ASAH1_HETGA
ID ASAH1_HETGA Reviewed; 395 AA.
AC A0A0P6JG37;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 20-JAN-2016, sequence version 1.
DT 03-AUG-2022, entry version 32.
DE RecName: Full=Acid ceramidase {ECO:0000303|PubMed:29692406};
DE Short=AC;
DE Short=ACDase {ECO:0000303|PubMed:29692406};
DE Short=Acid CDase;
DE EC=3.5.1.23 {ECO:0000250|UniProtKB:Q13510};
DE Contains:
DE RecName: Full=Acid ceramidase subunit alpha {ECO:0000305|PubMed:29692406};
DE Contains:
DE RecName: Full=Acid ceramidase subunit beta {ECO:0000305|PubMed:29692406};
DE Flags: Precursor;
GN Name=ASAH1 {ECO:0000312|EMBL:JAO03528.1};
OS Heterocephalus glaber (Naked mole rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Bathyergidae;
OC Heterocephalus.
OX NCBI_TaxID=10181 {ECO:0000312|EMBL:JAO03528.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=21993625; DOI=10.1038/nature10533;
RA Kim E.B., Fang X., Fushan A.A., Huang Z., Lobanov A.V., Han L.,
RA Marino S.M., Sun X., Turanov A.A., Yang P., Yim S.H., Zhao X.,
RA Kasaikina M.V., Stoletzki N., Peng C., Polak P., Xiong Z., Kiezun A.,
RA Zhu Y., Chen Y., Kryukov G.V., Zhang Q., Peshkin L., Yang L., Bronson R.T.,
RA Buffenstein R., Wang B., Han C., Li Q., Chen L., Zhao W., Sunyaev S.R.,
RA Park T.J., Zhang G., Wang J., Gladyshev V.N.;
RT "Genome sequencing reveals insights into physiology and longevity of the
RT naked mole rat.";
RL Nature 479:223-227(2011).
RN [2] {ECO:0000312|EMBL:JAO03528.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney {ECO:0000312|EMBL:JAO03528.1};
RX PubMed=26763976; DOI=10.1186/s12864-015-2349-8;
RA Bens M., Sahm A., Groth M., Jahn N., Morhart M., Holtze S.,
RA Hildebrandt T.B., Platzer M., Szafranski K.;
RT "FRAMA: from RNA-seq data to annotated mRNA assemblies.";
RL BMC Genomics 17:54-54(2016).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) OF 22-395 OF MUTANT ALA-143, ACTIVE
RP SITE, GLYCOSYLATION AT ASN-173; ASN-259 AND ASN-286, AND DISULFIDE BOND.
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).
CC -!- FUNCTION: Lysosomal ceramidase that hydrolyzes sphingolipid ceramides
CC into sphingosine and free fatty acids at acidic pH (By similarity).
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 (By similarity). Has a higher catalytic
CC efficiency towards C12-ceramides versus other ceramides (By
CC similarity). Also catalyzes the reverse reaction allowing the synthesis
CC of ceramides from fatty acids and sphingosine (By similarity). For the
CC reverse synthetic reaction, the natural sphingosine D-erythro isomer is
CC more efficiently utilized as a substrate compared to D-erythro-
CC dihydrosphingosine and D-erythro-phytosphingosine, while the fatty
CC acids with chain lengths of 12 or 14 carbons are the most efficiently
CC used (By similarity). Has also an N-acylethanolamine hydrolase activity
CC (By similarity). By regulating the levels of ceramides, sphingosine and
CC sphingosine-1-phosphate in the epidermis, mediates the calcium-induced
CC differentiation of epidermal keratinocytes (By similarity). Also
CC indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By
CC similarity). By regulating the intracellular balance between ceramides
CC and sphingosine, in adrenocortical cells, probably also acts as a
CC regulator of steroidogenesis (By similarity).
CC {ECO:0000250|UniProtKB:Q13510}.
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
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:0000250|UniProtKB:Q13510};
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000250|UniProtKB:Q13510}.
CC -!- SUBUNIT: Heterodimer; disulfide-linked. The heterodimer is composed of
CC the disulfide-linked alpha and beta chains produced by autocatalytic
CC cleavage of the precursor. {ECO:0000269|PubMed:29692406}.
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000250|UniProtKB:Q13510}. Secreted
CC {ECO:0000250|UniProtKB:Q13510}. Note=Secretion is extremely low and
CC localization to lysosomes is mannose-6-phosphate receptor-dependent.
CC {ECO:0000250|UniProtKB:Q13510}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:29692406}.
CC -!- PTM: Proteolytically cleaved into two chains alpha and beta that remain
CC associated via a disulfide bond (PubMed:29692406). Cleavage gives rise
CC to a conformation change that activates the enzyme. The same catalytic
CC Cys residue mediates the autoproteolytic cleavage and subsequent
CC hydrolysis of lipid substrates. The beta chain may undergo an
CC additional C-terminal processing (By similarity).
CC {ECO:0000250|UniProtKB:Q13510, ECO:0000269|PubMed:29692406}.
CC -!- SIMILARITY: Belongs to the acid ceramidase family. {ECO:0000305}.
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DR EMBL; AHKG01049371; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; GEBF01000105; JAO03528.1; -; Transcribed_RNA.
DR RefSeq; XP_004853125.1; XM_004853068.2.
DR PDB; 5U81; X-ray; 1.40 A; A=22-395.
DR PDBsum; 5U81; -.
DR AlphaFoldDB; A0A0P6JG37; -.
DR SMR; A0A0P6JG37; -.
DR STRING; 10181.XP_004853125.1; -.
DR iPTMnet; A0A0P6JG37; -.
DR Ensembl; ENSHGLT00000008821; ENSHGLP00000008726; ENSHGLG00000006285.
DR GeneID; 101724913; -.
DR KEGG; hgl:101724913; -.
DR CTD; 427; -.
DR OrthoDB; 745108at2759; -.
DR UniPathway; UPA00222; -.
DR Bgee; ENSHGLG00000006285; Expressed in thyroid gland and 10 other tissues.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
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:0017040; F:N-acylsphingosine amidohydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0046513; P:ceramide biosynthetic process; IEA:Ensembl.
DR GO; GO:0046514; P:ceramide catabolic process; IEA:Ensembl.
DR GO; GO:0006631; P:fatty acid metabolic process; IEA:InterPro.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0062098; P:regulation of programmed necrotic cell death; IEA:Ensembl.
DR GO; GO:0050810; P:regulation of steroid biosynthetic process; IEA:Ensembl.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IEA:Ensembl.
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; Disulfide bond; Glycoprotein; Hydrolase; Lipid metabolism;
KW Lysosome; Secreted; Signal; Sphingolipid metabolism; Zymogen.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..395
FT /note="Acid ceramidase"
FT /id="PRO_5006128967"
FT CHAIN 22..142
FT /note="Acid ceramidase subunit alpha"
FT /evidence="ECO:0000250|UniProtKB:Q13510"
FT /id="PRO_0000446622"
FT CHAIN 143..395
FT /note="Acid ceramidase subunit beta"
FT /evidence="ECO:0000250|UniProtKB:Q13510"
FT /id="PRO_0000446623"
FT ACT_SITE 143
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:29692406"
FT SITE 162
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:Q13510"
FT SITE 320
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:Q13510"
FT SITE 333
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:Q13510"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U81"
FT CARBOHYD 259
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U81"
FT CARBOHYD 286
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U81"
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:0007744|PDB:5U81"
FT DISULFID 388..392
FT /evidence="ECO:0000269|PubMed:29692406,
FT ECO:0007744|PDB:5U81"
FT MUTAGEN 143
FT /note="C->A: Loss of autoproteolytic cleavage."
FT /evidence="ECO:0000269|PubMed:29692406"
SQ SEQUENCE 395 AA; 45003 MW; 05758D13F7D98551 CRC64;
MLGRSRLTFV LLAAAVTCAE AQHAPPWTED CRKSTYPPSG PTYRGPVPWY TINLDLPPYK
RWHELMVDKG PMLKIIVNSF KNMVNTFVPS GKVMQMVDQK LPDLLGQFSG PYEEEMKGIA
DVTEIPLGEI ISFNIFYELF TMCTSIITED KKGHLLHVRN MDFGIFLGWN INNNTWVITE
ELKPLTVNLD FQRNSKTVFK ATSFAGYVGM LTGFKPGQFS LTLNERFSMN GGYLGLLEWI
LGKKDASWIG FITRSVLENA TSYEEAKNIL AKTKLLAPAY FILGGNQSGE GCVITRERKD
SLDIYELDPK QGRWYVVQTN YDRWKNPLFL DDRRTPAQTC LKRTTQENLS FATLYDILST
KPVLNKLTVF TALMDVTKNH YEAYLRDCPD PCVGW
