugh, S.W.; Bryan, L.; Kapitonov, D.; Wilczynska, K.M.; Gopalan, S.M.; Rokita, H.; Milstien, S.; Spiegel, S.; Kordula, T.
EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells
FASEB J.
22
455-465
2008
Homo sapiens
Kim, H.L.; Sacket, S.J.; Han, M.; Im, D.S.
Characterization of N,N,-dimethyl-D-erythro-sphingosine-induced apoptosis and signaling in U937 cells: independence of sphingosine kinase inhibition
Prostaglandins Other Lipid Mediat.
86
18-25
2008
Homo sapiens
Leroux, M.E.; Auzenne, E.; Evans, R.; Hail, N.; Spohn, W.; Ghosh, S.C.; Farquhar, D.; McDonnell, T.; Klostergaard, J.
Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells
Prostate
67
1699-1717
2007
Homo sapiens
Gamble, J.R.; Sun, W.Y.; Li, X.; Hahn, C.N.; Pitson, S.M.; Vadas, M.A.; Bonder, C.S.
Sphingosine kinase-1 associates with integrin alphaVbeta3 to mediate endothelial cell survival
Am. J. Pathol.
175
2217-2225
2009
Homo sapiens
Hayashi, H.; Nakagami, H.; Takami, Y.; Koriyama, H.; Mori, M.; Tamai, K.; Sun, J.; Nagao, K.; Morishita, R.; Kaneda, Y.
FHL-2 suppresses VEGF-induced phosphatidylinositol 3-kinase/Akt activation via interaction with sphingosine kinase-1
Arterioscler. Thromb. Vasc. Biol.
29
909-914
2009
Homo sapiens
Don, A.S.; Rosen, H.
A lipid binding domain in sphingosine kinase 2
Biochem. Biophys. Res. Commun.
380
87-92
2009
Homo sapiens
Erez-Roman, R.; Pienik, R.; Futerman, A.H.
Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression
Biochem. Biophys. Res. Commun.
391
219-223
2010
Homo sapiens
Xiang, Y.; Asmussen, G.; Booker, M.; Hirth, B.; Kane, J.L.; Liao, J.; Noson, K.D.; Yee, C.
Discovery of novel sphingosine kinase 1 inhibitors
Bioorg. Med. Chem. Lett.
19
6119-6121
2009
Homo sapiens
Foss, F.W.; Mathews, T.P.; Kharel, Y.; Kennedy, P.C.; Snyder, A.H.; Davis, M.D.; Lynch, K.R.; Macdonald, T.L.
Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs
Bioorg. Med. Chem.
17
6123-6136
2009
Homo sapiens, Mus musculus
Li, X.; Stankovic, M.; Bonder, C.S.; Hahn, C.N.; Parsons, M.; Pitson, S.M.; Xia, P.; Proia, R.L.; Vadas, M.A.; Gamble, J.R.
Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1
Blood
111
3489-3497
2008
Homo sapiens, Mus musculus
Guo, Q.; Li, Q.; Liu, H.; Li, R.; Wu, C.; Wang, L.
Sphingosine kinase 1 gene transfer reduces postoperative peritoneal adhesion in an experimental model
Br. J. Surg.
95
252-258
2008
Homo sapiens
Ader, I.; Brizuela, L.; Bouquerel, P.; Malavaud, B.; Cuvillier, O.
Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells
Cancer Res.
68
8635-8642
2008
Homo sapiens
Kapitonov, D.; Allegood, J.C.; Mitchell, C.; Hait, N.C.; Almenara, J.A.; Adams, J.K.; Zipkin, R.E.; Dent, P.; Kordula, T.; Milstien, S.; Spiegel, S.
Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts
Cancer Res.
69
6915-6923
2009
Homo sapiens, Mus musculus
Yan, G.; Chen, S.; You, B.; Sun, J.
Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids
Cardiovasc. Res.
78
308-314
2008
Homo sapiens
Limaye, V.; Vadas, M.A.; Pitson, S.M.; Gamble, J.R.
The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells
Cell. Mol. Biol. Lett.
14
411-423
2009
Homo sapiens
Limaye, V.; Xia, P.; Hahn, C.; Smith, M.; Vadas, M.A.; Pitson, S.M.; Gamble, J.R.
Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells
Cell. Mol. Biol. Lett.
14
424-441
2009
Homo sapiens
Hgenauer, K.; Billich, A.; Pally, C.; Streiff, M.; Wagner, T.; Welzenbach, K.; Nussbaumer, P.
Phosphorylation by sphingosine kinase 2 is essential for in vivo potency of FTY720 analogues
ChemMedChem
3
1027-1029
2008
Homo sapiens
Li, J.; Guan, H.Y.; Gong, L.Y.; Song, L.B.; Zhang, N.; Wu, J.; Yuan, J.; Zheng, Y.J.; Huang, Z.S.; Li, M.
Clinical significance of sphingosine kinase-1 expression in human astrocytomas progression and overall patient survival
Clin. Cancer Res.
14
6996-7003
2008
Homo sapiens
Li, W.; Yu, C.P.; Xia, J.T.; Zhang, L.; Weng, G.X.; Zheng, H.Q.; Kong, Q.L.; Hu, L.J.; Zeng, M.S.; Zeng, Y.X.; Li, M.; Li, J.; Song, L.B.
Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients
Clin. Cancer Res.
15
1393-1399
2009
Homo sapiens
Bergelin, N.; Blom, T.; Heikkilae, J.; Loef, C.; Alam, C.; Balthasar, S.; Slotte, J.P.; Hinkkanen, A.; Toernquist, K.
Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2
Endocrinology
150
2055-2063
2009
Homo sapiens
Sukocheva, O.; Wang, L.; Verrier, E.; Vadas, M.A.; Xia, P.
Restoring endocrine response in breast cancer cells by inhibition of the sphingosine kinase-1 signaling pathway
Endocrinology
150
4484-4492
2009
Homo sapiens
Gude, D.R.; Alvarez, S.E.; Paugh, S.W.; Mitra, P.; Yu, J.; Griffiths, R.; Barbour, S.E.; Milstien, S.; Spiegel, S.
Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal
FASEB J.
22
2629-2638
2008
Homo sapiens
Kawamori, T.; Kaneshiro, T.; Okumura, M.; Maalouf, S.; Uflacker, A.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M.
Role for sphingosine kinase 1 in colon carcinogenesis
FASEB J.
23
405-414
2009
Homo sapiens, Mus musculus
Billich, A.; Urtz, N.; Reuschel, R.; Baumruker, T.
Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells
Int. J. Biochem. Cell Biol.
41
1547-1555
2009
Homo sapiens, Mus musculus
Zebol, J.R.; Hewitt, N.M.; Moretti, P.A.; Lynn, H.E.; Lake, J.A.; Li, P.; Vadas, M.A.; Wattenberg, B.W.; Pitson, S.M.
The CCT/TRiC chaperonin is required for maturation of sphingosine kinase 1
Int. J. Biochem. Cell Biol.
41
822-827
2009
Homo sapiens
Weigert, A.; Schiffmann, S.; Sekar, D.; Ley, S.; Menrad, H.; Werno, C.; Grosch, S.; Geisslinger, G.; Bruene, B.
Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype
Int. J. Cancer
125
2114-2121
2009
Homo sapiens
Sauer, L.; Nunes, J.; Salunkhe, V.; Skalska, L.; Kohama, T.; Cuvillier, O.; Waxman, J.; Pchejetski, D.
Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel
Int. J. Cancer
125
2728-2736
2009
Homo sapiens
Sobue, S.; Nemoto, S.; Murakami, M.; Ito, H.; Kimura, A.; Gao, S.; Furuhata, A.; Takagi, A.; Kojima, T.; Nakamura, M.; Ito, Y.; Suzuki, M.; Banno, Y.; Nozawa, Y.; Murate, T.
Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells
Int. J. Hematol.
87
266-275
2008
Homo sapiens
Anelli, V.; Gault, C.; Cheng, A.; Obeid, L.
Sphingosine kinase 1 is up-regulated during hypoxia in U87MG glioma cells: Role of hypoxia-inducible factors 1 and 2
J. Biol. Chem.
283
3365-3375
2008
Homo sapiens
Paugh, B.S.; Bryan, L.; Paugh, S.W.; Wilczynska, K.M.; Alvarez, S.M.; Singh, S.K.; Kapitonov, D.; Rokita, H.; Wright, S.; Griswold-Prenner, I.; Milstien, S.; Spiegel, S.; Kordula, T.
Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells
J. Biol. Chem.
284
3408-3417
2009
Homo sapiens
Hong, J.H.; Youm, J.K.; Kwon, M.J.; Park, B.D.; Lee, Y.M.; Lee, S.I.; Shin, D.M.; Lee, S.H.
K6PC-5, a direct activator of sphingosine kinase 1, promotes epidermal differentiation through intracellular Ca2+ signaling
J. Invest. Dermatol.
128
2166-2178
2008
Homo sapiens, Mus musculus
Ren, S.; Babelova, A.; Moreth, K.; Xin, C.; Eberhardt, W.; Doller, A.; Pavenstaedt, H.; Schaefer, L.; Pfeilschifter, J.; Huwiler, A.
Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression
Kidney Int.
76
857-867
2009
Homo sapiens, Mus musculus
Bayerl, M.G.; Bruggeman, R.D.; Conroy, E.J.; Hengst, J.A.; King, T.S.; Jimenez, M.; Claxton, D.F.; Yun, J.K.
Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions
Leuk. Lymphoma
49
948-954
2008
Homo sapiens (Q9NYA1), Homo sapiens
Schnitzer, S.E.; Weigert, A.; Zhou, J.; Bruene, B.
Hypoxia enhances sphingosine kinase 2 activity and provokes sphingosine-1-phosphate-mediated chemoresistance in A549 lung cancer cells
Mol. Cancer Res.
7
393-401
2009
Homo sapiens
Pchejetski, D.; Doumerc, N.; Golzio, M.; Naymark, M.; Teissie, J.; Kohama, T.; Waxman, J.; Malavaud, B.; Cuvillier, O.
Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models
Mol. Cancer Ther.
7
1836-1845
2008
Homo sapiens
Miller, A.V.; Alvarez, S.E.; Spiegel, S.; Lebman, D.A.
Sphingosine kinases and sphingosine-1-phosphate are critical for transforming growth factor beta-induced extracellular signal-regulated kinase 1 and 2 activation and promotion of migration and invasion of esophageal cancer cells
Mol. Cell. Biol.
28
4142-4151
2008
Homo sapiens
Maceyka, M.; Alvarez, S.E.; Milstien, S.; Spiegel, S.
Filamin A links sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 at lamellipodia to orchestrate cell migration
Mol. Cell. Biol.
28
5687-5697
2008
Homo sapiens
Kamada, K.; Arita, N.; Tsubaki, T.; Takubo, N.; Fujino, T.; Soga, Y.; Miyazaki, T.; Yamamoto, H.; Nose, M.
Expression of sphingosine kinase 2 in synovial fibroblasts of rheumatoid arthritis contributing to apoptosis by a sphingosine analogue, FTY720
Pathol. Int.
59
382-389
2009
Homo sapiens
Dayon, A.; Brizuela, L.; Martin, C.; Mazerolles, C.; Pirot, N.; Doumerc, N.; Nogueira, L.; Golzio, M.; Teissie, J.; Serre, G.; Rischmann, P.; Malavaud, B.; Cuvillier, O.
Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival
PLoS ONE
4
e8048
2009
Homo sapiens
Kono, Y.; Nishiuma, T.; Okada, T.; Kobayashi, K.; Funada, Y.; Kotani, Y.; Jahangeer, S.; Nakamura, S.I.; Nishimura, Y.
Sphingosine kinase 1 regulates mucin production via ERK phosphorylation
Pulm. Pharmacol. Ther.
23
36-42
2010
Homo sapiens, Mus musculus
Hengst, J.; Guilford, J.; Conroy, E.; Wang, X.; Yun, J.
Enhancement of sphingosine kinase 1 catalytic activity by deletion of 21 amino acids from the COOH-terminus
Arch. Biochem. Biophys.
494
23-31
2010
Homo sapiens
Lim, K.G.; Tonelli, F.; Berdyshev, E.; Gorshkova, I.; Leclercq, T.; Pitson, S.M.; Bittman, R.; Pyne, S.; Pyne, N.J.
Inhibition kinetics and regulation of sphingosine kinase 1 expression in prostate cancer cells: functional differences between sphingosine kinase 1a and 1b
Int. J. Biochem. Cell Biol.
44
1457-1464
2012
Homo sapiens (Q9NYA1)
Lim, K.G.; Tonelli, F.; Li, Z.; Lu, X.; Bittman, R.; Pyne, S.; Pyne, N.J.
FTY720 analogues as sphingosine kinase 1 inhibitors: enzyme inhibition kinetics, allosterism, proteasomal degradation, and actin rearrangement in MCF-7 breast cancer cells
J. Biol. Chem.
286
18633-18640
2011
Homo sapiens (Q9NYA1)
Siow, D.L.; Anderson, C.D.; Berdyshev, E.V.; Skobeleva, A.; Pitson, S.M.; Wattenberg, B.W.
Intracellular localization of sphingosine kinase 1 alters access to substrate pools but does not affect the degradative fate of sphingosine-1-phosphate
J. Lipid Res.
51
2546-2559
2010
Homo sapiens (Q9NYA1)
Cho, S.Y.; Lee, H.J.; Jeong, S.J.; Lee, H.J.; Kim, H.S.; Chen, C.Y.; Lee, E.O.; Kim, S.H.
Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1alpha inactivation in hypoxic PC-3 prostate cancer cells
J. Pineal Res.
51
87-93
2011
Homo sapiens
Park, S.W.; Kim, M.; Kim, M.; DAgati, V.D.; Lee, H.T.
Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation
Kidney Int.
80
1315-1327
2011
Homo sapiens, Mus musculus
Gao, P.; Peterson, Y.; Smith, R.; Smith, C.
Characterization of isoenzyme-selective inhibitors of human sphingosine kinases
PLoS ONE
7
e44543
2012
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Baker, D.; Pham, T.; Sparks, M.
Structure and catalytic function of sphingosine kinases: analysis by site-directed mutagenesis and enzyme kinetics
Biochim. Biophys. Acta
1831
139-146
2013
Mus musculus (Q8CI15), Mus musculus (Q9JIA7), Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Dickinson, A.; Meyer, M.; Pawlak, E.; Gomez, S.; Jaspers, I.; Allbritton, N.
Analysis of sphingosine kinase activity in single natural killer cells from peripheral blood
Integr. Biol.
7
392-401
2015
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Adada, M.M.; Orr-Gandy, K.A.; Snider, A.J.; Canals, D.; Hannun, Y.A.; Obeid, L.M.; Clarke, C.J.
Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor kappaB activation
J. Biol. Chem.
288
27667-27679
2013
Homo sapiens (Q9NYA1)
Baek, D.; MacRitchie, N.; Anthony, N.; MacKay, S.; Pyne, S.; Pyne, N.; Bittman, R.
Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors
J. Med. Chem.
56
9310-9327
2013
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Patwardhan, N.N.; Morris, E.A.; Kharel, Y.; Raje, M.R.; Gao, M.; Tomsig, J.L.; Lynch, K.R.; Santos, W.L.
Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors
J. Med. Chem.
58
1879-1899
2015
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Wang, Z.; Min, X.; Xiao, S.H.; Johnstone, S.; Romanow, W.; Meininger, D.; Xu, H.; Liu, J.; Dai, J.; An, S.; Thibault, S.; Walker, N.
Molecular basis of sphingosine kinase 1 substrate recognition and catalysis
Structure
21
798-809
2013
Homo sapiens (Q9NYA1), Homo sapiens
Congdon, M.D.; Kharel, Y.; Brown, A.M.; Lewis, S.N.; Bevan, D.R.; Lynch, K.R.; Santos, W.L.
Structure-activity relationship studies and molecular modeling of naphthalene-based sphingosine kinase 2 inhibitors
ACS Med. Chem. Lett.
7
229-234
2016
Homo sapiens (Q9NRA0)
Houck, J.D.; Dawson, T.K.; Kennedy, A.J.; Kharel, Y.; Naimon, N.D.; Field, S.D.; Lynch, K.R.; Macdonald, T.L.
Structural requirements and docking analysis of amidine-based sphingosine kinase 1 inhibitors containing oxadiazoles
ACS Med. Chem. Lett.
7
487-492
2016
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Kashem, M.; Kennedy, C.; Fogarty, K.; Dimock, J.; Zhang, Y.; Sanville-Ross, M.; Skow, D.; Brunette, S.; Swantek, J.; Hummel, H.; Swindle, J.; Nelson, R.
A high-throughput genetic complementation assay in yeast cells identified selective inhibitors of sphingosine kinase 1 not found using a cell-free enzyme assay
Assay Drug Dev. Technol.
14
39-49
2016
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Vettorazzi, M.; Insuasty, D.; Lima, S.; Gutierrez, L.; Nogueras, M.; Marchal, A.; Abonia, R.; Andujar, S.; Spiegel, S.; Cobo, J.; Enriz, R.
Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors
Bioorg. Chem.
94
103414
2020
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1)
Bayraktar, O.; Ozkirimli, E.; Ulgen, K.
Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site
Comput. Biol. Chem.
69
64-76
2017
Homo sapiens (Q9NYA1), Homo sapiens
Tangadanchu, V.K.R.; Jiang, H.; Yu, Y.; Graham, T.J.A.; Liu, H.; Rogers, B.E.; Gropler, R.; Perlmutter, J.; Tu, Z.
Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors
Eur. J. Med. Chem.
206
112713
2020
Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Nishino, S.; Yamashita, H.; Tamori, M.; Mashimo, M.; Yamagata, K.; Nakamura, H.; Murayama, T.
Translocation and activation of sphingosine kinase 1 by ceramide-1-phosphate
J. Cell. Biochem.
120
5396-5408
2019
Homo sapiens (Q9NYA1), Homo sapiens
Worrell, B.L.; Brown, A.M.; Santos, W.L.; Bevan, D.R.
In silico characterization of structural distinctions between isoforms of human and mouse sphingosine kinases for accelerating drug discovery
J. Chem. Inf. Model.
59
2339-2351
2019
Mus musculus (Q8CI15), Mus musculus (Q9JIA7), Mus musculus, Homo sapiens (Q9NRA0), Homo sapiens (Q9NYA1), Homo sapiens
Sibley, C.D.; Morris, E.A.; Kharel, Y.; Brown, A.M.; Huang, T.; Bevan, D.R.; Lynch, K.R.; Santos, W.L.
Discovery of a small side cavity in sphingosine kinase 2 that enhances inhibitor potency and selectivity
J. Med. Chem.
63
1178-1198
2020
Homo sapiens (Q9NRA0)
Imbert, C.; Montfort, A.; Fraisse, M.; Marcheteau, E.; Gilhodes, J.; Martin, E.; Bertrand, F.; Marcellin, M.; Burlet-Schiltz, O.; Peredo, A.G.; Garcia, V.; Carpentier, S.; Tartare-Deckert, S.; Brousset, P.; Rochaix, P.; Puisset, F.; Filleron, T.; Meyer, N.; Lamant, L.; Levade, T.; Segui, B.; Andrieu-Abadie, N.; Colacios, C.
Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1
Nat. Commun.
11
437
2020
Homo sapiens (Q9NYA1), Homo sapiens
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