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Information on EC 2.3.1.299 - sphingoid base N-stearoyltransferase
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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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Word Map
The enzyme appears in viruses and cellular organisms
Synonyms
cers1, lass1, ceramide synthase 1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ceramide synthase 1
CerS1
LASS1
mammalian ceramide synthase 1
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UOG1
additional information
CerS1
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LASS1
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UOG1
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
stearoyl-CoA + a sphingoid base = an N-(stearoyl)-sphingoid base + CoA
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PATHWAY SOURCE
PATHWAYS
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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.
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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
arachidoyl-CoA + dihydrosphingosine
N-(arachidoyl)-dihydrosphingosine + CoA
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?
dihydrosphingosine + 2-hydroxystearoyl-CoA
N-2-hydroxystearoylsphingosine + CoA
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?
dihydrosphingosine + palmitoyl-CoA
N-palmitoyldihydrosphingosine + CoA
low activity
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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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?
D-erythro-sphinganine + stearoyl-CoA
N-stearoyl-D-sphinganine + CoA
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?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
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?
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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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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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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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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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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C18:0 fatty acid CoA, but not cis-C18:1 fatty acid CoAs, are substrates for LASS1
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additional information
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C18:0 fatty acid CoA, but not cis-C18:1 fatty acid CoAs, are substrates for LASS1
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additional information
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C18:0-CoA is the best substrate for Lass1-dependent ceramide synthesis. C18:1-CoA, which has the same chain length as C18:0, is not a good substrate at all. Recombinant Lass1 produces preferentially C18:0-ceramides in transgenic HEK-293T cells
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additional information
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C18:0-CoA is the best substrate for Lass1-dependent ceramide synthesis. C18:1-CoA, which has the same chain length as C18:0, is not a good substrate at all. Recombinant Lass1 produces preferentially C18:0-ceramides in transgenic HEK-293T cells
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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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?
dihydrosphingosine + palmitoyl-CoA
N-palmitoyldihydrosphingosine + CoA
low activity
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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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?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
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?
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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?
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+
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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
fumonisin B1
inhibits the increase in total cellular ceramide induced by UV-C irradiation
fumonisin B1
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reversible competitive inhibition, inhibits ceramide synthase in mouse brain microsomes with a competitive-like kinetic behavior with respect to both sphinganine and stearoyl-CoA. Fumonisin B1 inhibits ceramide synthase activity when palmitoyl-CoA, stearoyl-CoA, or lignoceroyl-CoA are used as the co-substrate, cf. EC 2.3.1.297 and 2.3.1.24
fumonisin B1
an in vitro inhibitor of (dihydro)-ceramide synthase, inhibits wild-type and mutant enzymes in vivo in HeLa cells
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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additional information
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fumonisins block sphingosine biosynthesis by inhibiting the conversion of sphinganine to dihydroceramides, which precedes introduction of the 4,5-trans-double bond of sphingosine. Fumonisins, mycotoxins produced by Fusarium moniliforme and a number of other fungi, cause neuronal degeneration, liver and renal toxicity, cancer, and other injury to animals. Fumonisin Bl inhibits complex sphirqolipid synthesis from galactose and sphinganine, effects on the amounts of free sphingosine and sphinganine and on total complex sphingolipids, overview
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Adenocarcinoma of Lung
Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1.
Ataxia
Progressive Myoclonic Epilepsy Type 8 Due to CERS1 Deficiency: A Novel Mutation with Prominent Ataxia.
Carcinoma
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.
Carcinoma
Increased killing of SCCVII squamous cell carcinoma cells after the combination of Pc 4 photodynamic therapy and dasatinib is associated with enhanced caspase-3 activity and ceramide synthase 1 upregulation.
Carcinoma, Squamous Cell
Increased killing of SCCVII squamous cell carcinoma cells after the combination of Pc 4 photodynamic therapy and dasatinib is associated with enhanced caspase-3 activity and ceramide synthase 1 upregulation.
Carcinoma, Squamous Cell
siRNA-mediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy.
Dementia
Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency.
Epilepsies, Myoclonic
Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency.
Glioblastoma
Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death.
Glioma
Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma.
Head and Neck Neoplasms
Diverse functions of ceramide in cancer cell death and proliferation.
Heart Failure
A tissue-specific screen of ceramide expression in aged mice identifies ceramide synthase-1 and ceramide synthase-5 as potential regulators of fiber size and strength in skeletal muscle.
Inflammatory Bowel Diseases
mTNF reverse signalling induced by TNF? antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease.
Insulin Resistance
A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism.
Insulin Resistance
Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice.
Mouth Neoplasms
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.
Myoclonic Epilepsies, Progressive
Progressive Myoclonic Epilepsy Type 8 Due to CERS1 Deficiency: A Novel Mutation with Prominent Ataxia.
Neoplasm Metastasis
Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells.
Neoplasms
Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells.
Neoplasms
Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas.
Neoplasms
Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing.
Neoplasms
The Potential Role of CERS1 in Autophagy Through PI3K/AKT Signaling Pathway in Hypophysoma.
Neuroblastoma
Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.
sphingoid base n-stearoyltransferase deficiency
Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency.
sphingoid base n-stearoyltransferase deficiency
Progressive Myoclonic Epilepsy Type 8 Due to CERS1 Deficiency: A Novel Mutation with Prominent Ataxia.
Squamous Cell Carcinoma of Head and Neck
Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis.
Squamous Cell Carcinoma of Head and Neck
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
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the enzyme kinetics are not exactly conform with Michaelis-Menten kinetics, the curve is hyperbolic or the activity of stearoyl-CoA : sphingosine stearoyltransferase in the liver preparation increases in a somewhat sigmoidal fashion with increasing lignoceroyl-CoA concentration up to about 0.004 mM
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.5
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
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
brenda
additional information
Lass1 is detected in brain and just weakly in muscle, indicating that expression is mostly brain-specific
brenda
additional information
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Lass1 is detected in brain and just weakly in muscle, indicating that expression is mostly brain-specific
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
Lag1 (longevity assurance gene 1) homologues, a family of transmembrane proteins found in all eukaryotes, is necessary for (dihydro)ceramide synthesis. All Lag1 homologues contain a highly conserved stretch of 52 amino acids known as the Lag1p motif, sequence comparisons, analysis of functional significance of the conserved Lag1p motif for (dihydro)ceramide synthesis, overview. The Lag1p motif is essential for the enzyme activity of all Lag1 homologues
evolution
Lass proteins are known to contain a TLC [TRAM/Lag1p/CLN8 (ceroid-lipofuscinoses, neuronal 8)] homology domain with the Lag1 motif. Lass family members Lass2, Lass4 and Lass5, but not Lass1, also contain a HOX (homeobox) domain
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
malfunction
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enzyme deletion, and the consequent reduction of C18:0 acyl-chain ceramide specifically in skeletal muscle, enhances whole-body glucose metabolism in obesity through increased muscle-derived circulating Fgf21 protein concentrations. Enzyme deficiency protects from insulin resistance
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
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
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
metabolism
the N-(stearoyl)-sphinganine produced by the enzyme most significantly impacts neutral glycosphingolipid synthesis
physiological function
C18 ceramide synthesized by CERS1 is implicated in apoptosis and lethal autophagy
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
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
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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
additional information
the N-terminus is essential for catalytic activity
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