ACER1_HUMAN
ID ACER1_HUMAN Reviewed; 264 AA.
AC Q8TDN7;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Alkaline ceramidase 1 {ECO:0000305};
DE Short=AlkCDase 1;
DE Short=Alkaline CDase 1;
DE EC=3.5.1.- {ECO:0000269|PubMed:20207939, ECO:0000269|PubMed:20628055};
DE EC=3.5.1.23 {ECO:0000269|PubMed:17713573};
DE AltName: Full=Acylsphingosine deacylase 3;
DE AltName: Full=N-acylsphingosine amidohydrolase 3;
GN Name=ACER1 {ECO:0000312|HGNC:HGNC:18356}; Synonyms=ASAH3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=12783875; DOI=10.1074/jbc.m303875200;
RA Mao C., Xu R., Szulc Z.M., Bielawski J., Becker K.P., Bielawska A.,
RA Galadari S.H., Hu W., Obeid L.M.;
RT "Cloning and characterization of a mouse endoplasmic reticulum alkaline
RT ceramidase: an enzyme that preferentially regulates metabolism of very long
RT chain ceramides.";
RL J. Biol. Chem. 278:31184-31191(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=16477081; DOI=10.1194/jlr.m600001-jlr200;
RA Houben E., Holleran W.M., Yaginuma T., Mao C., Obeid L.M., Rogiers V.,
RA Takagi Y., Elias P.M., Uchida Y.;
RT "Differentiation-associated expression of ceramidase isoforms in cultured
RT keratinocytes and epidermis.";
RL J. Lipid Res. 47:1063-1070(2006).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, SUBSTRATE
RP SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND INDUCTION BY CALCIUM.
RX PubMed=17713573; DOI=10.1038/sj.jid.5701025;
RA Sun W., Xu R., Hu W., Jin J., Crellin H.A., Bielawski J., Szulc Z.M.,
RA Thiers B.H., Obeid L.M., Mao C.;
RT "Upregulation of the human alkaline ceramidase 1 and acid ceramidase
RT mediates calcium-induced differentiation of epidermal keratinocytes.";
RL J. Invest. Dermatol. 128:389-397(2008).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=20207939; DOI=10.1096/fj.09-153635;
RA Xu R., Sun W., Jin J., Obeid L.M., Mao C.;
RT "Role of alkaline ceramidases in the generation of sphingosine and its
RT phosphate in erythrocytes.";
RL FASEB J. 24:2507-2515(2010).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20628055; DOI=10.1074/jbc.m110.105296;
RA Mao Z., Sun W., Xu R., Novgorodov S., Szulc Z.M., Bielawski J., Obeid L.M.,
RA Mao C.;
RT "Alkaline ceramidase 2 (ACER2) and its product dihydrosphingosine mediate
RT the cytotoxicity of N-(4-hydroxyphenyl)retinamide in tumor cells.";
RL J. Biol. Chem. 285:29078-29090(2010).
CC -!- FUNCTION: Endoplasmic reticulum ceramidase that catalyzes the
CC hydrolysis of ceramides into sphingosine and free fatty acids at
CC alkaline pH (PubMed:17713573, PubMed:20207939, PubMed:20628055).
CC Ceramides, sphingosine, and its phosphorylated form sphingosine-1-
CC phosphate are bioactive lipids that mediate cellular signaling pathways
CC regulating several biological processes including cell proliferation,
CC apoptosis and differentiation (PubMed:12783875). Exhibits a strong
CC substrate specificity towards the natural stereoisomer of ceramides
CC with D-erythro-sphingosine as a backbone and has a higher activity
CC towards very long-chain unsaturated fatty acids like the C24:1-ceramide
CC (PubMed:17713573, PubMed:20207939). May also hydrolyze dihydroceramides
CC to produce dihydrosphingosine (PubMed:20207939, PubMed:20628055). ACER1
CC is a skin-specific ceramidase that regulates the levels of ceramides,
CC sphingosine and sphingosine-1-phosphate in the epidermis, mediates the
CC calcium-induced differentiation of epidermal keratinocytes and more
CC generally plays an important role in skin homeostasis
CC (PubMed:17713573). {ECO:0000269|PubMed:17713573,
CC ECO:0000269|PubMed:20207939, ECO:0000269|PubMed:20628055,
CC ECO:0000303|PubMed:12783875}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-acylsphing-4-enine + H2O = a fatty acid + sphing-4-enine;
CC Xref=Rhea:RHEA:20856, ChEBI:CHEBI:15377, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:52639, ChEBI:CHEBI:57756; EC=3.5.1.23;
CC Evidence={ECO:0000269|PubMed:17713573};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20857;
CC Evidence={ECO:0000269|PubMed:17713573};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-tetracosanoyl-sphing-4-enine = sphing-4-enine +
CC tetracosanoate; Xref=Rhea:RHEA:41283, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:31014, ChEBI:CHEBI:57756, ChEBI:CHEBI:72965;
CC Evidence={ECO:0000269|PubMed:17713573};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41284;
CC Evidence={ECO:0000269|PubMed:17713573};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-acylsphinganine + H2O = a fatty acid + sphinganine;
CC Xref=Rhea:RHEA:33551, ChEBI:CHEBI:15377, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:31488, ChEBI:CHEBI:57817;
CC Evidence={ECO:0000269|PubMed:20207939, ECO:0000269|PubMed:20628055};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33552;
CC Evidence={ECO:0000269|PubMed:20628055};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(9Z-octadecenoyl)-sphing-4-enine = (9Z)-octadecenoate
CC + sphing-4-enine; Xref=Rhea:RHEA:41299, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:30823, ChEBI:CHEBI:57756, ChEBI:CHEBI:77996;
CC Evidence={ECO:0000269|PubMed:20628055};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41300;
CC Evidence={ECO:0000269|PubMed:20628055};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(15Z-tetracosenoyl)-sphing-4-enine = (15Z)-
CC tetracosenoate + sphing-4-enine; Xref=Rhea:RHEA:41267,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:32392, ChEBI:CHEBI:57756,
CC ChEBI:CHEBI:74450; Evidence={ECO:0000269|PubMed:17713573};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41268;
CC Evidence={ECO:0000269|PubMed:17713573};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q9NUN7};
CC -!- ACTIVITY REGULATION: Inhibited by sphingosine (By similarity). Activity
CC is Ca(2+)-dependent (PubMed:17713573). {ECO:0000250|UniProtKB:Q8R4X1,
CC ECO:0000269|PubMed:17713573}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 8.0. {ECO:0000269|PubMed:17713573};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:17713573, ECO:0000269|PubMed:20207939}.
CC -!- INTERACTION:
CC Q8TDN7; Q00013: MPP1; NbExp=3; IntAct=EBI-13074986, EBI-711788;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:17713573}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Mainly expressed in epidermis.
CC {ECO:0000269|PubMed:16477081, ECO:0000269|PubMed:17713573}.
CC -!- INDUCTION: Up-regulated by Ca(2+) (PubMed:17713573). Down-regulated by
CC epidermal growth factor/EGF (PubMed:17713573).
CC {ECO:0000269|PubMed:17713573}.
CC -!- SIMILARITY: Belongs to the alkaline ceramidase family. {ECO:0000305}.
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DR EMBL; AF347024; AAL83822.1; -; mRNA.
DR EMBL; BC112122; AAI12123.1; -; mRNA.
DR EMBL; BC112124; AAI12125.1; -; mRNA.
DR CCDS; CCDS12161.1; -.
DR RefSeq; NP_597999.1; NM_133492.2.
DR AlphaFoldDB; Q8TDN7; -.
DR SMR; Q8TDN7; -.
DR BioGRID; 125942; 2.
DR IntAct; Q8TDN7; 2.
DR STRING; 9606.ENSP00000301452; -.
DR ChEMBL; CHEMBL3351194; -.
DR SwissLipids; SLP:000000165; -.
DR BioMuta; ACER1; -.
DR DMDM; 74715919; -.
DR MassIVE; Q8TDN7; -.
DR PaxDb; Q8TDN7; -.
DR PeptideAtlas; Q8TDN7; -.
DR PRIDE; Q8TDN7; -.
DR Antibodypedia; 49939; 144 antibodies from 24 providers.
DR DNASU; 125981; -.
DR Ensembl; ENST00000301452.5; ENSP00000301452.3; ENSG00000167769.5.
DR GeneID; 125981; -.
DR KEGG; hsa:125981; -.
DR MANE-Select; ENST00000301452.5; ENSP00000301452.3; NM_133492.3; NP_597999.1.
DR UCSC; uc002mel.3; human.
DR CTD; 125981; -.
DR DisGeNET; 125981; -.
DR GeneCards; ACER1; -.
DR HGNC; HGNC:18356; ACER1.
DR HPA; ENSG00000167769; Tissue enriched (skin).
DR MIM; 613491; gene.
DR neXtProt; NX_Q8TDN7; -.
DR OpenTargets; ENSG00000167769; -.
DR PharmGKB; PA164714838; -.
DR VEuPathDB; HostDB:ENSG00000167769; -.
DR eggNOG; KOG2329; Eukaryota.
DR GeneTree; ENSGT00730000110920; -.
DR HOGENOM; CLU_088280_1_0_1; -.
DR InParanoid; Q8TDN7; -.
DR OMA; WTLAVAY; -.
DR OrthoDB; 969354at2759; -.
DR PhylomeDB; Q8TDN7; -.
DR TreeFam; TF313019; -.
DR BRENDA; 3.5.1.23; 2681.
DR PathwayCommons; Q8TDN7; -.
DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR SignaLink; Q8TDN7; -.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 125981; 22 hits in 1073 CRISPR screens.
DR ChiTaRS; ACER1; human.
DR GeneWiki; ACER1; -.
DR GenomeRNAi; 125981; -.
DR Pharos; Q8TDN7; Tbio.
DR PRO; PR:Q8TDN7; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q8TDN7; protein.
DR Bgee; ENSG00000167769; Expressed in skin of leg and 75 other tissues.
DR Genevisible; Q8TDN7; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:BHF-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0102121; F:ceramidase activity; IEA:UniProtKB-EC.
DR GO; GO:0071633; F:dihydroceramidase activity; IDA:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0017040; F:N-acylsphingosine amidohydrolase activity; IDA:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IMP:BHF-UCL.
DR GO; GO:0071277; P:cellular response to calcium ion; IDA:BHF-UCL.
DR GO; GO:0046514; P:ceramide catabolic process; IMP:UniProtKB.
DR GO; GO:0008544; P:epidermis development; IEP:BHF-UCL.
DR GO; GO:0030216; P:keratinocyte differentiation; IEP:BHF-UCL.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IEA:Ensembl.
DR GO; GO:0033561; P:regulation of water loss via skin; IEA:Ensembl.
DR GO; GO:0010446; P:response to alkaline pH; IDA:BHF-UCL.
DR GO; GO:0048733; P:sebaceous gland development; IEA:Ensembl.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0006665; P:sphingolipid metabolic process; ISS:BHF-UCL.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IDA:BHF-UCL.
DR InterPro; IPR008901; ACER.
DR PANTHER; PTHR46139; PTHR46139; 1.
DR Pfam; PF05875; Ceramidase; 1.
PE 1: Evidence at protein level;
KW Calcium; Endoplasmic reticulum; Hydrolase; Lipid metabolism; Membrane;
KW Metal-binding; Reference proteome; Sphingolipid metabolism; Transmembrane;
KW Transmembrane helix; Zinc.
FT CHAIN 1..264
FT /note="Alkaline ceramidase 1"
FT /id="PRO_0000247745"
FT TOPO_DOM 1..27
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 28..48
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 49..57
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 58..78
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 79..81
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 82..102
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 103..119
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 120..137
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 138
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 139..159
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 160..176
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 177..197
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 198..206
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 207..227
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 228..264
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT BINDING 13
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 14
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 16
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 18
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 27
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 77
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 206
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
FT BINDING 210
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NUN7"
SQ SEQUENCE 264 AA; 31095 MW; E16E5DB81D064F60 CRC64;
MPSIFAYQSS EVDWCESNFQ YSELVAEFYN TFSNIPFFIF GPLMMLLMHP YAQKRSRYIY
VVWVLFMIIG LFSMYFHMTL SFLGQLLDEI AILWLLGSGY SIWMPRCYFP SFLGGNRSQF
IRLVFITTVV STLLSFLRPT VNAYALNSIA LHILYIVCQE YRKTSNKELR HLIEVSVVLW
AVALTSWISD RLLCSFWQRI HFFYLHSIWH VLISITFPYG MVTMALVDAN YEMPGETLKV
RYWPRDSWPV GLPYVEIRGD DKDC
