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Information on EC 2.3.1.297 - very-long-chain ceramide synthase
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2.3.1.297 very-long-chain ceramide synthaseIUBMB Comments
This entry describes ceramide synthase enzymes that are specific for very-long-chain fatty acyl-CoA substrates. The two isoforms from yeast and the plant LOH1 and LOH3 isoforms transfer 24:0 and 26:0 acyl chains preferentially and use phytosphingosine as the preferred sphingoid base. The mammalian CERS2 isoform is specific for acyl donors of 20-26 carbons, which can be saturated or unsaturated. The mammalian CERS3 isoform catalyses this activity, but has a broader substrate range and also catalyses the activity of EC 2.3.1.298, ultra-long-chain ceramide synthase. Both mammalian enzymes can use multiple sphingoid bases, including sphinganine, sphingosine, and phytosphingosine.
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Word Map
- 2.3.1.297
- sphingolipids
- sphingomyelins
- dihydroceramide
-
cers1-6
- elovl1
- pnpla1
- cyp4f22
- alox12b
-
sdr9c7
-
nipal4
-
abca12
-
cerss
- aloxe3
- diagnostics
The enzyme appears in viruses and cellular organisms
Reaction Schemes
a very-long-chain fatty acyl-CoA
+
=
a very-long-chain ceramide
+
Synonyms
cers2, lass2, cers3, ceramide synthase 2, ceramide synthase 3, lass4, lass3, longevity assurance homologue 2, lag13, lag11, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
acyl-CoA : sphingosine N-acyltramferase
acyl-CoA ceramide synthase
ceramide synthase
ceramide synthase 2
ceramide synthase 4
ceramide synthase complex
CerS2
CerS3
CerS4
LAC1
-
-
-
-
Lac1p/Lag1p
LAG1
-
-
-
-
Lass2
LASS3
Lass4
LOH1
LOH3
mammalian ceramide synthase 2
-
-
-
-
sphingoid base N-very-long-chain fatty acyl-coA transferase
-
-
-
-
additional information
ceramide synthase 2
-
CerS3
-
-
-
-
LASS3
-
-
-
-
LOH1
-
-
-
-
LOH3
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a very-long-chain fatty acyl-CoA + a sphingoid base = a very-long-chain ceramide + CoA
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
very-long-chain fatty acyl-coA:sphingoid base N-acyltransferase
This entry describes ceramide synthase enzymes that are specific for very-long-chain fatty acyl-CoA substrates. The two isoforms from yeast and the plant LOH1 and LOH3 isoforms transfer 24:0 and 26:0 acyl chains preferentially and use phytosphingosine as the preferred sphingoid base. The mammalian CERS2 isoform is specific for acyl donors of 20-26 carbons, which can be saturated or unsaturated. The mammalian CERS3 isoform catalyses this activity, but has a broader substrate range and also catalyses the activity of EC 2.3.1.298, ultra-long-chain ceramide synthase. Both mammalian enzymes 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
a very-long-chain fatty acyl-CoA + sphinganine
a very-long-chain sphinganine + CoA
-
-
-
-
?
acyl-CoA + sphinganine
N-acylsphinganine + CoA
very low activity with sphinganine
-
-
?
behenoyl-CoA + dihydrosphingosine
CoA + N-behenoyldihydrosphingosine
-
-
-
?
dihydrosphingosine + palmitoyl-CoA
N-palmitoyldihydrosphingosine + CoA
low activity
-
-
?
dihydrosphingosine + stearoyl-CoA
N-stearoyldihydrosphingosine + CoA
low activity
-
-
?
hexacosanoyl-CoA + phytosphingosine
CoA + N-hexacosanoylphytosphingosine
-
-
-
?
hexacosenoyl-CoA + a sphingoid base
hexacosenoyl ceramide + CoA
-
-
-
-
?
nervonyl-CoA + a sphingoid base
nervonyl ceramide + CoA
-
-
-
-
?
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 + arachidoyl-CoA
N-arachidoylsphingosine + CoA
low activity
-
-
?
sphingosine + eicosanoyl-CoA
N-eicosanoylsphingosine + CoA
-
-
-
?
sphingosine + hexacosanoyl-CoA
N-hexacosanoylsphingosine + CoA
low activity
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
-
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
-
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
the enzyme synthesizes ceramides with very-long (C22-C24) acyl chains
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
Saccharomyces cerevisiae RH4838
-
-
-
?
D-erythro-sphinganine + behenoyl-CoA
N-behenoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + behenoyl-CoA
N-behenoyl-D-sphinganine + CoA
preferred substrate
-
-
?
D-erythro-sphinganine + behenoyl-CoA
N-behenoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
Saccharomyces cerevisiae RH4838
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
preferred substrate
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + nervonoyl-CoA
N-nervonoyl-D-sphinganine + CoA
-
-
-
?
dihydrosphingosine + lignoceroyl-CoA
N-lignoceroyldihydrosphingosine + CoA
-
-
-
?
dihydrosphingosine + lignoceroyl-CoA
N-lignoceroyldihydrosphingosine + CoA
low activity
-
-
?
dihydrosphingosine + nervonoyl-CoA
N-nervonoyldihydrosphingosine + CoA
-
-
-
?
dihydrosphingosine + nervonoyl-CoA
N-nervonoyldihydrosphingosine + CoA
highly preferred substrate
-
-
?
DL-erythro-sphingosine + nervonoyl-CoA
N-nervonoylsphingosine + CoA
-
both the threo and erythro isomers are active as acceptors, the latter is preferred
-
-
?
DL-erythro-sphingosine + nervonoyl-CoA
N-nervonoylsphingosine + CoA
-
both the threo and erythro isomers are active as acceptors, the latter is preferred
-
-
?
DL-threo-sphingosine + nervonoyl-CoA
N-nervonoylsphingosine + CoA
-
both the threo and erythro isomers are active as acceptors, the latter is preferred
-
-
?
DL-threo-sphingosine + nervonoyl-CoA
N-nervonoylsphingosine + CoA
-
both the threo and erythro isomers are active as acceptors, the latter is preferred
-
-
?
lignoceroyl-CoA + phytosphingosine
N-lignoceroylphytosphinganine + CoA
-
-
-
?
lignoceroyl-CoA + phytosphingosine
N-lignoceroylphytosphinganine + CoA
high activity
-
-
?
nervonoyl-CoA + NBD-sphinganine
CoA + N-nervonoyl-NBD-sphinganine
C24:1-CoA substrate and NBD-labeled sphinganine substrate, i.e. omega(7-nitro-2-1,3-benzoxadiazole-4-yl)(2S,3R)-2-aminooctadecane-1,3-diol
-
-
?
nervonoyl-CoA + NBD-sphinganine
CoA + N-nervonoyl-NBD-sphinganine
C24:1-CoA substrate and NBD-labeled sphinganine substrate, i.e. omega(7-nitro-2-1,3-benzoxadiazole-4-yl)(2S,3R)-2-aminooctadecane-1,3-diol
-
-
?
sphinganine + arachidoyl-CoA
N-arachidoylsphinganine + CoA
low activity
-
-
?
sphinganine + behenoyl-CoA
N-behenoylsphinganine + CoA
moderate activity
-
-
?
sphinganine + cerotoyl-CoA
N-cerotoylsphinganine + CoA
low activity
-
-
?
sphinganine + cerotoyl-CoA
N-cerotoylsphinganine + CoA
low activity
-
-
?
sphinganine + lignoceroyl-CoA
N-lignoceroylsphinganine + CoA
-
-
-
?
sphinganine + lignoceroyl-CoA
N-lignoceroylsphinganine + CoA
high activity
-
-
?
sphinganine + palmitoyl-CoA
N-palmitoylsphinganine + CoA
low activity
-
-
?
sphinganine + stearoyl-CoA
N-stearoylsphinganine + CoA
preferred substrate
-
-
?
sphingosine + lignoceroyl-CoA
N-lignoceroylsphingosine + CoA
-
-
-
?
sphingosine + lignoceroyl-CoA
N-lignoceroylsphingosine + CoA
-
-
-
?
sphingosine + stearoyl-CoA
N-stearoylsphingosine + CoA
low activity
-
-
?
additional information
?
-
specificity of three different isoforms of ceramide synthase, denoted LOH1, 2 and 3, for a range of long-chain base (LCB) and acyl-CoA substrates. The contribution of each of these isoforms to the synthesis of ceramide is investigated by in vitro ceramide synthase assays, overview. The plant LCB phytosphingosine is efficiently used by the LOH1 and 3 isoforms, with LOH1 having the lowest Km for the LCB substrate of the three isoforms. In contrast, sphinganine is used efficiently only by the LOH2 isoform. Acyl-CoA specificity is also distinguished between the three isoforms with LOH2 being almost completely specific for palmitoyl-CoA, while the LOH1 isoform shows greatest activity with lignoceroyl- and hexacosanoyl-CoA. Unsaturated acyl-CoAs are not used efficiently by any isoform while unsaturated LCB substrates are preferred by LOH2 and 3. LOH3 has at least twice as much activity with t18:1 substrates as LOH1. Both LOH1 and LOH3 demonstrate a strong preference for very long chain acyl-CoAs (>C18) although LOH1 has the greatest activity toward 24 and 26 carbon acyl-CoAs, while LOH3 shows little preference for acyl-CoAs between 20 and 26 carbons in length
-
-
?
additional information
?
-
specificity of three different isoforms of ceramide synthase, denoted LOH1, 2 and 3, for a range of long-chain base (LCB) and acyl-CoA substrates. The contribution of each of these isoforms to the synthesis of ceramide is investigated by in vitro ceramide synthase assays, overview. The plant LCB phytosphingosine is efficiently used by the LOH1 and 3 isoforms, with LOH1 having the lowest Km for the LCB substrate of the three isoforms. In contrast, sphinganine is used efficiently only by the LOH2 isoform. Acyl-CoA specificity is also distinguished between the three isoforms with LOH2 being almost completely specific for palmitoyl-CoA, while the LOH1 isoform shows greatest activity with lignoceroyl- and hexacosanoyl-CoA. Unsaturated acyl-CoAs are not used efficiently by any isoform while unsaturated LCB substrates are preferred by LOH2 and 3. LOH3 has at least twice as much activity with t18:1 substrates as LOH1. Both LOH1 and LOH3 demonstrate a strong preference for very long chain acyl-CoAs (>C18) although LOH1 has the greatest activity toward 24 and 26 carbon acyl-CoAs, while LOH3 shows little preference for acyl-CoAs between 20 and 26 carbons in length
-
-
?
additional information
?
-
CERS2 preferentially transfers very long chain fatty acids (C22-C26)
-
-
?
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
-
-
?
additional information
?
-
CERS2 preferentially transfers very long chain fatty acids (C22:0-C26:0) to dihydrosphingosine. 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
-
-
?
additional information
?
-
substrate specificity, overview. Long-chain preference of CerS2
-
-
?
additional information
?
-
substrate specificity, overview. Long-chain preference of CerS2
-
-
?
additional information
?
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
additional information
?
-
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
additional information
?
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass2 produces longer ceramides such as C22:0 ceramides and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass2 produces longer ceramides such as C22:0 ceramides and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass2 produces longer ceramides such as C22:0 ceramides and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass4 produces longer ceramides such as C22:0 and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass4 produces longer ceramides such as C22:0 and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
-
both C22:0- and C24:0-CoAs are used effectively for Lass2- and Lass4-dependent ceramide synthesis, and C26:0-, C20:0-, and C18:0-CoAs also act as substrates, albeit weakly. Recombinant Lass4 produces longer ceramides such as C22:0 and C24:0 ceramides in transgenic HEK-293T cells
-
-
?
additional information
?
-
CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24
-
-
?
additional information
?
-
-
CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24
-
-
?
additional information
?
-
CerS2 has a remarkable acyl-CoA specificity, it uses a wider range of acyl-CoAs, synthesizing ceramides containing C20:0, C22:0, C24:1, C24:0, C26:1, and C26:0 fatty acids, but does not synthesize ceramides containing C16:0 fatty acids and synthesizes only low, and statistically insignificant levels of C18:0-ceramide, overview
-
-
?
additional information
?
-
enzyme LASS3 shows a relatively broad substrate specificity. Both LASS3 isoforms increase the production of several ceramide species, including C18:0- and C24:0-ceramides. LASS3 exhibits relatively low substrate specificity toward fatty acyl-CoAs. Lysates prepared from LASS3-overproducing cells show significant activity toward several fatty acyl-CoAs, including C18:0-, C22:0-, and C24:0-CoA, with the highest activity for C18:0. C16:0-, C20:0-, and C26:0-CoA are also used as substrates by LASS3, albeit with low activity. LASS3-overproducing cells synthesize ceramide from C18:0-CoA with the highest activity at all concentrations tested. This in vitro result is quite consistent with the in vivo results
-
-
?
additional information
?
-
-
enzyme LASS3 shows a relatively broad substrate specificity. Both LASS3 isoforms increase the production of several ceramide species, including C18:0- and C24:0-ceramides. LASS3 exhibits relatively low substrate specificity toward fatty acyl-CoAs. Lysates prepared from LASS3-overproducing cells show significant activity toward several fatty acyl-CoAs, including C18:0-, C22:0-, and C24:0-CoA, with the highest activity for C18:0. C16:0-, C20:0-, and C26:0-CoA are also used as substrates by LASS3, albeit with low activity. LASS3-overproducing cells synthesize ceramide from C18:0-CoA with the highest activity at all concentrations tested. This in vitro result is quite consistent with the in vivo results
-
-
?
additional information
?
-
CerS2 has a remarkable acyl-CoA specificity, it uses a wider range of acyl-CoAs, synthesizing ceramides containing C20:0, C22:0, C24:1, C24:0, C26:1, and C26:0 fatty acids, but does not synthesize ceramides containing C16:0 fatty acids and synthesizes only low, and statistically insignificant levels of C18:0-ceramide, overview
-
-
?
additional information
?
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
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
a very-long-chain fatty acyl-CoA + sphinganine
a very-long-chain sphinganine + CoA
-
-
-
-
?
behenoyl-CoA + dihydrosphingosine
CoA + N-behenoyldihydrosphingosine
-
-
-
?
dihydrosphingosine + lignoceroyl-CoA
N-lignoceroyldihydrosphingosine + CoA
-
-
-
?
dihydrosphingosine + nervonoyl-CoA
N-nervonoyldihydrosphingosine + CoA
-
-
-
?
hexacosanoyl-CoA + phytosphingosine
CoA + N-hexacosanoylphytosphingosine
-
-
-
?
lignoceroyl-CoA + phytosphingosine
N-lignoceroylphytosphinganine + CoA
-
-
-
?
sphingosine + eicosanoyl-CoA
N-eicosanoylsphingosine + CoA
-
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
-
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
-
-
-
?
a very-long-chain fatty acyl-CoA + a sphingoid base
a very-long-chain ceramide + CoA
-
the enzyme synthesizes ceramides with very-long (C22-C24) acyl chains
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + arachidoyl-CoA
N-arachidoyl-D-sphinganine + CoA
Saccharomyces cerevisiae RH4838
-
-
-
?
D-erythro-sphinganine + behenoyl-CoA
N-behenoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + behenoyl-CoA
N-behenoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + cerotoyl-CoA
N-cerotoyl-D-sphinganine + CoA
Saccharomyces cerevisiae RH4838
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + lignoceroyl-CoA
N-lignoceroyl-D-sphinganine + CoA
-
-
-
-
?
D-erythro-sphinganine + nervonoyl-CoA
N-nervonoyl-D-sphinganine + CoA
-
-
-
?
sphinganine + cerotoyl-CoA
N-cerotoylsphinganine + CoA
low activity
-
-
?
sphinganine + lignoceroyl-CoA
N-lignoceroylsphinganine + CoA
-
-
-
?
sphingosine + lignoceroyl-CoA
N-lignoceroylsphingosine + CoA
-
-
-
?
additional information
?
-
CERS2 preferentially transfers very long chain fatty acids (C22-C26)
-
-
?
additional information
?
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
additional information
?
-
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
additional information
?
-
ceramide synthase 2 catalyzes the synthesis of dihydroceramides from dihydrosphingosine and very long fatty acyl (C22-C24)-CoAs
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
additional information
Mg2+
-
no absolute requirement for metal ions, magnesium ions stimulate the reaction
Mg2+
-
no absolute requirement for metal ions, magnesium ions stimulate the reaction
additional information
LOH1 is inhibited by most or all divalent cations tested
additional information
LOH1 is inhibited by most or all divalent cations tested
additional information
LOH3 is inhibited by most or all divalent cations tested
additional information
LOH3 is inhibited by most or all divalent cations tested
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 itself and not FTY720-P, is responsible for CerS2 inhibition. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs. 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. Inhibition of CerS2 by FTY720 does not occur via a nonspecific mechanism
FTY720
-
FTY720 is an effective immunomodulatory molecule and is a competitive inhibitor of ceramide synthase 2 toward dihydrosphingosine, it shows interference with sphingolipid de novo biosynthesis, overview. The inhibition of CerS2 activity is reversible as the potency of inhibition diminishes with the dilution of the enzyme-inhibitor preparation
fumonisin B1
mixed mode of inhibition with respect to the laong-chain base; mixed mode of inhibition with respect to the long-chain base
fumonisin B1
inhibits the increase in total cellular ceramide induced by UV-C irradiation
fumonisin B1
-
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
sphingosine 1-phosphate
significantly inhibits CerS2, CerS2 contains a sphingosine 1-phosphate receptor-like motif via which sphingosine 1-phosphate inhibits CerS2 activity
sphingosine 1-phosphate
S1P, noncompetitive inhibition. Bioactive sphingolipid sphingosine 1-phosphate has a regulatory function for CerS2. Residues Arg230 and Arg325 are essential for S1P binding to the S1P1 receptor. Mutation of both residues to alanine completely abolishes the inhibitory effect of S1P on CerS2 without affecting the basal activity of CerS2. Thus, S1P can regulate CerS2 activity via a direct interaction with an S1P receptor-like motif found uniquely in CerS2
additional information
LOH1 is inhibited by most or all divalent cations tested; LOH3 is inhibited by most or all divalent cations tested
-
additional information
LOH1 is inhibited by most or all divalent cations tested; LOH3 is inhibited by most or all divalent cations tested
-
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. Lysophosphatidic acid does not inhibit CerS2. Dimethylsphingosine has no effect on CerS2 activity
-
additional information
-
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
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
acyl-coenzyme A-binding protein
-
increases the activity of ceramide synthase 2 by more than 2fold. The compound binds very-long chain acyl-CoA esters, which is required for its ability to stimulate enzyme activity
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0032
D-erythro-sphinganine
pH 7.5, 37°C, recombinant enzyme, in presence of inhibitor sphingosine 1-phosphate
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
nonlinear fitting and Michaelis-Menten kinetic analyses
-
additional information
additional information
-
the enzyme kinetics are not exactly conform with Michaelis-Menten kinetics, the curve is hyperbolic or the activity of lignoceroyl-CoA : sphingosine lignoceroyltransferase in the liver preparation increases in a somewhat sigmoidal fashion with increasing lignoceroyl-CoA concentration up to about 0.004 mM
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0000006 - 0.0000535
pH 7.4, 37°C, enzyme activity in mouse tissues, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.5
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5 - 8.2
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
encoding subunits Lac1p, Lag1p, and Lip1p
UniProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
isozymes CerS2 (EC 2.3.1.297) and CerS6 (EC 2.3.1.24) mRNA is significantly elevated in breast cancer tissue compared to normal tissue, with approximately half of the individuals showing elevated CerS2 and CerS6 mRNA. A significant correlation is found between CerS2 and CerS6 isozyme expression, and between isozymes CerS4 (EC 2.3.1.24) and CerS2/CerS6 expression
CerS2 and CerS6 are the major very long-chain and long-chain CerS isoforms in MCF-7 cells, respectively
additional information
epidermal, expression analysis of the CerS family members during keratinocyte differentiation, overview. A slight increase in CerS4 mRNA is observed at the late stage of differentiation
epidermal, expression analysis of the CerS family members during keratinocyte differentiation, overview. Expression of CerS2 mRNA remains nearly unchanged during differentiation
additional information
cell-type-specific expression pattern of CerS2 protein, immunohistochemic analysis
additional information
-
cell-type-specific expression pattern of CerS2 protein, immunohistochemic analysis
additional information
CerS2 tissue expression analysis, comparisons with the other CerS isozymes (CerS1, 3, 4-6). CerS2 mRNA is widely distributed and found at high levels in various tissues
additional information
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass2 shows the highest expression in liver, but also high expression in kidney
additional information
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass2 shows the highest expression in liver, but also high expression in kidney
additional information
-
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass2 shows the highest expression in liver, but also high expression in kidney
additional information
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass4 is strongly expressed in skin, with no apparent expression in muscle, testis, or thymus
additional information
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass4 is strongly expressed in skin, with no apparent expression in muscle, testis, or thymus
additional information
-
isozymes mRNAs for Lass2, Lass4, Lass5 and Lass6 are found to be mostly ubiquitous, although no expression is detected in muscle for any of these. Lass4 is strongly expressed in skin, with no apparent expression in muscle, testis, or thymus
additional information
-
CerS2 tissue expression analysis, comparisons with the other CerS isozymes (CerS1, 3, 4-6). CerS2 mRNA is widely distributed and found at high levels in various tissues
-
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Lac1p and Lag1p are integral membrane proteins with six to eight predicted transmembrane domains. Co-subunit Lip1 is also an integral membrane protein, with one transmembrane domain. Its short N-terminal part is cytoplasmic and not required for ceramide synthesis. Analysis of membrane topology of the heterotrimer for ceramide synthase catalytic activity, overview
transmembrane topology of topology of the Lag1p and Lac1p subunits in yeast using insertion of glycosylation sites and factor Xa-cleavage sites in the loops between the predicted transmembrane segments, method, overview. The N- and C-termini of the proteins are in the cytoplasm and eight putative membrane-spanning domains are identified in Lag1p and Lac1p. The conserved Lag motif, potentially containing the active site, is most likely embedded in the membrane
Saccharomyces cerevisiae RH382
-
transmembrane topology of topology of the Lag1p and Lac1p subunits in yeast using insertion of glycosylation sites and factor Xa-cleavage sites in the loops between the predicted transmembrane segments, method, overview. The N- and C-termini of the proteins are in the cytoplasm and eight putative membrane-spanning domains are identified in Lag1p and Lac1p. The conserved Lag motif, potentially containing the active site, is most likely embedded in the membrane
-
Saccharomyces cerevisiae RH4838
-
Lac1p and Lag1p are integral membrane proteins with six to eight predicted transmembrane domains. Co-subunit Lip1 is also an integral membrane protein, with one transmembrane domain. Its short N-terminal part is cytoplasmic and not required for ceramide synthesis. Analysis of membrane topology of the heterotrimer for ceramide synthase catalytic activity, overview
-
liver microsomal membranes from CerS2 null mice display higher membrane fluidity and show morphological changes. Membrane morphology is studied by fluorescence microscopy, overview
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
metabolism
physiological function
additional information
malfunction
CerS2-deficient (gene trap) mice exhibit myelin and behavioral abnormalities
malfunction
CerS2 null mouse show ceramide and downstream sphingolipids devoid of very long (C22-C24) acyl chains, consistent with the substrate specificity of CerS2 toward acyl-CoAs. C16-ceramide levels are elevated, and as a result, total ceramide levels are unaltered. C16-ceramide synthesis in vitro is not increased. Levels of C22-, C24:0-, and C24:1-sphingolipids are reduced by 10-100fold in the CerS2 null mouse, but no significant reduction is seen in C20-sphingolipids. Levels of C26:1- and C26:0-sphingolipids are relatively low in the wild-type, and only a small reduction is observed in the CerS2 null mouse. Levels of sphinganine are significantly elevated by up to 50fold, reminiscent of the effect of the ceramide synthase inhibitor fumonisin B1. With the exceptions of glucosylceramide synthase and neutral sphingomyelinase 2, none of the other enzymes tested in either the sphingolipid biosynthetic or degradative pathways are significantly changed. Total glycerophospholipid and cholesterol levels are unaltered, although there is a marked elevation in C18:1 and C18:2 fatty acids in phosphatidylethanolamine, concomitant with a reduction in C18:0 and C20:4 fatty acids. Liver microsomal membranes from CerS2 null mice display higher membrane fluidity and show morphological changes. Expression of CerS5 is increased in the Cers2 mutants, and of CerS6 slightly. Mutant phenotype, overview
malfunction
in HeLa cells overproducing the fatty acid 2-hydroxylase FA2H, knockdown of CerS2 results in a reduction in total long-chain 2-hydroxy-ceramides, confirming enzyme substrate specificity for chain length. Profiles of non-hydroxylated and 2-hydroxy-ceramides in transgenic HeLa cells expressing different CerS isozymes and or different specific interfence RNAs, overview
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. Knockdown of CerS2 in untreated cells reduces very long-chain Cer and increases long-chain Cer both in untreated and UV-C-treated cells. 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
Lass4 overproduction caused increases in both middle- and long-chain ceramides
malfunction
overexpression of CerS2 results in partial protection from IR-induced apoptosis. Knockdown studies determines that CerS2 is responsible for all observable IR-induced C24:0 CerS activity. CerS2 and CerS5 overexpression significantly alters apoptosis
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
-
about 50% of enzyme-null mice develop pheochromocytoma by about 13 months, and the rest shows signs of medullary hyperplasia
malfunction
-
ceramide synthase 2 null mice are more susceptible to dextran sodium sulfate-induced colitis, and their survival rate is markedly decreased compared with that of wild type littermates. In the colon of enzyme-deficient mice, the expression of junctional adhesion molecule-A is markedly decreased and the phosphorylation of myosin light chain 2 is increased. Enzyme deficiency influences intestinal barrier function and the severity of experimental colitis
malfunction
-
disruption of the enzyme enhances plant sensitivity to dark submergence, but displays more resistance to submergence under light than wild type
malfunction
-
enzyme inhibition leads to altered root development and auxin transport
malfunction
-
enzyme-deficient mice show increased susceptibility to LCMV infection. Reduced levels of invariant natural killer T cells in the thymus of enzyme-null mice is due to their impaired maturation in the thymus
malfunction
-
CerS2-deficient (gene trap) mice exhibit myelin and behavioral abnormalities
-
metabolism
regulation of CerS isozymes, overview. The interplay among the CerS proteins takes place in a stress stimulus-, cell type-, and subcellular compartment-specific manner. CerS2 and CerS5 overexpression significantly alters apoptosis. Determination of ionizing radiation-induced mitochondrial ceramide elevations via CerS2, 5, and 6, overview. CerS2 and CerS5 overexpressions defines opposing roles in radiation-induced mitochondrial apoptosis
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
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
critical role for ceramide synthase 2 in liver homeostasis, molecular changes leading to hepatopathy, overview. Isozyme CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24. In addition, CerS2 displays complex modes of regulation and has genomic features characteristic of a housekeeping gene, no other CerS genes display these characteristics
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
distinct roles and modes of regulation for each of the ceramide synthases in Arabidopsis thaliana sphingolipid metabolism. Ceramides are organizing components of sphingolipids in the eukaryotic cell. Three ceramide synthase isoforms are found in Arabidopsis thaliana each with specific substrate preferences and sensitivity to inhibitors and activators, overview. Isozymes LOH1 and LOH3 are responsible for the synthesis of ceramides with trihydroxy long-chain bases and very long chain fatty acids (VLCFA)
physiological function
good correlation between CerS2 mRNA levels and levels of ceramide and sphingomyelin containing long acyl chains in tissues with CerS2 mRNA expression at high levels. The activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (S1P), via interaction of S1P with two residues that are part of an S1P receptor-like motif found only in CerS2
physiological function
Lag1p, Lac1p and Lip1p comprise the ceramide synthase. Lag1p and Lac1p are subunits of the acyl-CoA-dependent ceramide synthase. The other essential component of the ceramide synthase, Lip1p, which forms a heteromeric complex with Lac1p and Lag1p. Lip1p is required for ceramide synthesis in vivo and in vitro
physiological function
overproduction of LASS3 causes increased levels of C18:0-, C22:0-, and C24:0-ceramides
physiological function
proteins Lag1p, Lac1p, and Lip1p are required for ceramide synthase activity in Saccharomyces cerevisiae
physiological function
selective tissue and subcellular distribution of the six mammalian CerS isoforms, combined with distinct fatty acyl chain length substrate preferences, implicate differential functions of specific ceramide species in cellular signaling. Ionizing radiation (IR) induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating isozymes CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes. Isozyme CerS2 is responsible for all observable IR-induced C24:0 CerS activity. IR-induced CerS-mediated ceramide generation, and subsequent apoptosis, occurs in a cell-type specific manner. CerS2 and CerS5 overexpressions defines opposing roles in radiation-induced mitochondrial apoptosis
physiological function
sphingolipid ceramides are widely implicated in the regulation of programmed cell death or apoptosis. CerS2 regulates very long-chain Cer synthesis. CerS2 and CerS6 are the major very long-chain and long-chain CerS isoforms in MCF-7 cells, respectively
physiological function
very long chain ceramides synthesized by CERS2 are essential constituents of myelin. CERS2 demonstrates a preference for the monounsaturated C24:1 fatty acid substrate compared to the saturated C24:0 substrate, potentially explaining why myelin is enriched in ceramides containing the monounsaturated form of very long chain fatty acids
physiological function
-
the enzyme is essential for plant growth and development
physiological function
Saccharomyces cerevisiae RH4838
-
Lag1p, Lac1p and Lip1p comprise the ceramide synthase. Lag1p and Lac1p are subunits of the acyl-CoA-dependent ceramide synthase. The other essential component of the ceramide synthase, Lip1p, which forms a heteromeric complex with Lac1p and Lag1p. Lip1p is required for ceramide synthesis in vivo and in vitro
-
physiological function
-
good correlation between CerS2 mRNA levels and levels of ceramide and sphingomyelin containing long acyl chains in tissues with CerS2 mRNA expression at high levels. The activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (S1P), via interaction of S1P with two residues that are part of an S1P receptor-like motif found only in CerS2
-
physiological function
Saccharomyces cerevisiae RH382
-
proteins Lag1p, Lac1p, and Lip1p are required for ceramide synthase activity in Saccharomyces cerevisiae
-
additional information
chimeric mutant CerS5:TM:CerS2-HA displays slightly more activity using C16-CoA as substrate than CerS5, but remarkably, CerS2 activity measured using C22-CoA is elevated by 3fold. Isozymes CerS5 and CerS6 modulate CerS2 activity upon co-expression. This increase in CerS2 activity is abolished using a noncatalytically active form of CerS5 in the constitutive dimer (CerS5HH:TM:CerS2-HA), demonstrating that optimal CerS2 activity depends on an interaction with a catalytically active form of CerS5
additional information
the conserved Lag motif, potentially containing the active site, is most likely embedded in the membrane. Histidine and aspartic acid residues in the Lag motif are essential for the function of Lag1p in vivo
additional information
the N-terminus is essential for catalytic activity
additional information
the N-terminus is essential for catalytic activity
additional information
two transcriptional variants of mouse LASS3 cDNA encoding the LASS3 isoforms, which differ in transcriptional initiation sites and polypeptides length, LASS3 and LASS3-long
additional information
-
two transcriptional variants of mouse LASS3 cDNA encoding the LASS3 isoforms, which differ in transcriptional initiation sites and polypeptides length, LASS3 and LASS3-long
additional information
Saccharomyces cerevisiae RH382
-
the conserved Lag motif, potentially containing the active site, is most likely embedded in the membrane. Histidine and aspartic acid residues in the Lag motif are essential for the function of Lag1p in vivo
-
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). LAC1_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
418
7
48992
Swiss-Prot
other Location (Reliability: 4)
LAG1_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
411
7
48455
Swiss-Prot
other Location (Reliability: 4)
CERS2_BOVIN
380
5
44903
Swiss-Prot
Secretory Pathway (Reliability: 3)
CERS2_HUMAN
380
5
44876
Swiss-Prot
Secretory Pathway (Reliability: 2)
CERS2_MOUSE
380
6
45024
Swiss-Prot
Secretory Pathway (Reliability: 2)
CERS3_HUMAN
383
5
46316
Swiss-Prot
Secretory Pathway (Reliability: 4)
CERS3_MOUSE
383
5
46081
Swiss-Prot
other Location (Reliability: 5)
CERS4_MOUSE
393
6
46017
Swiss-Prot
Chloroplast (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37000
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
42000
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
dimer CerS activity can be modulated by dimer formation. CerS2 activity is enhanced by co-expression with a catalytically active form of CerS5 or CerS6. CerS dimers are formed rapidly upon stimulation of ceramide synthesis
heterotrimer
additional information
?
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
?
x * 46100, about, isozyme LASS3, sequence calculation, x * 50000, about, isozyme LASS3-long, sequence calculation
?
-
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
-
heterotrimer
subunits Lac1p, Lag1p, and Lip1p
additional information
Lag1p, Lac1p and Lip1p comprise the ceramide synthase. Lag1p/Lac1p interacting protein, 28 kDa, Lip1p is an essential component of the ceramide synthase, which forms a heteromeric complex with Lac1p and Lag1p. Lip1p is required for ceramide synthesis in vivo and in vitro. It is possible that Lip1p is modified by O-linked glycosylation. Its short, highly charged N-terminus is cytoplasmic and dispensible for ceramide synthase activity
additional information
Saccharomyces cerevisiae RH4838
-
Lag1p, Lac1p and Lip1p comprise the ceramide synthase. Lag1p/Lac1p interacting protein, 28 kDa, Lip1p is an essential component of the ceramide synthase, which forms a heteromeric complex with Lac1p and Lag1p. Lip1p is required for ceramide synthesis in vivo and in vitro. It is possible that Lip1p is modified by O-linked glycosylation. Its short, highly charged N-terminus is cytoplasmic and dispensible for ceramide synthase activity
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
glycoprotein
the N-glycosylation of Lass2 appears as three bands, deglycosylation of Lass2 with PNGase F (N-glycosidase F)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
complementation of the growth defect of DELTAlag1/DELTAlac1 yeast deletion mutant by recombinant GST-/FLAG-tagged LOH1. Upon isolation of a microsomal membrane fraction from yeast expressing the construct, LOH1 shows significant activity by an in vitro ceramide synthase assay
additional information
complementation of the growth defect of DELTAlag1/DELTAlac1 yeast deletion mutant by recombinant GST-/FLAG-tagged LOH1. Upon isolation of a microsomal membrane fraction from yeast expressing the construct, LOH1 shows significant activity by an in vitro ceramide synthase assay
additional information
complementation of the growth defect of DELTAlag1/DELTAlac1 yeast deletion mutant by recombinant GST-/FLAG-tagged LOH3. Upon isolation of a microsomal membrane fraction from yeast expressing the construct, LOH3 shows significant activity by an in vitro ceramide synthase assay
additional information
complementation of the growth defect of DELTAlag1/DELTAlac1 yeast deletion mutant by recombinant GST-/FLAG-tagged LOH3. Upon isolation of a microsomal membrane fraction from yeast expressing the construct, LOH3 shows significant activity by an in vitro ceramide synthase assay
additional information
cloning of a chimeric HA-tagged CerS5:CerS2 isozymes heterodimer, insertion of a transmembrane (TM) domain3 between the two monomers of the dimer (CerS5:TM:CerS5-HA). Chimeric mutant CerS5:TM:CerS2-HA displays slightly more activity using C16-CoA as substrate than CerS5, but remarkably, CerS2 activity measured using C22-CoA is elevated by 3fold. Isozymes CerS5 and CerS6 modulate CerS2 activity upon coexpression. This increase in CerS2 activity is abolished using a noncatalytically active form of CerS5 in the constitutive dimer (CerS5HH:TM:CerS2-HA), demonstrating that optimal CerS2 activity depends on an interaction with a catalytically active form of CerS5
additional information
in HeLa cells overproducing the fatty acid 2-hydroxylase FA2H, knockdown of CerS2 by siRNA results in a reduction in total long-chain 2-hydroxy-ceramides, confirming enzyme substrate specificity for chain length. 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
in HeLa cells overproducing the fatty acid 2-hydroxylase FA2H, knockdown of CerS2 by siRNA results in a reduction in total long-chain 2-hydroxy-ceramides, confirming enzyme substrate specificity for chain length. 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
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
CerS2 null mouse generation from embryonic stem cells harboring a gene trap (GT) retroviral vector insertion in the first intron of the CerS2 gene, and characterization of the changes in the long chain base and sphingolipid composition of livers from these mice. Ceramide and downstream sphingolipids are devoid of very long (C22-C24) acyl chains, consistent with the substrate specificity of CerS2 toward acyl-CoAs. C16-ceramide levels are elevated, and as a result, total ceramide levels are unaltered. C16-ceramide synthesis in vitro is not increased. Levels of sphinganine are significantly elevated by up to 50fold, reminiscent of the effect of the ceramide synthase inhibitor fumonisin B1. With the exceptions of glucosylceramide synthase and neutral sphingomyelinase 2, none of the other enzymes tested in either the sphingolipid biosynthetic or degradative pathways are significantly changed. Total glycerophospholipid and cholesterol levels are unaltered, although there is a marked elevation in C18:1 and C18:2 fatty acids in phosphatidylethanolamine, concomitant with a reduction in C18:0 and C20:4 fatty acids
additional information
-
CerS2 null mouse generation from embryonic stem cells harboring a gene trap (GT) retroviral vector insertion in the first intron of the CerS2 gene, and characterization of the changes in the long chain base and sphingolipid composition of livers from these mice. Ceramide and downstream sphingolipids are devoid of very long (C22-C24) acyl chains, consistent with the substrate specificity of CerS2 toward acyl-CoAs. C16-ceramide levels are elevated, and as a result, total ceramide levels are unaltered. C16-ceramide synthesis in vitro is not increased. Levels of sphinganine are significantly elevated by up to 50fold, reminiscent of the effect of the ceramide synthase inhibitor fumonisin B1. With the exceptions of glucosylceramide synthase and neutral sphingomyelinase 2, none of the other enzymes tested in either the sphingolipid biosynthetic or degradative pathways are significantly changed. Total glycerophospholipid and cholesterol levels are unaltered, although there is a marked elevation in C18:1 and C18:2 fatty acids in phosphatidylethanolamine, concomitant with a reduction in C18:0 and C20:4 fatty acids
additional information
Lass4 overproduction causing increases in both middle- and long-chain ceramides
additional information
Lass4 overproduction causing increases in both middle- and long-chain ceramides
additional information
-
Lass4 overproduction causing increases in both middle- and long-chain ceramides
additional information
topology study of Lag1p and Lac1p using insertion of glycosylation sites and fXa (factor Xa)-cleavage sites in the loops between the predicted transmembrane segments, hydropathy profiles of Lag1p and Lac1p and positions of fusion insertions, method, overview
additional information
Saccharomyces cerevisiae RH382
-
topology study of Lag1p and Lac1p using insertion of glycosylation sites and fXa (factor Xa)-cleavage sites in the loops between the predicted transmembrane segments, hydropathy profiles of Lag1p and Lac1p and positions of fusion insertions, method, overview
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
high concentrations of glycerol are essential in preventing deactivation of the enzyme
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, 48 h, liver enzyme loses 70% of activity, brain enzyme looes 41% of activity
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
native enzyme 2.7 and 4.9fold from liver and brain microsomes partially, respectively, by gel filtration
-
native enzyme 3420fold subunits from isolated digitonin-treated membranes by solubilization with 1% Triton X-100 and affinity chromatography
subcellular fractionation of HeLa cells recombinantly expressing the CerS isozyme
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination and analysis, sequence comparisons, phylogenetic tree, recombinant expression of HA-tagged enzyme in HEK-293T cells
gene CERS2, quantitative real-time PCR expression analysis, recombinant expression of C-terminally HA-tagged CerS2 in the endoplasmic reticulum of yeast cells, recombinant expression of FLAG-tagged CerS2 in HEK-293T cells
gene CERS2, recombinant expression in HEK-293T cells, quantitative real-time quantitative PCR enzyme expression analysis
gene CERS2, recombinant expression of C-terminally HA-tagged CerS2 and of chimeric HA-tagged CerS5:CerS2 heterodimer in HEK-293 cells, recombinant expression of FLAG-tagged CerS2 in HEK-293 cells. Isozymes CerS5 and CerS6 modulate CerS2 activity upon coexpression
gene CERS2, recombinant FLAG-tagged isozyme overexpression in HeLa cells, quantitative real-time PCR enzyme expression analysis. CerS2, CerS5, and CerS6 form heterocomplexes in transformed HeLa cells
gene CERS3, DNA and amino acid sequence determination and analysis, cloning of two transcriptional variants of LASS3 cDNA, which encode a 384-amino-acid protein (LASS3) and a 419-amino-acid protein (LASS3-long), reverse transcription (RT)-PCR expression analysis, recombinant expression in HEK-293T cells
gene CERS4, recombinant expression in HEK-293T cells, quantitative real-time quantitative PCR enzyme expression analysis
gene LAG1, recombinant expression of codon-optimized LAG1 as N-terminally FLAG-tagged enzyme in Saccharomyces cerevisiae membranes
gene LAG3, recombinant expression of codon-optimized LAG3 as N-terminally FLAG-tagged enzyme in Saccharomyces cerevisiae membranes
genes LAC1, LAG1, and LIP1. LIP1 DNA and amino acid sequence determination and analysis, sequence comparisons, recombinant expression of all three subunits as N-terminally FLAG- or HA-tagged proteins in Saccharomyces cerevisiae strains
genes LAG1, LAC1 and LIP1, encodes the three subunits of the hetereotrimeric enzyme, sequence comparisons, recombinant expression of wild-type and point/insertion mutant FLAG- and/or c-Myc-tagged subunits in Saccharomyces cerevisiae strains, overview
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
ceramide synthase 2 activity is significantly reduced in the testes of acyl-coenzyme A-binding protein-deficient mice
-
ionizing radiation (IR) induces de novo synthesis of ceramide by specifically activating CerS isoforms 2, 5, and 6
the mRNA level of the enzyme increases 1.23fold in the presence of 0.03 mM Asterias amurensis-derived sphingoid bases
-
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
recombinant HA-tagged chimeric mutant CerS5:TM:CerS2 is reconstituted in 1,2-dioleoyl-sn-glycero-3-phosphocholine liposomes
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
important role for the CerS genes in breast cancer etiology or diagnosis, overview
REF.
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TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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Cell-type-specific expression pattern of ceramide synthase 2 protein in mouse tissues
Histochem. Cell Biol.
140
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2013
Mus musculus (Q924Z4), Mus musculus, Mus musculus C57BL/6 (Q924Z4)
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
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391
219-223
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390
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398
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398
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Saccharomyces cerevisiae (P28496 AND P38703 AND Q03579), Saccharomyces cerevisiae RH382 (P28496 AND P38703 AND Q03579)
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473
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2016
Arabidopsis thaliana (Q6NQI8), Arabidopsis thaliana (Q9LDF2)
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125
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1966
Cavia porcellus, Gallus gallus
Narimatsu, S.; Soeda, S.; Tanaka, T.; Kishimoto, Y.
Solubilization and partial characterization of fatty acyl-CoA sphingosine acyltransferase (ceramide synthetase) from rat liver and brain
Biochim. Biophys. Acta
877
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1986
Rattus norvegicus
Mesicek, J.; Lee, H.; Feldman, T.; Jiang, X.; Skobeleva, A.; Berdyshev, E.V.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R.
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22
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2010
Homo sapiens (Q96G23)
Vallee, B.; Riezman, H.
Lip1p a novel subunit of acyl-CoA ceramide synthase
EMBO J.
24
730-741
2005
Saccharomyces cerevisiae (P28496 AND P38703 AND Q03579), Saccharomyces cerevisiae RH4838 (P28496 AND P38703 AND Q03579)
Merrill, A.H.; van Echten, G.; Wang, E.; Sandhoff, K.
Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ
J. Biol. Chem.
268
27299-27306
1993
Mus musculus, Mus musculus NMRI
Laviad, E.L.; Albee, L.; Pankova-Kholmyansky, I.; Epstein, S.; Park, H.; Merrill, A.H.; Futerman, A.H.
Characterization of ceramide synthase 2 tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate
J. Biol. Chem.
283
5677-5684
2008
Mus musculus (Q924Z4), Mus musculus C57BL/6 (Q924Z4)
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 (Q96G23)
Berdyshev, E.V.; Gorshkova, I.; Skobeleva, A.; Bittman, R.; Lu, X.; Dudek, S.M.; Mirzapoiazova, T.; Garcia, J.G.; Natarajan, V.
FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells
J. Biol. Chem.
284
5467-5477
2009
Homo sapiens
Pewzner-Jung, Y.; Brenner, O.; Braun, S.; Laviad, E.L.; Ben-Dor, S.; Feldmesser, E.; Horn-Saban, S.; Amann-Zalcenstein, D.; Raanan, C.; Berkutzki, T.; Erez-Roman, R.; Ben-David, O.; Levy, M.; Holzman, D.; Park, H.; Nyska, A.; Merrill, A.H.; Futerman, A.H.
A critical role for ceramide synthase 2 in liver homeostasis II. insights into molecular changes leading to hepatopathy
J. Biol. Chem.
285
10911-10923
2010
Mus musculus (Q924Z4), Mus musculus
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 (Q96G23)
Laviad, E.L.; Kelly, S.; Merrill, A.H.; Futerman, A.H.
Modulation of ceramide synthase activity via dimerization
J. Biol. Chem.
287
21025-21033
2012
Homo sapiens (Q96G23)
Ferreira, N.S.; Engelsby, H.; Neess, D.; Kelly, S.L.; Volpert, G.; Merrill, A.H.; Futerman, A.H.; Faergeman, N.J.
Regulation of very-long acyl chain ceramide synthesis by acyl-CoA-binding protein
J. Biol. Chem.
292
7588-7597
2017
Mus musculus
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 (Q96G23), Homo sapiens (Q9HA82)
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 (Q96G23)
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 (Q96G23)
Park, W.J.; Brenner, O.; Kogot-Levin, A.; Saada, A.; Merrill, A.H.; Pewzner-Jung, Y.; Futerman, A.H.
Development of pheochromocytoma in ceramide synthase 2 null mice
Endocr. Relat. Cancer
22
623-632
2015
Mus musculus
Saroha, A.; Pewzner-Jung, Y.; Ferreira, N.S.; Sharma, P.; Jouan, Y.; Kelly, S.L.; Feldmesser, E.; Merrill, A.H.; Trottein, F.; Paget, C.; Lang, K.S.; Futerman, A.H.
Critical role for very-long chain sphingolipids in invariant natural killer T cell development and homeostasis
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8
1386
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Mus musculus
Kim, Y.R.; Volpert, G.; Shin, K.O.; Kim, S.Y.; Shin, S.H.; Lee, Y.; Sung, S.H.; Lee, Y.M.; Ahn, J.H.; Pewzner-Jung, Y.; Park, W.J.; Futerman, A.H.; Park, J.W.
Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability
J. Cell. Mol. Med.
21
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2017
Mus musculus
Mikami, D.; Sakai, S.; Sasaki, S.; Igarashi, Y.
Effects of Asterias amurensis-derived sphingoid bases on the de novo ceramide synthesis in cultured normal human epidermal keratinocytes
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65
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2016
Homo sapiens
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Sphingolipids containing very-long-chain fatty acids define a secretory pathway for specific polar plasma membrane protein targeting in Arabidopsis
Plant Cell
23
2362-2378
2011
Arabidopsis thaliana
Xie, L.; Chen, Q.; Chen, M.; Yu, L.; Huang, L.; Chen, L.; Wang, F.; Xia, F.; Zhu, T.; Wu, J.; Yin, J.; Liao, B.; Shi, J.; Zhang, J.; Aharoni, A.; Yao, N.; Shu, W.; Xiao, S.
Unsaturation of very-long-chain ceramides protects plant from hypoxia-induced damages by modulating ethylene signaling in Arabidopsis
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11
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2015
Arabidopsis thaliana
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