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Information on EC 2.3.1.298 - ultra-long-chain ceramide synthase and Organism(s) Homo sapiens and UniProt Accession Q8IU89
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2.3.1.298 ultra-long-chain ceramide synthaseIUBMB Comments
Mammals have six ceramide synthases that exhibit relatively strict specificity regarding the chain-length of their acyl-CoA substrates. Ceramide synthase 3 (CERS3) is the only enzyme that is active with ultra-long-chain acyl-CoA donors (C28 or longer). It is active in the epidermis, where its products are incorporated into acylceramides. CERS3 also accepts (2R)-2-hydroxy fatty acids and omega-hydroxy fatty acids, and can accept very-long-chain acyl-CoA substrates (see EC 2.3.1.297, very-long-chain ceramide synthase). It can use multiple sphingoid bases including sphinganine, sphingosine, phytosphingosine, and (6R)-6-hydroxysphingosine.
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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
Reaction Schemes
an ultra-long-chain fatty acyl-CoA
+
=
an ultra-long-chain ceramide
+
Synonyms
(dihydro)ceramide synthase, ceramide synthase, ceramide synthase 3, CerS3, LASS3, LASS3-long, longevity assurance homologue 3, mammalian ceramide synthase 3, phytoceramide synthase, sphingoid base N-ultra-long-chain fatty acyl-coA transferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CerS3
mammalian ceramide synthase 3
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-
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sphingoid base N-ultra-long-chain fatty acyl-coA transferase
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CerS3
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SYSTEMATIC NAME
IUBMB Comments
ultra-long-chain fatty acyl-coA:sphingoid base N-acyltransferase
Mammals have six ceramide synthases that exhibit relatively strict specificity regarding the chain-length of their acyl-CoA substrates. Ceramide synthase 3 (CERS3) is the only enzyme that is active with ultra-long-chain acyl-CoA donors (C28 or longer). It is active in the epidermis, where its products are incorporated into acylceramides. CERS3 also accepts (2R)-2-hydroxy fatty acids and omega-hydroxy fatty acids, and can accept very-long-chain acyl-CoA substrates (see EC 2.3.1.297, very-long-chain ceramide synthase). It can use multiple sphingoid bases including sphinganine, sphingosine, phytosphingosine, and (6R)-6-hydroxysphingosine.
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
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
the enzyme exhibits a broad acyl chain preference synthesizing C26-C32 acyl chain ceramides
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-
?
sphingosine + 2-hydroxybehenoyl-CoA
N-2-hydroxybehenoylsphingosine + CoA
-
-
-
?
sphingosine + 2-hydroxyeicosanoyl-CoA
N-2-hydroxyeicosanoylsphingosine + CoA
-
-
-
?
sphingosine + 2-hydroxylignoceroyl-CoA
N-2-hydroxylignoceroylsphingosine + CoA
-
-
-
?
sphingosine + 2-hydroxypalmitoyl-CoA
N-2-hydroxypalmitoylsphingosine + CoA
-
-
-
?
sphingosine + 2-hydroxystearoyl-CoA
N-2-hydroxystearoylsphingosine + CoA
-
-
-
?
behenoyl-CoA + dihydrosphingosine
CoA + N-behenoyldihydrosphingosine
-
-
-
?
lignoceroyl-CoA + dihydrosphingosine
CoA + N-lignoceroyldihydrosphingosine
highest activity
-
-
?
montanoyl-CoA + sphingosine
montanoyl ceramide + CoA
-
bona fide substrate
-
-
?
stearoyl-CoA + dihydrosphingosine
CoA + N-stearoyldihydrosphingosine
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
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-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
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C26-C36
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-
?
additional information
?
-
CERS3 transfers much longer chain fatty acids (C26, C28), forming highly hydrophobic ceramides that are a very important part of the water barrier function of skin
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-
?
additional information
?
-
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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isozyme CerS3 exhibits broad substrate specificity toward medium- to long-chain fatty acyl-CoAs (short-chain having less than C18, medium-chain with C18-C22, and long-chain with more than C22). In HEK-293T cells overproducing both CerS3 and 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase (FA2H), no 2-hydroxy-C16:0-ceramide is detected, but both medium- and long-chain 2-hydroxy-ceramides. CerS3 may use both medium- and long-chain 2-hydroxy-fatty acyl-CoAs as substrates
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-
?
additional information
?
-
isozyme CerS3 exhibits broad substrate specificity toward medium- to long-chain fatty acyl-CoAs (short-chain having less than C18, medium-chain with C18-C22, and long-chain with more than C22). In HEK-293T cells overproducing both CerS3 and 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase (FA2H), no 2-hydroxy-C16:0-ceramide is detected, but both medium- and long-chain 2-hydroxy-ceramides. CerS3 may use both medium- and long-chain 2-hydroxy-fatty acyl-CoAs as substrates
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-
?
additional information
?
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the enzyme also uses long-chain and very-long-chain fatty acyl-CoAs as substrate
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-
?
additional information
?
-
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the enzyme can also use both medium- and long-chain 2-hydroxy-fatty acyl-CoAs as substrates
-
-
?
additional information
?
-
the enzyme can also use both medium- and long-chain 2-hydroxy-fatty acyl-CoAs as substrates
-
-
?
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
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
the enzyme exhibits a broad acyl chain preference synthesizing C26-C32 acyl chain ceramides
-
-
?
additional information
?
-
CERS3 transfers much longer chain fatty acids (C26, C28), forming highly hydrophobic ceramides that are a very important part of the water barrier function of skin
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
-
-
-
?
an ultra-long-chain fatty acyl-CoA + a sphingoid base
an ultra-long-chain ceramide + CoA
-
C26-C36
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-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
epidermal, expression analysis of the CerS family members during keratinocyte differentiation, overview. Upon differentiation, CerS3 mRNA expression significantly increases and remains high throughout differentiation
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
profiles of non-hydroxylated and 2-hydroxy-ceramides in transgenic HeLa cells expressing different CerS isozymes and or different specific interfence RNAs, overview
physiological function
malfunction
-
enzyme knockdown causes a reduction in the elongase activities toward ultra-long-chain acyl-CoAs
metabolism
-
the enzyme positively regulates very-long chain and ultra-long-chain fatty acid synthesis in keratinocytes. The enzyme regulates activities of ELOVL1 and ELOVL4 in differentiated keratinocytes
physiological function
-
the enzyme is essential for spermatogenesis and fertility
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
isozyme CerS3 may be important in ceramide and 2-hydroxy-ceramide synthesis in epidermis. 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
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). CERS3_HUMAN
383
5
46316
Swiss-Prot
Secretory Pathway (Reliability: 4)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
phosphorylation mildly increases the catalytic activity of the enzyme by 28%
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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
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 CERS3, recombinant expression in HEK-293T cells, quantitative real-time quantitative PCR enzyme expression analysis
expressed in HEK-293T cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme mRNA expression significantly increases and remains high throughout keratinocyte differentiation
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Holmes, R.S.; Barron, K.A.; Krupenko, N.I.
Ceramide synthase 6 comparative analysis, phylogeny and evolution
Biomolecules
8
111
2018
Danio rerio (A0A140LFW4), Gallus gallus (F1N8P2), Homo sapiens (Q8IU89), Mus musculus (Q1A3B0)
Jennemann, R.; Rabionet, M.; Gorgas, K.; Epstein, S.; Dalpke, A.; Rothermel, U.; Bayerle, A.; van der Hoeven, F.; Imgrund, S.; Kirsch, J.; Nickel, W.; Willecke, K.; Riezman, H.; Groene, H.J.; Sandhoff, R.
Loss of ceramide synthase 3 causes lethal skin barrier disruption
Hum. Mol. Genet.
21
586-608
2012
Homo sapiens, Mus musculus
Sassa, T.; Hirayama, T.; Kihara, A.
Enzyme activities of the ceramide synthases CERS2-6 are regulated by phosphorylation in the C-terminal region
J. Biol. Chem.
291
7477-7487
2016
Homo sapiens
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, Homo sapiens (Q8IU89)
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 (Q8IU89)
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