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Information on EC 2.3.1.299 - sphingoid base N-stearoyltransferase and Organism(s) Homo sapiens and UniProt Accession P27544
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2.3.1.299 sphingoid base N-stearoyltransferaseIUBMB Comments
Mammals have six ceramide synthases that exhibit relatively strict specificity regarding the chain-length of their acyl-CoA substrates. Ceramide synthase 1 (CERS1) is structurally and functionally distinctive from all other CERS enzymes, and is specific for stearoyl-CoA as the acyl donor. It can use multiple sphingoid bases including sphinganine, sphingosine, and phytosphingosine.
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
cers1, lass1, ceramide synthase 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ceramide synthase 1
CerS1
LASS1
mammalian ceramide synthase 1
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UOG1
CerS1
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LASS1
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UOG1
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PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
stearoyl-CoA:sphingoid base N-stearoyltransferase
Mammals have six ceramide synthases that exhibit relatively strict specificity regarding the chain-length of their acyl-CoA substrates. Ceramide synthase 1 (CERS1) is structurally and functionally distinctive from all other CERS enzymes, and is specific for stearoyl-CoA as the acyl donor. It can use multiple sphingoid bases including sphinganine, sphingosine, and phytosphingosine.
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
dihydrosphingosine + 2-hydroxystearoyl-CoA
N-2-hydroxystearoylsphingosine + CoA
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-
-
?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
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-
-
?
arachidoyl-CoA + dihydrosphingosine
N-(arachidoyl)-dihydrosphingosine + CoA
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-
-
-
?
dihydrosphingosine + palmitoyl-CoA
N-palmitoyldihydrosphingosine + CoA
low activity
-
-
?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
highly preferred substrate
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-
?
stearoyl-CoA + a sphingoid base
an N-(stearoyl)-sphingoid base + CoA
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-
-
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?
stearoyl-CoA + dihydrosphingosine
N-(stearoyl)-dihydrosphingosine + CoA
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?
stearoyl-CoA + NBD-dihydrosphingosine
N-(stearoyl)-NBD-dihydroceramide + CoA
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?
stearoyl-CoA + NBD-labelled sphinganine
N-(stearoyl)-sphinganine + CoA
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NBD-labelled sphinganine is (2S,3R)-2-amino-18-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)octadecane-1,3-diol
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?
additional information
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CERS1 preferentially catalyzes the transfer of a C18:0 fatty acid, forming C18:0 dihydroceramide (d18:0/18:0 ceramide)
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?
additional information
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CERS activity is assayed using LC-MS/MS for product quantification, crude extracts containing cell membranes are firstly prepared from tissues or cultured cells, reactions contain deuterated dihydrosphingosine (or sphingosine) and a fatty acid substrate linked to CoA (C16:0 to C24:0/24:1), detailed method descritpion and evaluation, overview
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?
additional information
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substrate specificity, overview. CerS1 can use C18:0-CoA but not C18:1-CoA as a substrate
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?
additional information
?
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clear preference for the C18:0 NBD-dihydroceramide synthesis is observed with extracts of human frontal cortex grey matter
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additional information
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CERS1-expressing HEK293 cell extracts show a clear preference for utilisation of the C18:0 fatty acid substrate when presented with equimolar concentrations of C16:0, C18:0, C24:0, and C24:1 fatty acid substrates. CERS1 preferentially catalyses the addition of 18-carbon (C18:0) fatty acids to dihydrosphingosine. No activity with lignoceroyl-CA, and poor activity with nervonoyl-CoA. Improvement of a fluorescent assay, using HPLC using C16:0, C18:0, and C24:1 fatty acids and commercially available sphinganine-NBD, i.e. 7-nitro-2-1,3-benzoxadiazole-labelled dihydrosphingosine or (2S,3R)-2-amino-18((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)octadecane-1-3-diol, as substrates, very accurate and sensitive method for quantification of CERS activity, method evaluation
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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
dihydrosphingosine + 2-hydroxystearoyl-CoA
N-2-hydroxystearoylsphingosine + CoA
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-
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?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
-
-
-
?
dihydrosphingosine + palmitoyl-CoA
N-palmitoyldihydrosphingosine + CoA
low activity
-
-
?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
highly preferred substrate
-
-
?
stearoyl-CoA + a sphingoid base
an N-(stearoyl)-sphingoid base + CoA
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-
-
-
?
stearoyl-CoA + NBD-labelled sphinganine
N-(stearoyl)-sphinganine + CoA
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NBD-labelled sphinganine is (2S,3R)-2-amino-18-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)octadecane-1,3-diol
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?
additional information
?
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CERS1 preferentially catalyzes the transfer of a C18:0 fatty acid, forming C18:0 dihydroceramide (d18:0/18:0 ceramide)
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?
additional information
?
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clear preference for the C18:0 NBD-dihydroceramide synthesis is observed with extracts of human frontal cortex grey matter
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?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FTY720
inhibits ceramide synthases and upregulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. FTY720 is a sphingosine analogue and in clinical trials as an immunomodulator. Multifaceted mode of interaction between FTY720 and CerS. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs, dependence on acyl-CoA chain length of inhibition of CerS activity by FTY720. Sphinganine first binds to CerS to form an E-S (CerS-sphinganine) complex, and only after formation of this complex can FTY720 bind. The binding sites of FTY720 and acyl-CoA appear to be distinct, but the interaction between sphinganine binding and FTY720 binding nevertheless impacts the rate of the reaction with respect to acyl-CoA. FTY720 inhibits ceramide synthesis at high sphinganine concentrations in vivo, but not at low concentrations, supporting a complex, possibly allosteric mode of interaction between sphinganine and FTY720 and is consistent with uncompetitive inhibitors being most effective at high substrate concentrations. FTY720 acts as a noncompetitive inhibitor toward C18-CoA. The inhibition of FTY720 toward C18-CoA is allosteric under the normal reaction conditions. Sphingolipid composition of HEK cells treated with FTY720, overview
additional information
in contrast to the dual effects of fumonisin B1, which is only observed in cells overexpressing CerS, FTY720 elevates ceramide levels in untransfected cells
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fumonisin B1
inhibits the increase in total cellular ceramide induced by UV-C irradiation
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
expression analysis of the CerS family members during epidermal keratinocyte differentiation, overview. For all CerS family members except CerS1, mRNA expression is detected in undifferentiated keratinocytes
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
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enzyme knockdown leads to inhibition of photodynamic therapy-induced caspase 3-like activation, of apoptosis and cell death. Enzyme knockdown is associated with global and selective decreases in ceramides and dihydroceramides, in particular C18-, C18:1- and C20-ceramide post-photodynamic therapy
physiological function
malfunction
inhibition of CerS is able to protect from cell death. Moreover, this protection occurs downstream or independently of mitochondrial permeabilization. Inhibition of CerS greatly inhibits plasma membrane permeabilization. Individual CerS knockdown does not significantly inhibit total ceramide accumulation. CerS1 knockdown has minimal effects in untreated cells and fails to prevent the accumulation of any Cer species following irradiation. Inhibition of CerS but not de novo synthesis inhibits plasma membrane rupture that is not specific to UV-C irradiation or MCF-7 cells
malfunction
profiles of non-hydroxylated and 2-hydroxy-ceramides in transgenic HeLa cells expressing different CerS isozymes and or different specific interfence RNAs, overview
malfunction
upon incubation of HEK cells with inhibitor FTY720, an increase in ceramide levels is observed, with no change in endogenous sphinganine levels. Similar increases are observed for hexosylceramide and sphingomyelin. Moreover, levels of C18-C22-ceramide are significantly increased, as are levels of C18-C22-hexosylceramide and C18-C22-sphingomyelin. This result is consistent with a complex mode of interaction of FTY720 with CerS, perhaps involving an allosteric element that is not preserved in vitro, whereby ceramide synthesis is stimulated in cells despite its inhibition by FTY720 in vitro
metabolism
in HEK-293 cells, both endogenous human CerS1 and ectopically expressed murine CerS1 have rapid basal turnover, the turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC), p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover
metabolism
regulation of sphingolipid metabolism by UV-C irradiation, overview. Ceramide species that are the least abundant (e.g. C18-Cer, C18:1-Cer, C20-Cer, C22:1-Cer, etc.) exhibit the greatest fold increases. More abundant ceramide species (e.g. C16-Cer, C24-Cer, and C24:1-Cer) show more modest fold changes, although they account for much more of the overall increase in ceramides
physiological function
ceramide synthase 1 (CerS1) is the most structurally and functionally distinct from the other CerS enzymes, the enzyme is regulated via a regulatory mechanism that specifically controls the level of CerS1 via ubiquitination and proteasome dependent protein turnover
physiological function
ceramides are synthesized by ceramide synthases through the addition of a variable length fatty acid to the amine group of a sphingoid base. In mammalian cells, the sphingoid base used for de novo ceramide synthesis is usually the C18:0 lipid dihydrosphingosine. Ceramide synthesis is catalyzed by a family of six ceramide synthases (CERS1-6), each of which preferentially transfers fatty acids of different lengths to the amine group of dihydrosphingosine
physiological function
differences in the expression patterns of CerS family members may play an important role in the production of the CER/2-hydroxy ceramide (CER) compositions of different chain lengths observed in different cell types and even in the altered production that occurring during keratinocyte differentiation
physiological function
sphingolipid ceramides are widely implicated in the regulation of programmed cell death or apoptosis. CerS1 regulates C18:0-Cer synthesis
physiological function
C18 ceramide synthesized by CERS1 is implicated in apoptosis and lethal autophagy
physiological function
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enzyme overexpression in HEK-293 cells increases sensitivity to the chemotherapeutic agents cisplatin, carboplatin, doxorubicin and vincristine. The enzyme is a negative regulator of head and neck squamous cell carcinoma cells
physiological function
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enzyme overexpression inhibits cell viability and induces cell death by activating endoplasmic reticulum stress, which induces lethal autophagy and inhibits PI3K/AKT signal pathway in U-251 and A-172 glioma cells. Enzyme overexpression also increases the sensitivity of U-251 and A-172 glioma cells to teniposide (VM-26)
physiological function
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the enzyme regulates apoptotic resistance to photodynamic therapy for cancer treatment
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). CERS1_HUMAN
350
5
39536
Swiss-Prot
other Location (Reliability: 3)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
CerS1 is phosphorylated in vivo and activation of protein kinase C increases the phosphorylation of the protein
phosphoprotein
the enzyme turnover is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC). p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. The enzyme is phosphorylated in vivo and activation of PKC increases the phosphorylation of the protein
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H182A/H183A
the mutant shows greatly reduced activity compared to the wild type enzyme
additional information
additional information
-
in HEK-293 cells, both endogenous human CerS1 and ectopically expressed murine CerS1 have rapid basal turnover, the turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC), p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. Recombinant isozyme CerS1 sensitizes cells to a wide range of drugs including cisplatin, carboplatin, doxorubicin and vincristine, in contrast to isozymes CerS4 and CerS5. The specific effect of CerS1 is mediated through the activation of the MAP kinase p38
additional information
in HEK-293 cells, both endogenous human CerS1 and ectopically expressed murine CerS1 have rapid basal turnover, the turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC), p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. Recombinant isozyme CerS1 sensitizes cells to a wide range of drugs including cisplatin, carboplatin, doxorubicin and vincristine, in contrast to isozymes CerS4 and CerS5. The specific effect of CerS1 is mediated through the activation of the MAP kinase p38
additional information
profiles of non-hydroxylated and 2-hydroxy-ceramides in transgenic HeLa cells expressing different CerS isozymes and or different specific interfence RNAs, overview
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene CERS1, recombinant expression in HEK-293T cells, quantitative real-time quantitative PCR enzyme expression analysis
gene CERS1, recombinant overexpression in HEK cells, FTY720 inhibits CerS1 activity to a greater extent than CerS5 in the overexpressing cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
diverse stresses including chemotherapeutic drugs, UV light and DTT can induce CerS1 turnover
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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the combined therapy of enzyme and teniposide VM-26 is a therapeutic strategy for the treatment of human glioma
medicine
-
the enzyme is a molecular target for controlling resistance to photodynamic therapy
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sridevi, P.; Alexander, H.; Laviad, E.L.; Pewzner-Jung, Y.; Hannink, M.; Futerman, A.H.; Alexander, S.
Ceramide synthase 1 is regulated by proteasomal mediated turnover
Biochim. Biophys. Acta
1793
1218-1227
2009
Homo sapiens, Homo sapiens (P27544), Mus musculus (P27545)
Lahiri, S.; Park, H.; Laviad, E.L.; Lu, X.; Bittman, R.; Futerman, A.H.
Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner
J. Biol. Chem.
284
16090-16098
2009
Homo sapiens (P27544)
Mullen, T.D.; Jenkins, R.W.; Clarke, C.J.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M.
Ceramide synthase-dependent ceramide generation and programmed cell death involvement of salvage pathway in regulating postmitochondrial events
J. Biol. Chem.
286
15929-15942
2011
Homo sapiens (P27544)
Mizutani, Y.; Kihara, A.; Chiba, H.; Tojo, H.; Igarashi, Y.
2-Hydroxy-ceramide synthesis by ceramide synthase family enzymatic basis for the preference of FA chain length
J. Lipid Res.
49
2356-2364
2008
Homo sapiens (P27544)
Couttas, T.A.; Lim, X.Y.; Don, A.S.
A three-step assay for ceramide synthase activity using a fluorescent substrate and HPLC
Lipids
50
101-109
2015
Homo sapiens (P27545)
Lim, X.Y.; Pickford, R.; Don, A.S.
Assaying ceramide synthase activity in vitro and in living cells using liquid chromatography-mass spectrometry
Methods Mol. Biol.
1376
11-22
2016
Homo sapiens (P27544)
Separovic, D.; Breen, P.; Joseph, N.; Bielawski, J.; Pierce, J.S.; VAN Buren, E.; Gudz, T.I.
siRNA-mediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy
Anticancer Res.
32
2479-2485
2012
Homo sapiens
Mullen, T.D.; Hannun, Y.A.; Obeid, L.M.
Ceramide synthases at the centre of sphingolipid metabolism and biology
Biochem. J.
441
789-802
2012
Homo sapiens, Mus musculus
Kim, H.J.; Qiao, Q.; Toop, H.D.; Morris, J.C.; Don, A.S.
A fluorescent assay for ceramide synthase activity
J. Lipid Res.
53
1701-1707
2012
Homo sapiens
Couttas, T.; Don, A.
Fluorescent assays for ceramide synthase activity
Methods Mol. Biol.
1376
23-33
2016
Homo sapiens
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