ASAH1_HUMAN
ID ASAH1_HUMAN Reviewed; 395 AA.
AC Q13510; E9PDS0; Q6W898; Q96AS2;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2009, sequence version 5.
DT 03-AUG-2022, entry version 209.
DE RecName: Full=Acid ceramidase {ECO:0000303|PubMed:29692406, ECO:0000303|PubMed:8955159, ECO:0000305};
DE Short=AC;
DE Short=ACDase {ECO:0000303|PubMed:30525581};
DE Short=Acid CDase;
DE EC=3.5.1.23 {ECO:0000269|PubMed:10610716, ECO:0000269|PubMed:11451951, ECO:0000269|PubMed:12815059, ECO:0000269|PubMed:15655246, ECO:0000269|PubMed:29692406, ECO:0000269|PubMed:7744740, ECO:0000269|PubMed:8955159};
DE AltName: Full=Acylsphingosine deacylase;
DE AltName: Full=N-acylethanolamine hydrolase ASAH1 {ECO:0000305|PubMed:15655246};
DE EC=3.5.1.- {ECO:0000269|PubMed:15655246};
DE AltName: Full=N-acylsphingosine amidohydrolase;
DE AltName: Full=Putative 32 kDa heart protein;
DE Short=PHP32;
DE Contains:
DE RecName: Full=Acid ceramidase subunit alpha {ECO:0000303|PubMed:7744740};
DE Contains:
DE RecName: Full=Acid ceramidase subunit beta {ECO:0000303|PubMed:7744740};
DE Flags: Precursor;
GN Name=ASAH1 {ECO:0000312|HGNC:HGNC:735}; Synonyms=ASAH;
GN ORFNames=HSD-33, HSD33;
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] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANT
RP FRBRL LYS-222, VARIANTS MET-72; VAL-93 AND ALA-246, GLYCOSYLATION, AND
RP CATALYTIC ACTIVITY.
RC TISSUE=Fibroblast, Pituitary, and Urine;
RX PubMed=8955159; DOI=10.1074/jbc.271.51.33110;
RA Koch J., Gaertner S., Li C.M., Quintern L.E., Bernardo K., Levran O.,
RA Schnabel D., Desnick R.J., Schuchman E.H., Sandhoff K.;
RT "Molecular cloning and characterization of a full-length complementary DNA
RT encoding human acid ceramidase. Identification of the first molecular
RT lesion causing Farber disease.";
RL J. Biol. Chem. 271:33110-33115(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS MET-72; VAL-93 AND
RP ALA-246.
RA Churchill J.R., Wieland S.J., Hoffman S., Gallin E.K., Murphy P.M.;
RT "A new gene family predicted by a novel human heart cDNA.";
RL Mol. Biol. Cell 6:418-418(1995).
RN [3]
RP SEQUENCE REVISION.
RA Wieland S.J., Hoffman S., Churchill J.R., Gallin E.K., Murphy P.M.;
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RA Fan M.M., Miao S.Y., Zhang X.D., Qiao Y., Liang G., Wang L.F.;
RT "A new spermatogenesis related gene.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS FRBRL HIS-22; ASP-23; VAL-138;
RP LYS-222 AND ASP-320, AND VARIANTS MET-72; VAL-93 AND ALA-246.
RX PubMed=10993717; DOI=10.1006/mgme.2000.3029;
RA Zhang Z., Mandal A.K., Mital A., Popescu N., Zimonjic D., Moser A.,
RA Moser H., Mukherjee A.B.;
RT "Human acid ceramidase gene: novel mutations in Farber disease.";
RL Mol. Genet. Metab. 70:301-309(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, PATHWAY,
RP VARIANTS FRBRL VAL-138; GLY-254 AND ARG-362, CHARACTERIZATION OF VARIANTS
RP FRBRL VAL-138; GLY-254 AND ARG-362, AND TISSUE SPECIFICITY.
RX PubMed=10610716; DOI=10.1006/geno.1999.5940;
RA Li C.M., Park J.H., He X., Levy B., Chen F., Arai K., Adler D.A.,
RA Disteche C.M., Koch J., Sandhoff K., Schuchman E.H.;
RT "The human acid ceramidase gene (ASAH): structure, chromosomal location,
RT mutation analysis, and expression.";
RL Genomics 62:223-231(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND VARIANTS
RP MET-72; VAL-93 AND ALA-246.
RC TISSUE=Bone marrow, and Skin;
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 [9]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY,
RP SUBUNIT, SUBCELLULAR LOCATION, AND PTM.
RX PubMed=7744740; DOI=10.1074/jbc.270.19.11098;
RA Bernardo K., Hurwitz R., Zenk T., Desnick R.J., Ferlinz K., Schuchman E.H.,
RA Sandhoff K.;
RT "Purification, characterization, and biosynthesis of human acid
RT ceramidase.";
RL J. Biol. Chem. 270:11098-11102(1995).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, SUBCELLULAR LOCATION, PTM,
RP GLYCOSYLATION, AND MUTAGENESIS OF ASN-173; ASN-195; ASN-259; ASN-286;
RP ASN-342 AND ASN-348.
RX PubMed=11451951; DOI=10.1074/jbc.m103066200;
RA Ferlinz K., Kopal G., Bernardo K., Linke T., Bar J., Breiden B.,
RA Neumann U., Lang F., Schuchman E.H., Sandhoff K.;
RT "Human acid ceramidase: processing, glycosylation, and lysosomal
RT targeting.";
RL J. Biol. Chem. 276:35352-35360(2001).
RN [11]
RP FUNCTION, SUBSTRATE SPECIFICITY, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBCELLULAR LOCATION.
RX PubMed=12764132; DOI=10.1074/jbc.m303310200;
RA Okino N., He X., Gatt S., Sandhoff K., Ito M., Schuchman E.H.;
RT "The reverse activity of human acid ceramidase.";
RL J. Biol. Chem. 278:29948-29953(2003).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PTM.
RX PubMed=12815059; DOI=10.1074/jbc.m301936200;
RA He X., Okino N., Dhami R., Dagan A., Gatt S., Schulze H., Sandhoff K.,
RA Schuchman E.H.;
RT "Purification and characterization of recombinant, human acid ceramidase.
RT Catalytic reactions and interactions with acid sphingomyelinase.";
RL J. Biol. Chem. 278:32978-32986(2003).
RN [13]
RP GLYCOSYLATION AT ASN-259 AND ASN-286.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15655246; DOI=10.1074/jbc.m413473200;
RA Tsuboi K., Sun Y.-X., Okamoto Y., Araki N., Tonai T., Ueda N.;
RT "Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase,
RT a novel member of the choloylglycine hydrolase family with structural and
RT functional similarity to acid ceramidase.";
RL J. Biol. Chem. 280:11082-11092(2005).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-259.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-259.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.m500324-mcp200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [17]
RP FUNCTION, 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 [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-259 AND ASN-286.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP FUNCTION (ISOFORM 2), INTERACTION WITH NR5A1 (ISOFORM 2), SUBCELLULAR
RP LOCATION (ISOFORM 2), AND MUTAGENESIS (ISOFORM 2).
RX PubMed=22927646; DOI=10.1128/mcb.00378-12;
RA Lucki N.C., Li D., Bandyopadhyay S., Wang E., Merrill A.H., Sewer M.B.;
RT "Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene
RT transcription in H295R human adrenocortical cells by binding to the
RT receptor.";
RL Mol. Cell. Biol. 32:4419-4431(2012).
RN [21]
RP FUNCTION.
RX PubMed=22261821; DOI=10.1210/me.2011-1150;
RA Lucki N.C., Bandyopadhyay S., Wang E., Merrill A.H., Sewer M.B.;
RT "Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity
RT and adrenocortical gene expression.";
RL Mol. Endocrinol. 26:228-243(2012).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [24] {ECO:0007744|PDB:6MHM}
RP X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF 22-395 IN COMPLEX WITH SYNTHETIC
RP INHIBITOR, ACTIVE SITE, GLYCOSYLATION AT ASN-173; ASN-259 AND ASN-286,
RP SUBUNIT, PROTEOLYTIC CLEAVAGE, AND DISULFIDE BOND.
RX PubMed=30525581; DOI=10.1021/acs.jmedchem.8b01723;
RA Dementiev A., Joachimiak A., Nguyen H., Gorelik A., Illes K., Shabani S.,
RA Gelsomino M., Ahn E.E., Nagar B., Doan N.;
RT "Molecular mechanism of inhibition of acid ceramidase by carmofur.";
RL J. Med. Chem. 62:987-992(2019).
RN [25] {ECO:0007744|PDB:5U7Z}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 22-395, CATALYTIC ACTIVITY,
RP ACTIVE SITE, GLYCOSYLATION AT ASN-173; ASN-259; ASN-286 AND ASN-342,
RP SUBUNIT, PROTEOLYTIC CLEAVAGE, DISULFIDE BOND, AND MUTAGENESIS OF LEU-80;
RP THR-141; CYS-143; ARG-159; ASP-162; 165-VAL--LEU-167; 169-TRP--ILE-171;
RP TRP-176; ASN-320; 328-PHE--LEU-330 AND ARG-333.
RX PubMed=29692406; DOI=10.1038/s41467-018-03844-2;
RA Gebai A., Gorelik A., Li Z., Illes K., Nagar B.;
RT "Structural basis for the activation of acid ceramidase.";
RL Nat. Commun. 9:1621-1621(2018).
RN [26]
RP VARIANTS FRBRL CYS-36 AND ASP-320.
RX PubMed=11241842; DOI=10.1002/humu.5;
RA Bar J., Linke T., Ferlinz K., Neumann U., Schuchman E.H., Sandhoff K.;
RT "Molecular analysis of acid ceramidase deficiency in patients with Farber
RT disease.";
RL Hum. Mutat. 17:199-209(2001).
RN [27]
RP VARIANTS FRBRL VAL-96 DEL; GLU-97 AND ARG-235, CHARACTERIZATION OF VARIANTS
RP FRBRL VAL-96 DEL; GLU-97 AND ARG-235, VARIANT ILE-369, AND CATALYTIC
RP ACTIVITY.
RX PubMed=12638942; DOI=10.1023/a:1022047408477;
RA Muramatsu T., Sakai N., Yanagihara L., Yamada M., Nishigaki T., Kokubu C.,
RA Tsukamoto H., Ito M., Inui K.;
RT "Mutation analysis of the acid ceramidase gene in Japanese patients with
RT Farber disease.";
RL J. Inherit. Metab. Dis. 25:585-592(2002).
RN [28]
RP VARIANT FRBRL VAL-182.
RX PubMed=16951918; DOI=10.1007/s10038-006-0019-z;
RA Devi A.R.R., Gopikrishna M., Ratheesh R., Savithri G., Swarnalata G.,
RA Bashyam M.;
RT "Farber lipogranulomatosis: clinical and molecular genetic analysis reveals
RT a novel mutation in an Indian family.";
RL J. Hum. Genet. 51:811-814(2006).
RN [29]
RP VARIANT FRBRL TRP-168.
RX PubMed=20609603; DOI=10.1016/j.ejpn.2010.06.002;
RA Cvitanovic-Sojat L., Gjergja Juraski R., Sabourdy F., Fensom A.H.,
RA Fumic K., Paschke E., Levade T.;
RT "Farber lipogranulomatosis type 1--late presentation and early death in a
RT Croatian boy with a novel homozygous ASAH1 mutation.";
RL Eur. J. Paediatr. Neurol. 15:171-173(2011).
RN [30]
RP VARIANT SMAPME MET-42, CHARACTERIZATION OF VARIANT SMAPME MET-42, AND
RP CATALYTIC ACTIVITY.
RX PubMed=22703880; DOI=10.1016/j.ajhg.2012.05.001;
RA Zhou J., Tawk M., Tiziano F.D., Veillet J., Bayes M., Nolent F., Garcia V.,
RA Servidei S., Bertini E., Castro-Giner F., Renda Y., Carpentier S.,
RA Andrieu-Abadie N., Gut I., Levade T., Topaloglu H., Melki J.;
RT "Spinal muscular atrophy associated with progressive myoclonic epilepsy is
RT caused by mutations in ASAH1.";
RL Am. J. Hum. Genet. 91:5-14(2012).
RN [31]
RP VARIANT FRBRL GLY-97.
RX PubMed=21893389; DOI=10.1016/j.braindev.2011.07.003;
RA Chedrawi A.K., Al-Hassnan Z.N., Al-Muhaizea M., Colak D., Al-Younes B.,
RA Albakheet A., Tulba S., Kaya N.;
RT "Novel V97G ASAH1 mutation found in Farber disease patients: unique
RT appearance of the disease with an intermediate severity, and marked early
RT involvement of central and peripheral nervous system.";
RL Brain Dev. 34:400-404(2012).
RN [32]
RP VARIANTS FRBRL ARG-185 AND GLN-382 (ISOFORM 2).
RX PubMed=21982811; DOI=10.1016/j.braindev.2011.09.006;
RA Al Jasmi F.;
RT "A novel mutation in an atypical presentation of the rare infantile Farber
RT disease.";
RL Brain Dev. 34:533-535(2012).
RN [33]
RP VARIANTS SMAPME ASN-152 AND 284-GLY--TRP-395 DEL.
RX PubMed=24164096; DOI=10.1111/cge.12307;
RG FORGE Canada Consortium;
RA Dyment D.A., Sell E., Vanstone M.R., Smith A.C., Garandeau D., Garcia V.,
RA Carpentier S., Le Trionnaire E., Sabourdy F., Beaulieu C.L.,
RA Schwartzentruber J.A., McMillan H.J., Majewski J., Bulman D.E., Levade T.,
RA Boycott K.M.;
RT "Evidence for clinical, genetic and biochemical variability in spinal
RT muscular atrophy with progressive myoclonic epilepsy.";
RL Clin. Genet. 86:558-563(2014).
RN [34]
RP VARIANTS FRBRL ARG-235 AND CYS-333.
RX PubMed=27411168; DOI=10.1002/ajmg.a.37846;
RA Kim S.Y., Choi S.A., Lee S., Lee J.S., Hong C.R., Lim B.C., Kang H.J.,
RA Kim K.J., Park S.H., Choi M., Chae J.H.;
RT "Atypical presentation of infantile-onset farber disease with novel ASAH1
RT mutations.";
RL Am. J. Med. Genet. A 170:3023-3027(2016).
RN [35]
RP VARIANTS FRBRL ARG-169 AND GLY-254.
RX PubMed=26945816; DOI=10.1002/art.39659;
RA Bonafe L., Kariminejad A., Li J., Royer-Bertrand B., Garcia V., Mahdavi S.,
RA Bozorgmehr B., Lachman R.L., Mittaz-Crettol L., Campos-Xavier B.,
RA Nampoothiri S., Unger S., Rivolta C., Levade T., Superti-Furga A.;
RT "Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid
RT Ceramidase) Mutations: A New Presentation of Farber's Disease.";
RL Arthritis Rheum. 68:2323-2327(2016).
RN [36]
RP VARIANT SMAPME ALA-42, CHARACTERIZATION OF VARIANT SMAPME ALA-42, AND
RP CATALYTIC ACTIVITY.
RX PubMed=27026573; DOI=10.1038/ejhg.2016.28;
RA Filosto M., Aureli M., Castellotti B., Rinaldi F., Schiumarini D.,
RA Valsecchi M., Lualdi S., Mazzotti R., Pensato V., Rota S., Gellera C.,
RA Filocamo M., Padovani A.;
RT "ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a
RT clinical, biochemical and molecular study.";
RL Eur. J. Hum. Genet. 24:1578-1583(2016).
RN [37]
RP VARIANT SMAPME ASN-152.
RX PubMed=33798445; DOI=10.1016/j.ajhg.2021.03.013;
RA Courage C., Oliver K.L., Park E.J., Cameron J.M., Grabinska K.A., Muona M.,
RA Canafoglia L., Gambardella A., Said E., Afawi Z., Baykan B., Brandt C.,
RA di Bonaventura C., Chew H.B., Criscuolo C., Dibbens L.M., Castellotti B.,
RA Riguzzi P., Labate A., Filla A., Giallonardo A.T., Berecki G.,
RA Jackson C.B., Joensuu T., Damiano J.A., Kivity S., Korczyn A., Palotie A.,
RA Striano P., Uccellini D., Giuliano L., Andermann E., Scheffer I.E.,
RA Michelucci R., Bahlo M., Franceschetti S., Sessa W.C., Berkovic S.F.,
RA Lehesjoki A.E.;
RT "Progressive myoclonus epilepsies-Residual unsolved cases have marked
RT genetic heterogeneity including dolichol-dependent protein glycosylation
RT pathway genes.";
RL Am. J. Hum. Genet. 108:722-738(2021).
CC -!- FUNCTION: Lysosomal ceramidase that hydrolyzes sphingolipid ceramides
CC into sphingosine and free fatty acids at acidic pH (PubMed:10610716,
CC PubMed:7744740, PubMed:15655246, PubMed:11451951). Ceramides,
CC sphingosine, and its phosphorylated form sphingosine-1-phosphate are
CC bioactive lipids that mediate cellular signaling pathways regulating
CC several biological processes including cell proliferation, apoptosis
CC and differentiation (PubMed:10610716). Has a higher catalytic
CC efficiency towards C12-ceramides versus other ceramides
CC (PubMed:7744740, PubMed:15655246). Also catalyzes the reverse reaction
CC allowing the synthesis of ceramides from fatty acids and sphingosine
CC (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction,
CC the natural sphingosine D-erythro isomer is more efficiently utilized
CC as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-
CC phytosphingosine, while the fatty acids with chain lengths of 12 or 14
CC carbons are the most efficiently used (PubMed:12764132). Has also an N-
CC acylethanolamine hydrolase activity (PubMed:15655246). By regulating
CC the levels of ceramides, sphingosine and sphingosine-1-phosphate in the
CC epidermis, mediates the calcium-induced differentiation of epidermal
CC keratinocytes (PubMed:17713573). Also indirectly regulates tumor
CC necrosis factor/TNF-induced apoptosis (By similarity). By regulating
CC the intracellular balance between ceramides and sphingosine, in
CC adrenocortical cells, probably also acts as a regulator of
CC steroidogenesis (PubMed:22261821). {ECO:0000250|UniProtKB:Q9WV54,
CC ECO:0000269|PubMed:10610716, ECO:0000269|PubMed:11451951,
CC ECO:0000269|PubMed:12764132, ECO:0000269|PubMed:12815059,
CC ECO:0000269|PubMed:15655246, ECO:0000269|PubMed:17713573,
CC ECO:0000269|PubMed:22261821, ECO:0000269|PubMed:7744740,
CC ECO:0000303|PubMed:10610716}.
CC -!- FUNCTION: [Isoform 2]: May directly regulate steroidogenesis by binding
CC the nuclear receptor NR5A1 and negatively regulating its
CC transcriptional activity. {ECO:0000305|PubMed:22927646}.
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:10610716, ECO:0000269|PubMed:11451951,
CC ECO:0000269|PubMed:12638942, ECO:0000269|PubMed:12815059,
CC ECO:0000269|PubMed:15655246, ECO:0000269|PubMed:22703880,
CC ECO:0000269|PubMed:27026573, ECO:0000269|PubMed:29692406,
CC ECO:0000269|PubMed:7744740, ECO:0000269|PubMed:8955159};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-dodecanoylsphing-4-enine = dodecanoate + sphing-4-
CC enine; Xref=Rhea:RHEA:41291, ChEBI:CHEBI:15377, ChEBI:CHEBI:18262,
CC ChEBI:CHEBI:57756, ChEBI:CHEBI:72956;
CC Evidence={ECO:0000269|PubMed:11451951, ECO:0000269|PubMed:12764132,
CC ECO:0000269|PubMed:12815059, ECO:0000269|PubMed:15655246,
CC ECO:0000269|PubMed:29692406, ECO:0000269|PubMed:7744740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41292;
CC Evidence={ECO:0000269|PubMed:7744740, ECO:0000305|PubMed:11451951,
CC ECO:0000305|PubMed:12815059, ECO:0000305|PubMed:15655246};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:41293;
CC Evidence={ECO:0000269|PubMed:12764132, ECO:0000305|PubMed:12815059};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-tetradecanoylsphing-4-enine = sphing-4-enine +
CC tetradecanoate; Xref=Rhea:RHEA:41287, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:30807, ChEBI:CHEBI:57756, ChEBI:CHEBI:72957;
CC Evidence={ECO:0000269|PubMed:12764132};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:41289;
CC Evidence={ECO:0000305|PubMed:12764132};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-hexadecanoylsphing-4-enine = hexadecanoate + sphing-4-
CC enine; Xref=Rhea:RHEA:38891, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57756, ChEBI:CHEBI:72959;
CC Evidence={ECO:0000269|PubMed:12764132, ECO:0000269|PubMed:15655246};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38892;
CC Evidence={ECO:0000305|PubMed:15655246};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:38893;
CC Evidence={ECO:0000305|PubMed:12764132};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-octadecanoylsphing-4-enine = octadecanoate + sphing-4-
CC enine; Xref=Rhea:RHEA:41279, ChEBI:CHEBI:15377, ChEBI:CHEBI:25629,
CC ChEBI:CHEBI:57756, ChEBI:CHEBI:72961;
CC Evidence={ECO:0000269|PubMed:12764132, ECO:0000269|PubMed:7744740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41280;
CC Evidence={ECO:0000305|PubMed:7744740};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:41281;
CC Evidence={ECO:0000305|PubMed:12764132};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-dodecanoyl-(4R)-hydroxysphinganine = (4R)-
CC hydroxysphinganine + dodecanoate; Xref=Rhea:RHEA:41303,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:18262, ChEBI:CHEBI:64124,
CC ChEBI:CHEBI:78001; Evidence={ECO:0000269|PubMed:12764132};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:41305;
CC Evidence={ECO:0000305|PubMed:12764132};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(dodecanoyl)-sphinganine = dodecanoate + sphinganine;
CC Xref=Rhea:RHEA:45448, ChEBI:CHEBI:15377, ChEBI:CHEBI:18262,
CC ChEBI:CHEBI:57817, ChEBI:CHEBI:85261;
CC Evidence={ECO:0000269|PubMed:12764132};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:45450;
CC Evidence={ECO:0000305|PubMed:12764132};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(acetyl)-sphing-4-enine = acetate + sphing-4-enine;
CC Xref=Rhea:RHEA:58484, ChEBI:CHEBI:15377, ChEBI:CHEBI:30089,
CC ChEBI:CHEBI:46979, ChEBI:CHEBI:57756;
CC Evidence={ECO:0000269|PubMed:7744740};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(hexanoyl)sphing-4-enine = hexanoate + sphing-4-enine;
CC Xref=Rhea:RHEA:41295, ChEBI:CHEBI:15377, ChEBI:CHEBI:17120,
CC ChEBI:CHEBI:57756, ChEBI:CHEBI:63867;
CC Evidence={ECO:0000269|PubMed:7744740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41296;
CC Evidence={ECO:0000305|PubMed:7744740};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-octanoylsphing-4-enine = octanoate + sphing-4-enine;
CC Xref=Rhea:RHEA:45092, ChEBI:CHEBI:15377, ChEBI:CHEBI:25646,
CC ChEBI:CHEBI:45815, ChEBI:CHEBI:57756;
CC Evidence={ECO:0000269|PubMed:7744740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45093;
CC Evidence={ECO:0000305|PubMed:7744740};
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:7744740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41300;
CC Evidence={ECO:0000305|PubMed:7744740};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-dodecanoylethanolamine = dodecanoate + ethanolamine;
CC Xref=Rhea:RHEA:45456, ChEBI:CHEBI:15377, ChEBI:CHEBI:18262,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:85263;
CC Evidence={ECO:0000269|PubMed:15655246};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45457;
CC Evidence={ECO:0000305|PubMed:15655246};
CC -!- ACTIVITY REGULATION: Activated by Ca(2+), Mg(2+) and Na(+) cations
CC (PubMed:12764132). Inhibited by Zn(2+) (PubMed:12764132).
CC Phosphatidylserine and phosphatidic acid stimulate while cardiolipin,
CC phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine,
CC phosphatidylinositol and sphingomyelin inhibit the reverse ceramide
CC synthase activity (PubMed:12764132). Phosphatidic acid,
CC phosphatidylinositol and C16-ceramide inhibit the ceramidase/hydrolase
CC activity (PubMed:12764132). {ECO:0000269|PubMed:12764132}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=149 uM for N-dodecanoylsphing-4-enine (at 37 degrees Celsius and
CC pH 4.2) {ECO:0000269|PubMed:7744740};
CC KM=389 uM for N-dodecanoylsphing-4-enine (at 37 degrees Celsius and
CC pH 4.5) {ECO:0000269|PubMed:12815059};
CC KM=24 uM for sphingosine (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:12764132};
CC KM=74 uM for dodecanoate (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:12764132};
CC KM=55 uM for N-dodecanoylethanolamine (at 37 degrees Celsius and pH
CC 4.5) {ECO:0000269|PubMed:15655246};
CC Vmax=136 nmol/h/mg enzyme for the hydrolysis of N-dodecanoylsphing-4-
CC enine (at 37 degrees Celsius and pH 4.2)
CC {ECO:0000269|PubMed:7744740};
CC Vmax=28 nmol/h/mg enzyme for the hydrolysis of N-dodecanoylsphing-4-
CC enine (at 37 degrees Celsius and pH 4.5)
CC {ECO:0000269|PubMed:12815059};
CC Vmax=208 pmol/h/ug enzyme toward sphingosine for the synthesis of N-
CC dodecanoylsphing-4-enine (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:12764132};
CC Vmax=233 pmol/h/ug enzyme toward dodecanoate for the synthesis of N-
CC dodecanoylsphing-4-enine (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:12764132};
CC pH dependence:
CC Optimum pH is 3.8-5.0 for the hydrolysis of N-dodecanoylsphing-4-
CC enine (PubMed:7744740, PubMed:12815059). Optimum pH is 5.5-6.5 for
CC the synthesis of N-dodecanoylsphing-4-enine (PubMed:12815059).
CC {ECO:0000269|PubMed:12815059, ECO:0000269|PubMed:7744740};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:10610716, ECO:0000269|PubMed:7744740}.
CC -!- SUBUNIT: Heterodimer; disulfide-linked (PubMed:7744740,
CC PubMed:11451951, PubMed:30525581, PubMed:29692406). The heterodimer is
CC composed of the disulfide-linked alpha and beta chains produced by
CC autocatalytic cleavage of the precursor (PubMed:7744740,
CC PubMed:11451951, PubMed:30525581, PubMed:29692406). Isoform 2: May
CC interact with NR5A1 in the nucleus; the direct interaction would
CC negatively regulate NR5A1 transcriptional activity (Probable).
CC {ECO:0000269|PubMed:11451951, ECO:0000269|PubMed:29692406,
CC ECO:0000269|PubMed:30525581, ECO:0000269|PubMed:7744740,
CC ECO:0000305|PubMed:22927646}.
CC -!- INTERACTION:
CC Q13510-3; Q9Y5Z0: BACE2; NbExp=3; IntAct=EBI-25917771, EBI-11282723;
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:12764132}. Secreted
CC {ECO:0000269|PubMed:7744740}. Note=Secretion is extremely low and
CC localization to lysosomes is mannose-6-phosphate receptor-dependent.
CC {ECO:0000269|PubMed:11451951}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000305|PubMed:22927646}. Cytoplasm {ECO:0000305|PubMed:22927646}.
CC Note=A localization to the nucleus and the cytoplasm has also been
CC reported for ASAH1, most probably for isoforms devoid of a signal
CC peptide. {ECO:0000305|PubMed:22927646}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q13510-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13510-2; Sequence=VSP_037504;
CC Name=3;
CC IsoId=Q13510-3; Sequence=VSP_037504, VSP_046284, VSP_046285;
CC -!- TISSUE SPECIFICITY: Broadly expressed with higher expression in heart.
CC {ECO:0000269|PubMed:10610716}.
CC -!- INDUCTION: Up-regulated by Ca(2+). {ECO:0000269|PubMed:17713573}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11451951,
CC ECO:0000269|PubMed:29692406, ECO:0000269|PubMed:30525581,
CC ECO:0000269|PubMed:8955159}.
CC -!- PTM: Proteolytically cleaved into two chains alpha and beta that remain
CC associated via a disulfide bond (PubMed:7744740, PubMed:11451951,
CC PubMed:30525581, PubMed:29692406). Cleavage gives rise to a
CC conformation change that activates the enzyme. The same catalytic Cys
CC residue mediates the autoproteolytic cleavage and subsequent hydrolysis
CC of lipid substrates (PubMed:30525581, PubMed:29692406). The beta chain
CC may undergo an additional C-terminal processing (PubMed:12815059).
CC {ECO:0000269|PubMed:11451951, ECO:0000269|PubMed:12815059,
CC ECO:0000269|PubMed:29692406, ECO:0000269|PubMed:30525581,
CC ECO:0000269|PubMed:7744740}.
CC -!- DISEASE: Farber lipogranulomatosis (FRBRL) [MIM:228000]: An autosomal
CC recessive lysosomal storage disorder characterized by subcutaneous
CC lipid-loaded nodules, excruciating pain in the joints and extremities,
CC and marked accumulation of ceramide in lysosomes. Disease severity is
CC variable. The most severe disease subtype is a rare neonatal form with
CC death occurring before 1 year of age. {ECO:0000269|PubMed:10610716,
CC ECO:0000269|PubMed:10993717, ECO:0000269|PubMed:11241842,
CC ECO:0000269|PubMed:12638942, ECO:0000269|PubMed:16951918,
CC ECO:0000269|PubMed:20609603, ECO:0000269|PubMed:21893389,
CC ECO:0000269|PubMed:21982811, ECO:0000269|PubMed:26945816,
CC ECO:0000269|PubMed:27411168, ECO:0000269|PubMed:8955159}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Spinal muscular atrophy with progressive myoclonic epilepsy
CC (SMAPME) [MIM:159950]: An autosomal recessive neuromuscular disorder
CC characterized by childhood onset of motor deficits and progressive
CC myoclonic seizures, after normal developmental milestones. Proximal
CC muscle weakness and generalized muscular atrophy are due to
CC degeneration of spinal motor neurons. Myoclonic epilepsy is generally
CC resistant to conventional therapy. The disease course is progressive
CC and leads to respiratory muscle involvement and severe handicap or
CC early death from respiratory insufficiency.
CC {ECO:0000269|PubMed:22703880, ECO:0000269|PubMed:24164096,
CC ECO:0000269|PubMed:27026573, ECO:0000269|PubMed:33798445}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Mutagenesis in position: 25:L->A (Loss of
CC interaction with NR5A1). {ECO:0000269|PubMed:22927646, ECO:0000305}.
CC -!- SIMILARITY: Belongs to the acid ceramidase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC73009.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U70063; AAC50907.1; -; mRNA.
DR EMBL; U47674; AAC73009.1; ALT_FRAME; mRNA.
DR EMBL; AY305384; AAQ75550.1; -; mRNA.
DR EMBL; AF220175; AAF91230.1; -; Genomic_DNA.
DR EMBL; AF220172; AAF91230.1; JOINED; Genomic_DNA.
DR EMBL; AF220173; AAF91230.1; JOINED; Genomic_DNA.
DR EMBL; AC124242; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC016481; AAH16481.1; -; mRNA.
DR EMBL; BC016828; AAH16828.1; -; mRNA.
DR CCDS; CCDS47813.1; -. [Q13510-3]
DR CCDS; CCDS6005.1; -. [Q13510-2]
DR CCDS; CCDS6006.1; -. [Q13510-1]
DR RefSeq; NP_001120977.1; NM_001127505.2. [Q13510-3]
DR RefSeq; NP_004306.3; NM_004315.5. [Q13510-2]
DR RefSeq; NP_808592.2; NM_177924.4. [Q13510-1]
DR PDB; 5U7Z; X-ray; 2.50 A; A/C=22-142, B/D=143-395.
DR PDB; 6MHM; X-ray; 2.74 A; A/C=22-142, B/D=143-395.
DR PDBsum; 5U7Z; -.
DR PDBsum; 6MHM; -.
DR AlphaFoldDB; Q13510; -.
DR SMR; Q13510; -.
DR BioGRID; 106920; 69.
DR CORUM; Q13510; -.
DR IntAct; Q13510; 30.
DR MINT; Q13510; -.
DR STRING; 9606.ENSP00000371152; -.
DR BindingDB; Q13510; -.
DR ChEMBL; CHEMBL5463; -.
DR SwissLipids; SLP:000000162; -.
DR MEROPS; C89.001; -.
DR GlyConnect; 986; 25 N-Linked glycans (4 sites).
DR GlyGen; Q13510; 8 sites, 26 N-linked glycans (4 sites), 1 O-linked glycan (1 site).
DR iPTMnet; Q13510; -.
DR PhosphoSitePlus; Q13510; -.
DR SwissPalm; Q13510; -.
DR BioMuta; ASAH1; -.
DR DMDM; 239938949; -.
DR EPD; Q13510; -.
DR jPOST; Q13510; -.
DR MassIVE; Q13510; -.
DR MaxQB; Q13510; -.
DR PaxDb; Q13510; -.
DR PeptideAtlas; Q13510; -.
DR PRIDE; Q13510; -.
DR ProteomicsDB; 19735; -.
DR ProteomicsDB; 59511; -. [Q13510-1]
DR ProteomicsDB; 59512; -. [Q13510-2]
DR TopDownProteomics; Q13510-1; -. [Q13510-1]
DR Antibodypedia; 1611; 310 antibodies from 31 providers.
DR DNASU; 427; -.
DR Ensembl; ENST00000314146.10; ENSP00000326970.10; ENSG00000104763.20. [Q13510-3]
DR Ensembl; ENST00000381733.9; ENSP00000371152.4; ENSG00000104763.20. [Q13510-2]
DR Ensembl; ENST00000635998.1; ENSP00000490506.1; ENSG00000104763.20. [Q13510-1]
DR Ensembl; ENST00000637790.2; ENSP00000490272.1; ENSG00000104763.20. [Q13510-1]
DR GeneID; 427; -.
DR KEGG; hsa:427; -.
DR MANE-Select; ENST00000637790.2; ENSP00000490272.1; NM_177924.5; NP_808592.2.
DR UCSC; uc003wyl.3; human. [Q13510-1]
DR CTD; 427; -.
DR DisGeNET; 427; -.
DR GeneCards; ASAH1; -.
DR GeneReviews; ASAH1; -.
DR HGNC; HGNC:735; ASAH1.
DR HPA; ENSG00000104763; Tissue enhanced (heart).
DR MalaCards; ASAH1; -.
DR MIM; 159950; phenotype.
DR MIM; 228000; phenotype.
DR MIM; 613468; gene.
DR neXtProt; NX_Q13510; -.
DR OpenTargets; ENSG00000104763; -.
DR Orphanet; 333; Farber disease.
DR Orphanet; 2590; Spinal muscular atrophy-progressive myoclonic epilepsy syndrome.
DR PharmGKB; PA35025; -.
DR VEuPathDB; HostDB:ENSG00000104763; -.
DR eggNOG; ENOG502QVBG; Eukaryota.
DR GeneTree; ENSGT00530000063548; -.
DR HOGENOM; CLU_054401_0_0_1; -.
DR InParanoid; Q13510; -.
DR OMA; RWKNPLF; -.
DR OrthoDB; 606683at2759; -.
DR PhylomeDB; Q13510; -.
DR TreeFam; TF313219; -.
DR BRENDA; 3.5.1.23; 2681.
DR PathwayCommons; Q13510; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SABIO-RK; Q13510; -.
DR SignaLink; Q13510; -.
DR UniPathway; UPA00222; -.
DR BioGRID-ORCS; 427; 18 hits in 1079 CRISPR screens.
DR ChiTaRS; ASAH1; human.
DR GeneWiki; ASAH1; -.
DR GenomeRNAi; 427; -.
DR Pharos; Q13510; Tchem.
DR PRO; PR:Q13510; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q13510; protein.
DR Bgee; ENSG00000104763; Expressed in heart right ventricle and 204 other tissues.
DR ExpressionAtlas; Q13510; baseline and differential.
DR Genevisible; Q13510; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:1904724; C:tertiary granule lumen; TAS:Reactome.
DR GO; GO:0102121; F:ceramidase activity; IEA:UniProtKB-EC.
DR GO; GO:0017064; F:fatty acid amide hydrolase activity; IEA:InterPro.
DR GO; GO:0016810; F:hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds; IBA:GO_Central.
DR GO; GO:0016811; F:hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides; IDA:UniProtKB.
DR GO; GO:0017040; F:N-acylsphingosine amidohydrolase activity; IDA:UniProtKB.
DR GO; GO:0016922; F:nuclear receptor binding; IPI:UniProtKB.
DR GO; GO:0003714; F:transcription corepressor activity; IMP:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0046514; P:ceramide catabolic process; IDA:UniProtKB.
DR GO; GO:0006631; P:fatty acid metabolic process; IEA:InterPro.
DR GO; GO:0030216; P:keratinocyte differentiation; IMP:UniProtKB.
DR GO; GO:1903507; P:negative regulation of nucleic acid-templated transcription; IMP:UniProtKB.
DR GO; GO:0062098; P:regulation of programmed necrotic cell death; ISS:UniProtKB.
DR GO; GO:0050810; P:regulation of steroid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IDA:UniProtKB.
DR InterPro; IPR016699; Acid_ceramidase-like.
DR InterPro; IPR029130; Acid_ceramidase_N.
DR InterPro; IPR029132; CBAH/NAAA_C.
DR Pfam; PF02275; CBAH; 1.
DR Pfam; PF15508; NAAA-beta; 1.
DR PIRSF; PIRSF017632; Acid_ceramidase-like; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Direct protein sequencing;
KW Disease variant; Disulfide bond; Epilepsy; Glycoprotein; Hydrolase;
KW Lipid metabolism; Lysosome; Neurodegeneration; Nucleus; Reference proteome;
KW Secreted; Signal; Sphingolipid metabolism.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..142
FT /note="Acid ceramidase subunit alpha"
FT /evidence="ECO:0000305|PubMed:29692406"
FT /id="PRO_0000002312"
FT CHAIN 143..395
FT /note="Acid ceramidase subunit beta"
FT /evidence="ECO:0000305|PubMed:29692406"
FT /id="PRO_0000002313"
FT ACT_SITE 143
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0000269|PubMed:30525581"
FT SITE 162
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000269|PubMed:29692406"
FT SITE 320
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000269|PubMed:29692406"
FT SITE 333
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000269|PubMed:29692406"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U7Z"
FT CARBOHYD 195
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 259
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12754519,
FT ECO:0000269|PubMed:16263699, ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U7Z"
FT CARBOHYD 286
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12754519,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U7Z"
FT CARBOHYD 342
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U7Z"
FT CARBOHYD 348
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 31..340
FT /note="Interchain (between alpha and beta subunits)"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0000269|PubMed:30525581, ECO:0007744|PDB:5U7Z,
FT ECO:0007744|PDB:6MHM"
FT DISULFID 388..392
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0000269|PubMed:30525581, ECO:0007744|PDB:5U7Z,
FT ECO:0007744|PDB:6MHM"
FT VAR_SEQ 1..26
FT /note="MPGRSCVALVLLAAAVSCAVAQHAPP -> MNCCIGLGEKARGSHRASYPSL
FT SALFTEASILGFGSFAVKAQ (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4"
FT /id="VSP_037504"
FT VAR_SEQ 42
FT /note="T -> TVFPAVIR (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_046284"
FT VAR_SEQ 73..101
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_046285"
FT VARIANT 22
FT /note="Q -> H (in FRBRL)"
FT /evidence="ECO:0000269|PubMed:10993717"
FT /id="VAR_038166"
FT VARIANT 23
FT /note="H -> D (in FRBRL)"
FT /evidence="ECO:0000269|PubMed:10993717"
FT /id="VAR_038167"
FT VARIANT 36
FT /note="Y -> C (in FRBRL; dbSNP:rs137853595)"
FT /evidence="ECO:0000269|PubMed:11241842"
FT /id="VAR_021579"
FT VARIANT 42
FT /note="T -> A (in SMAPME; unknown pathological
FT significance; decreased ceramide catabolic process;
FT dbSNP:rs779888892)"
FT /evidence="ECO:0000269|PubMed:27026573"
FT /id="VAR_081279"
FT VARIANT 42
FT /note="T -> M (in SMAPME; results in reduced activity;
FT dbSNP:rs145873635)"
FT /evidence="ECO:0000269|PubMed:22703880"
FT /id="VAR_068722"
FT VARIANT 70
FT /note="A -> V (in dbSNP:rs10103355)"
FT /id="VAR_057979"
FT VARIANT 72
FT /note="V -> M (in dbSNP:rs1071645)"
FT /evidence="ECO:0000269|PubMed:10993717,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:8955159,
FT ECO:0000269|Ref.2"
FT /id="VAR_008860"
FT VARIANT 88
FT /note="V -> M (in dbSNP:rs1071645)"
FT /id="VAR_057980"
FT VARIANT 93
FT /note="I -> V (in dbSNP:rs1049874)"
FT /evidence="ECO:0000269|PubMed:10993717,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:8955159,
FT ECO:0000269|Ref.2"
FT /id="VAR_008861"
FT VARIANT 96
FT /note="Missing (in FRBRL; decreased ceramide catabolic
FT process)"
FT /evidence="ECO:0000269|PubMed:12638942"
FT /id="VAR_021580"
FT VARIANT 97
FT /note="V -> E (in FRBRL; decreased ceramide catabolic
FT process)"
FT /evidence="ECO:0000269|PubMed:12638942"
FT /id="VAR_021581"
FT VARIANT 97
FT /note="V -> G (in FRBRL)"
FT /evidence="ECO:0000269|PubMed:21893389"
FT /id="VAR_071994"
FT VARIANT 124
FT /note="D -> E (in dbSNP:rs2472205)"
FT /id="VAR_038168"
FT VARIANT 138
FT /note="E -> V (in FRBRL; loss of ceramidase activity;
FT dbSNP:rs137853594)"
FT /evidence="ECO:0000269|PubMed:10610716,
FT ECO:0000269|PubMed:10993717"
FT /id="VAR_021582"
FT VARIANT 152
FT /note="K -> N (in SMAPME; decreased protein abundance;
FT alters the splicing of ASAH1 transcripts;
FT dbSNP:rs200455852)"
FT /evidence="ECO:0000269|PubMed:24164096,
FT ECO:0000269|PubMed:33798445"
FT /id="VAR_072247"
FT VARIANT 168
FT /note="G -> W (in FRBRL)"
FT /evidence="ECO:0000269|PubMed:20609603"
FT /id="VAR_071995"
FT VARIANT 169
FT /note="W -> R (in FRBRL; unknown pathological significance;
FT dbSNP:rs756455049)"
FT /evidence="ECO:0000269|PubMed:26945816"
FT /id="VAR_081280"
FT VARIANT 182
FT /note="L -> V (in FRBRL; dbSNP:rs137853597)"
FT /evidence="ECO:0000269|PubMed:16951918"
FT /id="VAR_038169"
FT VARIANT 222
FT /note="T -> K (in FRBRL; dbSNP:rs137853593)"
FT /evidence="ECO:0000269|PubMed:10993717,
FT ECO:0000269|PubMed:8955159"
FT /id="VAR_008862"
FT VARIANT 235
FT /note="G -> R (in FRBRL; decreased ceramide catabolic
FT process; dbSNP:rs1554808625)"
FT /evidence="ECO:0000269|PubMed:12638942,
FT ECO:0000269|PubMed:27411168"
FT /id="VAR_021583"
FT VARIANT 246
FT /note="V -> A (in dbSNP:rs10103355)"
FT /evidence="ECO:0000269|PubMed:10993717,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:8955159,
FT ECO:0000269|Ref.2"
FT /id="VAR_038170"
FT VARIANT 254
FT /note="R -> G (in FRBRL; unknown pathological significance;
FT loss of ceramidase activity)"
FT /evidence="ECO:0000269|PubMed:10610716,
FT ECO:0000269|PubMed:26945816"
FT /id="VAR_021584"
FT VARIANT 284..395
FT /note="Missing (in SMAPME; loss of protein abundance; the
FT corresponding mRNA is not detected and probably degraded)"
FT /evidence="ECO:0000269|PubMed:24164096"
FT /id="VAR_081281"
FT VARIANT 320
FT /note="N -> D (in FRBRL; dbSNP:rs137853596)"
FT /evidence="ECO:0000269|PubMed:10993717,
FT ECO:0000269|PubMed:11241842"
FT /id="VAR_021585"
FT VARIANT 333
FT /note="R -> C (in FRBRL; unknown pathological significance;
FT dbSNP:rs543697946)"
FT /evidence="ECO:0000269|PubMed:27411168"
FT /id="VAR_081282"
FT VARIANT 362
FT /note="P -> R (in FRBRL; loss of ceramidase activity)"
FT /evidence="ECO:0000269|PubMed:10610716"
FT /id="VAR_021586"
FT VARIANT 369
FT /note="V -> I (in dbSNP:rs17636067)"
FT /evidence="ECO:0000269|PubMed:12638942"
FT /id="VAR_021587"
FT MUTAGEN 80
FT /note="L->Q: No effect on autocatalytic processing, but
FT loss of ceramidase activity, when associated with 165-Q--Q-
FT 167."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 141
FT /note="T->A: Decreased rate of autocatalytic processing."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 143
FT /note="C->A: Loss of autocatalytic processing. Loss of
FT ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 159
FT /note="R->Q: Strongly decreased autocatalytic processing.
FT Moderately decreased ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 162
FT /note="D->N: Strongly decreased autocatalytic processing.
FT Strongly decreased ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 165..167
FT /note="VFL->QFQ: No effect on autocatalytic processing, but
FT loss of ceramidase activity, when associated with Q-80."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 169..171
FT /note="WNI->QNQ: Moderately decreased autocatalytic
FT processing, but loss of ceramidase activity, when
FT associated with Q-176."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 173
FT /note="N->Q: Loss of ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT MUTAGEN 176
FT /note="W->Q: Moderately decreased autocatalytic processing,
FT but loss of ceramidase activity, when associated with 169-
FT Q--Q-171."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 195
FT /note="N->Q: No effect on ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT MUTAGEN 259
FT /note="N->Q: Loss of ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT MUTAGEN 286
FT /note="N->Q: No effect on ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT MUTAGEN 320
FT /note="N->A: Strongly decreased autocatalytic processing.
FT Mildly decreased ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 328..330
FT /note="FFL->QQQ: No effect on autocatalytic processing, but
FT strongly decreased ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 333
FT /note="R->Q: Mildly decreased autocatalytic processing.
FT Loss of ceramidase activity."
FT /evidence="ECO:0000269|PubMed:29692406"
FT MUTAGEN 342
FT /note="N->Q: Loss of ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT MUTAGEN 348
FT /note="N->Q: No effect on ceramide catabolic process."
FT /evidence="ECO:0000269|PubMed:11451951"
FT CONFLICT 122
FT /note="V -> A (in Ref. 4; AAQ75550)"
FT /evidence="ECO:0000305"
FT CONFLICT 142
FT /note="I -> V (in Ref. 8; AAH16828)"
FT /evidence="ECO:0000305"
FT CONFLICT 155
FT /note="L -> P (in Ref. 4; AAQ75550)"
FT /evidence="ECO:0000305"
FT CONFLICT 233
FT /note="Y -> N (in Ref. 4; AAQ75550)"
FT /evidence="ECO:0000305"
FT CONFLICT 364
FT /note="L -> P (in Ref. 4; AAQ75550)"
FT /evidence="ECO:0000305"
FT TURN 36..38
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 43..46
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 49..53
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 58..60
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 63..87
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 90..105
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 112..123
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 127..134
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 144..149
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 155..162
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 171..174
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 177..182
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 183..185
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 186..193
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 196..204
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 211..215
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 216..218
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 219..225
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 231..240
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 249..259
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 263..272
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 275..277
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 279..284
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 291..296
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 301..306
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 309..312
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 315..318
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 323..325
FT /evidence="ECO:0007829|PDB:6MHM"
FT STRAND 328..330
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 334..344
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 346..348
FT /evidence="ECO:0007829|PDB:5U7Z"
FT HELIX 351..357
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 361..363
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 368..375
FT /evidence="ECO:0007829|PDB:5U7Z"
FT TURN 376..379
FT /evidence="ECO:0007829|PDB:5U7Z"
FT STRAND 380..386
FT /evidence="ECO:0007829|PDB:5U7Z"
FT VARIANT Q13510-2:185
FT /note="W -> R (in FRBRL; dbSNP:rs756455049)"
FT /evidence="ECO:0000269|PubMed:21982811"
FT /id="VAR_082799"
FT VARIANT Q13510-2:382
FT /note="K -> Q (in FRBRL; dbSNP:rs1588973202)"
FT /evidence="ECO:0000269|PubMed:21982811"
FT /id="VAR_082800"
SQ SEQUENCE 395 AA; 44660 MW; 83467DBE8917DB6D CRC64;
MPGRSCVALV LLAAAVSCAV AQHAPPWTED CRKSTYPPSG PTYRGAVPWY TINLDLPPYK
RWHELMLDKA PVLKVIVNSL KNMINTFVPS GKIMQVVDEK LPGLLGNFPG PFEEEMKGIA
AVTDIPLGEI ISFNIFYELF TICTSIVAED KKGHLIHGRN MDFGVFLGWN INNDTWVITE
QLKPLTVNLD FQRNNKTVFK ASSFAGYVGM LTGFKPGLFS LTLNERFSIN GGYLGILEWI
LGKKDVMWIG FLTRTVLENS TSYEEAKNLL TKTKILAPAY FILGGNQSGE GCVITRDRKE
SLDVYELDAK QGRWYVVQTN YDRWKHPFFL DDRRTPAKMC LNRTSQENIS FETMYDVLST
KPVLNKLTVY TTLIDVTKGQ FETYLRDCPD PCIGW
