CERS1_MOUSE
ID CERS1_MOUSE Reviewed; 350 AA.
AC P27545;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1992, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Ceramide synthase 1 {ECO:0000303|PubMed:17977534};
DE Short=CerS1 {ECO:0000303|PubMed:17977534};
DE AltName: Full=Longevity assurance gene 1 protein homolog 1 {ECO:0000303|PubMed:15823095};
DE AltName: Full=Protein UOG-1 {ECO:0000303|PubMed:2034669};
DE AltName: Full=Sphingoid base N-stearoyltransferase CERS1 {ECO:0000305};
DE EC=2.3.1.299 {ECO:0000269|PubMed:15823095, ECO:0000269|PubMed:16951403, ECO:0000269|PubMed:17977534, ECO:0000269|PubMed:18541923};
GN Name=Cers1 {ECO:0000303|PubMed:17977534, ECO:0000312|MGI:MGI:2136690};
GN Synonyms=Lass1 {ECO:0000303|PubMed:15823095},
GN Uog-1 {ECO:0000303|PubMed:2034669}, Uog1 {ECO:0000303|PubMed:2034669};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2034669; DOI=10.1073/pnas.88.10.4250;
RA Lee S.-J.;
RT "Expression of growth/differentiation factor 1 in the nervous system:
RT conservation of a bicistronic structure.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:4250-4254(1991).
RN [2]
RP FUNCTION, AND PATHWAY.
RX PubMed=12105227; DOI=10.1074/jbc.m205211200;
RA Venkataraman K., Riebeling C., Bodennec J., Riezman H., Allegood J.C.,
RA Sullards M.C., Merrill A.H. Jr., Futerman A.H.;
RT "Upstream of growth and differentiation factor 1 (uog1), a mammalian
RT homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-
RT stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-
RT independent manner in mammalian cells.";
RL J. Biol. Chem. 277:35642-35649(2002).
RN [3]
RP TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY.
RX PubMed=15823095; DOI=10.1042/bj20050291;
RA Mizutani Y., Kihara A., Igarashi Y.;
RT "Mammalian Lass6 and its related family members regulate synthesis of
RT specific ceramides.";
RL Biochem. J. 390:263-271(2005).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, ACTIVITY REGULATION, AND MUTAGENESIS
RP OF HIS-182; HIS-183; LEU-189; SER-193; ASP-210; ASP-213; LEU-216 AND
RP LYS-220.
RX PubMed=16951403; DOI=10.1074/jbc.m608092200;
RA Spassieva S., Seo J.G., Jiang J.C., Bielawski J., Alvarez-Vasquez F.,
RA Jazwinski S.M., Hannun Y.A., Obeid L.M.;
RT "Necessary role for the Lag1p motif in (dihydro)ceramide synthase
RT activity.";
RL J. Biol. Chem. 281:33931-33938(2006).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17977534; DOI=10.1016/j.febslet.2007.10.018;
RA Lahiri S., Lee H., Mesicek J., Fuks Z., Haimovitz-Friedman A.,
RA Kolesnick R.N., Futerman A.H.;
RT "Kinetic characterization of mammalian ceramide synthases: determination of
RT K(m) values towards sphinganine.";
RL FEBS Lett. 581:5289-5294(2007).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=18541923; DOI=10.1194/jlr.m800158-jlr200;
RA Mizutani Y., Kihara A., Chiba H., Tojo H., Igarashi Y.;
RT "2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis
RT for the preference of FA chain length.";
RL J. Lipid Res. 49:2356-2364(2008).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, INVOLVEMENT IN NEURODEGENERATION, VARIANT
RP ASP-266, AND CHARACTERIZATION OF VARIANT ALA-266.
RX PubMed=21625621; DOI=10.1371/journal.pgen.1002063;
RA Zhao L., Spassieva S.D., Jucius T.J., Shultz L.D., Shick H.E.,
RA Macklin W.B., Hannun Y.A., Obeid L.M., Ackerman S.L.;
RT "A deficiency of ceramide biosynthesis causes cerebellar purkinje cell
RT neurodegeneration and lipofuscin accumulation.";
RL PLoS Genet. 7:e1002063-e1002063(2011).
RN [8]
RP ACETYLATION, AND DEACETYLATION BY SIRT3.
RX PubMed=26620563; DOI=10.1074/jbc.m115.668228;
RA Novgorodov S.A., Riley C.L., Keffler J.A., Yu J., Kindy M.S., Macklin W.B.,
RA Lombard D.B., Gudz T.I.;
RT "SIRT3 deacetylates ceramide synthases: Implications for mitochondrial
RT dysfunction and brain injury.";
RL J. Biol. Chem. 291:1957-1973(2016).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, TISSUE SPECIFICITY, AND INDUCTION BY
RP HIGH-FAT DIET.
RX PubMed=30605666; DOI=10.1016/j.celrep.2018.12.031;
RA Turpin-Nolan S.M., Hammerschmidt P., Chen W., Jais A., Timper K.,
RA Awazawa M., Brodesser S., Bruening J.C.;
RT "CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced
RT Insulin Resistance.";
RL Cell Rep. 26:1-10(2019).
CC -!- FUNCTION: Ceramide synthase that catalyzes the transfer of the acyl
CC chain from acyl-CoA to a sphingoid base, with high selectivity toward
CC stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA). N-acylates sphinganine and
CC sphingosine bases to form dihydroceramides and ceramides in de novo
CC synthesis and salvage pathways, respectively (PubMed:12105227,
CC PubMed:16951403, PubMed:17977534, PubMed:18541923, PubMed:30605666).
CC Plays a predominant role in skeletal muscle in regulating C18 ceramide
CC and dihydroceramide levels with an impact on whole-body glucose
CC metabolism and insulin sensitivity. Protects from diet-induced obesity
CC by suppressing the uptake of glucose in multiple organs in a FGF21-
CC dependent way (PubMed:30605666). Generates C18 ceramides in the brain,
CC playing a critical role in cerebellar development and Purkinje cell
CC function (PubMed:21625621). In response to cellular stress mediates
CC mitophagy, a known defense mechanism against cell transformation and
CC aging. Upon mitochondria fission, generates C18 ceramides that anchor
CC lipidated MAP1LC3B/LC3B-II autophagolysosomes to outer mitochondrial
CC membranes to eliminate damaged mitochondria (By similarity).
CC {ECO:0000250|UniProtKB:P27544, ECO:0000269|PubMed:12105227,
CC ECO:0000269|PubMed:16951403, ECO:0000269|PubMed:17977534,
CC ECO:0000269|PubMed:18541923, ECO:0000269|PubMed:21625621,
CC ECO:0000269|PubMed:30605666}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingoid base + octadecanoyl-CoA = an N-octadecanoyl-
CC sphingoid base + CoA + H(+); Xref=Rhea:RHEA:61476, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57394, ChEBI:CHEBI:84410,
CC ChEBI:CHEBI:144711; EC=2.3.1.299;
CC Evidence={ECO:0000269|PubMed:15823095, ECO:0000269|PubMed:16951403,
CC ECO:0000269|PubMed:17977534, ECO:0000269|PubMed:18541923};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61477;
CC Evidence={ECO:0000269|PubMed:15823095, ECO:0000269|PubMed:16951403,
CC ECO:0000269|PubMed:17977534, ECO:0000269|PubMed:18541923};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=octadecanoyl-CoA + sphinganine = CoA + H(+) + N-
CC (octadecanoyl)-sphinganine; Xref=Rhea:RHEA:36547, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57394, ChEBI:CHEBI:57817,
CC ChEBI:CHEBI:67033; Evidence={ECO:0000269|PubMed:15823095,
CC ECO:0000269|PubMed:16951403, ECO:0000269|PubMed:17977534,
CC ECO:0000269|PubMed:18541923};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36548;
CC Evidence={ECO:0000269|PubMed:15823095, ECO:0000269|PubMed:16951403,
CC ECO:0000269|PubMed:17977534, ECO:0000269|PubMed:18541923,
CC ECO:0000269|PubMed:30605666};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hexadecasphinganine + octadecanoyl-CoA = CoA + H(+) + N-
CC octadecanoylhexadecasphinganine; Xref=Rhea:RHEA:43044,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57287, ChEBI:CHEBI:57394,
CC ChEBI:CHEBI:71009, ChEBI:CHEBI:82811;
CC Evidence={ECO:0000250|UniProtKB:P27544};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43045;
CC Evidence={ECO:0000250|UniProtKB:P27544};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=octadecanoyl-CoA + sphing-4-enine = CoA + H(+) + N-
CC octadecanoylsphing-4-enine; Xref=Rhea:RHEA:36691, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57394, ChEBI:CHEBI:57756,
CC ChEBI:CHEBI:72961; Evidence={ECO:0000250|UniProtKB:P27544,
CC ECO:0000305|PubMed:30605666};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36692;
CC Evidence={ECO:0000250|UniProtKB:P27544, ECO:0000305|PubMed:30605666};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=heptadecasphing-4-enine + octadecanoyl-CoA = CoA + H(+) + N-
CC octadecanoyl-heptadecasphing-4-enine; Xref=Rhea:RHEA:67596,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57287, ChEBI:CHEBI:57394,
CC ChEBI:CHEBI:74166, ChEBI:CHEBI:172405;
CC Evidence={ECO:0000269|PubMed:21625621};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67597;
CC Evidence={ECO:0000305|PubMed:21625621};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-hydroxyoctadecanoyl-CoA + sphinganine = CoA + H(+) + N-(2-
CC hydroxyoctadecanoyl)-sphinganine; Xref=Rhea:RHEA:36615,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57287, ChEBI:CHEBI:57817,
CC ChEBI:CHEBI:67034, ChEBI:CHEBI:74116;
CC Evidence={ECO:0000269|PubMed:18541923};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36616;
CC Evidence={ECO:0000269|PubMed:18541923};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=eicosanoyl-CoA + sphinganine = CoA + H(+) + N-
CC eicosanoylsphinganine; Xref=Rhea:RHEA:36555, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57380, ChEBI:CHEBI:57817,
CC ChEBI:CHEBI:67027; Evidence={ECO:0000269|PubMed:15823095};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36556;
CC Evidence={ECO:0000269|PubMed:15823095};
CC -!- ACTIVITY REGULATION: Inhibited by fumonisin B1.
CC {ECO:0000269|PubMed:16951403}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.5 uM for sphinganine {ECO:0000269|PubMed:17977534};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:12105227, ECO:0000269|PubMed:16951403,
CC ECO:0000269|PubMed:17977534, ECO:0000269|PubMed:18541923,
CC ECO:0000269|PubMed:30605666}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P27544}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed in brain, skeletal muscle, heart and
CC perigonadal white adipose tissue. {ECO:0000269|PubMed:15823095,
CC ECO:0000269|PubMed:30605666}.
CC -!- INDUCTION: Up-regulated in skeletal muscle in response to high-fat
CC diet. {ECO:0000269|PubMed:30605666}.
CC -!- PTM: Acetylated (PubMed:26620563). Deacetylation by SIRT3 increases
CC enzyme activity and promotes mitochondrial ceramide accumulation
CC (PubMed:26620563). {ECO:0000269|PubMed:26620563}.
CC -!- DISEASE: Note=Defects in CERS1 cause cerebellar ataxia and Purkinje
CC cell degeneration. Two mouse strains flincher (fln) and toppler (to)
CC carry spontaneous recessive mutations at the TLC domain of CERS1,
CC resulting in complete loss of the catalytic activity associated with a
CC reduction in sphingolipid biosynthesis and accumulation of lipofuscin
CC in many brain regions. {ECO:0000269|PubMed:21625621}.
CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which
CC also produces the GDF1 protein from a non-overlapping reading frame.
CC {ECO:0000269|PubMed:2034669}.
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DR EMBL; M62301; AAA37675.1; -; mRNA.
DR CCDS; CCDS52570.1; -.
DR PIR; B39364; B39364.
DR RefSeq; NP_619588.1; NM_138647.3.
DR AlphaFoldDB; P27545; -.
DR SMR; P27545; -.
DR STRING; 10090.ENSMUSP00000120598; -.
DR SwissLipids; SLP:000000115; -.
DR PhosphoSitePlus; P27545; -.
DR SwissPalm; P27545; -.
DR MaxQB; P27545; -.
DR PaxDb; P27545; -.
DR PRIDE; P27545; -.
DR ProteomicsDB; 280008; -.
DR DNASU; 93898; -.
DR Ensembl; ENSMUST00000140239; ENSMUSP00000120598; ENSMUSG00000087408.
DR GeneID; 93898; -.
DR KEGG; mmu:93898; -.
DR CTD; 10715; -.
DR MGI; MGI:2136690; Cers1.
DR VEuPathDB; HostDB:ENSMUSG00000087408; -.
DR eggNOG; KOG1607; Eukaryota.
DR GeneTree; ENSGT00940000162926; -.
DR HOGENOM; CLU_028277_0_0_1; -.
DR InParanoid; P27545; -.
DR OMA; FFCAFLW; -.
DR PhylomeDB; P27545; -.
DR TreeFam; TF314319; -.
DR BRENDA; 2.3.1.299; 3474.
DR Reactome; R-MMU-1660661; Sphingolipid de novo biosynthesis.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 93898; 2 hits in 30 CRISPR screens.
DR PRO; PR:P27545; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; P27545; protein.
DR Bgee; ENSMUSG00000087408; Expressed in striatum and 44 other tissues.
DR ExpressionAtlas; P27545; baseline and differential.
DR Genevisible; P27545; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:BHF-UCL.
DR GO; GO:0016410; F:N-acyltransferase activity; IMP:UniProtKB.
DR GO; GO:0050291; F:sphingosine N-acyltransferase activity; IDA:UniProtKB.
DR GO; GO:0007420; P:brain development; IMP:MGI.
DR GO; GO:0072721; P:cellular response to dithiothreitol; ISO:MGI.
DR GO; GO:0036146; P:cellular response to mycotoxin; ISO:MGI.
DR GO; GO:0071492; P:cellular response to UV-A; ISO:MGI.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; ISO:MGI.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0046325; P:negative regulation of glucose import; IMP:UniProtKB.
DR GO; GO:0051974; P:negative regulation of telomerase activity; ISO:MGI.
DR GO; GO:1901526; P:positive regulation of mitophagy; ISO:MGI.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; ISO:MGI.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR006634; TLC-dom.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF03798; TRAM_LAG1_CLN8; 1.
DR SMART; SM00724; TLC; 1.
DR PROSITE; PS50922; TLC; 1.
PE 1: Evidence at protein level;
KW Acetylation; Endoplasmic reticulum; Lipid biosynthesis; Lipid metabolism;
KW Membrane; Reference proteome; Transferase; Transmembrane;
KW Transmembrane helix.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P27544"
FT CHAIN 2..350
FT /note="Ceramide synthase 1"
FT /id="PRO_0000185508"
FT TRANSMEM 53..73
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 103..123
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 148..168
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 176..196
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 239..259
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 287..307
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 97..311
FT /note="TLC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00205"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P27544"
FT VARIANT 266
FT /note="A -> D (in toppler (to) mice; impairs ceramide
FT synthase activity)"
FT /evidence="ECO:0000269|PubMed:21625621"
FT MUTAGEN 182
FT /note="H->D: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 183
FT /note="H->D: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 189
FT /note="L->E: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 193
FT /note="S->A: Does not affect ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 210
FT /note="D->N: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 213
FT /note="D->N: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 216
FT /note="L->E: Decreased ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
FT MUTAGEN 220
FT /note="K->L: Does not affect ceramide synthase activity."
FT /evidence="ECO:0000269|PubMed:16951403"
SQ SEQUENCE 350 AA; 40100 MW; 8AF3D9738CF75A02 CRC64;
MAAAAATPRL EAPEPMPSYA QMLQRSWASA LAAAQGCGDC GWGLARRGLA EHAHLAAPEL
LLAVLCALGW TALRWAATTH IFRPLAKRCR LQPRDAARLP ESAWKLLFYL ACWSYCAYLL
LGTSYPFFHD PPSVFYDWRS GMAVPWDIAV AYLLQGSFYC HSIYATVYMD SWRKDSVVML
VHHVVTLLLI ASSYAFRYHN VGLLVFFLHD VSDVQLEFTK LNIYFKARGG AYHRLHGLVA
NLGCLSFCFC WFWFRLYWFP LKVLYATCHC SLQSVPDIPY YFFFNILLLL LMVMNIYWFL
YIVAFAAKVL TGQMRELEDL REYDTLEAQT AKPCKAEKPL RNGLVKDKLF
