ID   GBA1_PANTR              Reviewed;         536 AA.
AC   Q9BDT0;
DT   21-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   27-MAR-2024, entry version 123.
DE   RecName: Full=Lysosomal acid glucosylceramidase {ECO:0000305};
DE            EC=3.2.1.45 {ECO:0000250|UniProtKB:P04062};
DE   AltName: Full=Acid beta-glucosidase;
DE   AltName: Full=Beta-glucocerebrosidase;
DE   AltName: Full=Cholesterol glucosyltransferase {ECO:0000250|UniProtKB:P04062};
DE            Short=SGTase {ECO:0000250|UniProtKB:P04062};
DE            EC=2.4.1.- {ECO:0000250|UniProtKB:P04062};
DE   AltName: Full=Cholesteryl-beta-glucosidase {ECO:0000250|UniProtKB:P04062};
DE            EC=3.2.1.- {ECO:0000250|UniProtKB:P04062};
DE   AltName: Full=D-glucosyl-N-acylsphingosine glucohydrolase;
DE   AltName: Full=Lysosomal cholesterol glycosyltransferase {ECO:0000305};
DE   AltName: Full=Lysosomal galactosylceramidase {ECO:0000305};
DE            EC=3.2.1.46 {ECO:0000250|UniProtKB:P04062};
DE   AltName: Full=Lysosomal glycosylceramidase {ECO:0000305};
DE   Flags: Precursor;
GN   Name=GBA1; Synonyms=GBA {ECO:0000250|UniProtKB:P04062}, GC;
OS   Pan troglodytes (Chimpanzee).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pan.
OX   NCBI_TaxID=9598;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Martinez-Arias R., Comas D., Bertranpetit J.;
RT   "Allelic variability on the glucocerebrosidase pseudogene.";
RL   Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Glucosylceramidase that catalyzes, within the lysosomal
CC       compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-
CC       D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as
CC       N-acylsphing-4-enine) and glucose. Plays a central role in the
CC       degradation of complex lipids and the turnover of cellular membranes.
CC       Through the production of ceramides, participates in the PKC-activated
CC       salvage pathway of ceramide formation. Catalyzes the glucosylation of
CC       cholesterol, through a transglucosylation reaction where glucose is
CC       transferred from GlcCer to cholesterol. GlcCer containing mono-
CC       unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-
CC       sphing-4-enine) are preferred as glucose donors for cholesterol
CC       glucosylation when compared with GlcCer containing same chain length of
CC       saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-
CC       enine). Under specific conditions, may alternatively catalyze the
CC       reverse reaction, transferring glucose from cholesteryl 3-beta-D-
CC       glucoside to ceramide. Can also hydrolyze cholesteryl 3-beta-D-
CC       glucoside producing glucose and cholesterol. Catalyzes the hydrolysis
CC       of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-
CC       acylsphing-4-enine), as well as the transfer of galactose between
CC       GalCers and cholesterol in vitro, but with lower activity than with
CC       GlcCers. Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as
CC       beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate
CC       for hydrolysis, however it is a good xylose donor for transxylosylation
CC       activity to form cholesteryl 3-beta-D-xyloside.
CC       {ECO:0000250|UniProtKB:P04062}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = an N-
CC         acylsphing-4-enine + D-glucose; Xref=Rhea:RHEA:13269,
CC         ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, ChEBI:CHEBI:22801,
CC         ChEBI:CHEBI:52639; EC=3.2.1.45;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13270;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H2O = an
CC         N-acylsphing-4-enine + D-galactose; Xref=Rhea:RHEA:14297,
CC         ChEBI:CHEBI:4139, ChEBI:CHEBI:15377, ChEBI:CHEBI:18390,
CC         ChEBI:CHEBI:52639; EC=3.2.1.46;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14298;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cholesteryl 3-beta-D-glucoside + H2O = cholesterol + D-
CC         glucose; Xref=Rhea:RHEA:11956, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:16113, ChEBI:CHEBI:17495;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11957;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + cholesterol
CC         = an N-acylsphing-4-enine + cholesteryl 3-beta-D-glucoside;
CC         Xref=Rhea:RHEA:58264, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495,
CC         ChEBI:CHEBI:22801, ChEBI:CHEBI:52639;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58265;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58266;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine +
CC         cholesterol = cholesteryl 3-beta-D-glucoside + N-(9Z-octadecenoyl)-
CC         sphing-4-enine; Xref=Rhea:RHEA:58324, ChEBI:CHEBI:16113,
CC         ChEBI:CHEBI:17495, ChEBI:CHEBI:77996, ChEBI:CHEBI:139140;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58325;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58326;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-glucosyl-N-octanoylsphing-4E-enine + cholesterol =
CC         cholesteryl 3-beta-D-glucoside + N-octanoylsphing-4-enine;
CC         Xref=Rhea:RHEA:70303, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495,
CC         ChEBI:CHEBI:45815, ChEBI:CHEBI:65222;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70304;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70305;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-glucosyl-N-dodecanoylsphing-4-enine + cholesterol =
CC         cholesteryl 3-beta-D-glucoside + N-dodecanoylsphing-4-enine;
CC         Xref=Rhea:RHEA:70307, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495,
CC         ChEBI:CHEBI:72956, ChEBI:CHEBI:76297;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70308;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70309;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-glucosyl-(1<->1)-N-octadecanoylsphing-4-enine +
CC         cholesterol = cholesteryl 3-beta-D-glucoside + N-octadecanoylsphing-
CC         4-enine; Xref=Rhea:RHEA:70311, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495,
CC         ChEBI:CHEBI:72961, ChEBI:CHEBI:84719;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70312;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70313;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-glucosyl-(1<->1')-N-(15Z-tetracosenoyl)-sphing-4-enine
CC         + cholesterol = cholesteryl 3-beta-D-glucoside + N-(15Z-
CC         tetracosenoyl)-sphing-4-enine; Xref=Rhea:RHEA:70315,
CC         ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, ChEBI:CHEBI:74450,
CC         ChEBI:CHEBI:76302; Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70316;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70317;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine +
CC         cholesterol = an N-acylsphing-4-enine + cholesteryl 3-beta-D-
CC         galactoside; Xref=Rhea:RHEA:70235, ChEBI:CHEBI:16113,
CC         ChEBI:CHEBI:18390, ChEBI:CHEBI:52639, ChEBI:CHEBI:189066;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70236;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70237;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol
CC         = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine;
CC         Xref=Rhea:RHEA:70255, ChEBI:CHEBI:16113, ChEBI:CHEBI:72956,
CC         ChEBI:CHEBI:73432, ChEBI:CHEBI:189066;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70256;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70257;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine + cholesterol =
CC         an N-acylsphing-4-enine + cholesteryl 3-beta-D-xyloside;
CC         Xref=Rhea:RHEA:70239, ChEBI:CHEBI:16113, ChEBI:CHEBI:52639,
CC         ChEBI:CHEBI:189067, ChEBI:CHEBI:189068;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70240;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=beta-D-xylosyl-(1<->1')-N-(9Z-octadecenoyl)-sphing-4-enine +
CC         cholesterol = cholesteryl 3-beta-D-xyloside + N-(9Z-octadecenoyl)-
CC         sphing-4-enine; Xref=Rhea:RHEA:70251, ChEBI:CHEBI:16113,
CC         ChEBI:CHEBI:77996, ChEBI:CHEBI:189067, ChEBI:CHEBI:189081;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70252;
CC         Evidence={ECO:0000250|UniProtKB:P04062};
CC   -!- PATHWAY: Steroid metabolism; cholesterol metabolism.
CC       {ECO:0000250|UniProtKB:P04062}.
CC   -!- PATHWAY: Sphingolipid metabolism. {ECO:0000250|UniProtKB:P04062}.
CC   -!- SUBUNIT: Interacts with saposin-C. Interacts with SCARB2. Interacts
CC       with TCP1. Interacts with GRN; this interaction prevents aggregation of
CC       GBA1-SCARB2 complex via interaction with HSPA1A upon stress (By
CC       similarity). {ECO:0000250|UniProtKB:P04062}.
CC   -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:P04062};
CC       Peripheral membrane protein {ECO:0000250|UniProtKB:P04062}; Lumenal
CC       side {ECO:0000250|UniProtKB:P04062}. Note=Interaction with saposin-C
CC       promotes membrane association. Targeting to lysosomes occurs through an
CC       alternative MPR-independent mechanism via SCARB2.
CC       {ECO:0000250|UniProtKB:P04062}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 30 family. {ECO:0000305}.
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DR   EMBL; AF285236; AAK18162.1; -; Genomic_DNA.
DR   RefSeq; NP_001008997.1; NM_001008997.1.
DR   RefSeq; XP_016804027.1; XM_016948538.1.
DR   RefSeq; XP_016804063.1; XM_016948574.1.
DR   AlphaFoldDB; Q9BDT0; -.
DR   SMR; Q9BDT0; -.
DR   STRING; 9598.ENSPTRP00000051730; -.
DR   CAZy; GH30; Glycoside Hydrolase Family 30.
DR   GlyCosmos; Q9BDT0; 5 sites, No reported glycans.
DR   PaxDb; 9598-ENSPTRP00000051730; -.
DR   Ensembl; ENSPTRT00000002601.6; ENSPTRP00000051730.4; ENSPTRG00000001416.5.
DR   GeneID; 449571; -.
DR   KEGG; ptr:449571; -.
DR   CTD; 2629; -.
DR   VGNC; VGNC:58837; GBA1.
DR   eggNOG; KOG2566; Eukaryota.
DR   GeneTree; ENSGT00390000009464; -.
DR   InParanoid; Q9BDT0; -.
DR   OMA; FGGIAWH; -.
DR   OrthoDB; 3473901at2759; -.
DR   UniPathway; UPA00296; -.
DR   Proteomes; UP000002277; Chromosome 1.
DR   Bgee; ENSPTRG00000001416; Expressed in dorsolateral prefrontal cortex and 21 other cell types or tissues.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR   GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR   GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR   GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR   GO; GO:0004336; F:galactosylceramidase activity; IEA:RHEA.
DR   GO; GO:0004348; F:glucosylceramidase activity; ISS:UniProtKB.
DR   GO; GO:0046527; F:glucosyltransferase activity; ISS:UniProtKB.
DR   GO; GO:0005124; F:scavenger receptor binding; IEA:Ensembl.
DR   GO; GO:0050295; F:steryl-beta-glucosidase activity; ISS:UniProtKB.
DR   GO; GO:0006914; P:autophagy; ISS:UniProtKB.
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:0008203; P:cholesterol metabolic process; ISS:UniProtKB.
DR   GO; GO:0006680; P:glucosylceramide catabolic process; ISS:UniProtKB.
DR   GO; GO:0030259; P:lipid glycosylation; ISS:UniProtKB.
DR   GO; GO:0007040; P:lysosome organization; ISS:UniProtKB.
DR   GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR   GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IEA:Ensembl.
DR   GO; GO:1904457; P:positive regulation of neuronal action potential; IEA:Ensembl.
DR   GO; GO:0035307; P:positive regulation of protein dephosphorylation; IEA:Ensembl.
DR   GO; GO:1903061; P:positive regulation of protein lipidation; IEA:Ensembl.
DR   GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IEA:Ensembl.
DR   GO; GO:0032006; P:regulation of TOR signaling; ISS:UniProtKB.
DR   GO; GO:0046512; P:sphingosine biosynthetic process; IEA:Ensembl.
DR   GO; GO:0023021; P:termination of signal transduction; IEA:Ensembl.
DR   Gene3D; 3.20.20.80; Glycosidases; 1.
DR   InterPro; IPR033452; GH30_C.
DR   InterPro; IPR001139; Glyco_hydro_30.
DR   InterPro; IPR033453; Glyco_hydro_30_TIM-barrel.
DR   InterPro; IPR017853; Glycoside_hydrolase_SF.
DR   PANTHER; PTHR11069; GLUCOSYLCERAMIDASE; 1.
DR   PANTHER; PTHR11069:SF33; LYSOSOMAL ACID GLUCOSYLCERAMIDASE; 1.
DR   Pfam; PF02055; Glyco_hydro_30; 1.
DR   Pfam; PF17189; Glyco_hydro_30C; 1.
DR   PRINTS; PR00843; GLHYDRLASE30.
DR   SUPFAM; SSF51445; (Trans)glycosidases; 1.
DR   SUPFAM; SSF51011; Glycosyl hydrolase domain; 2.
PE   3: Inferred from homology;
KW   Cholesterol metabolism; Disulfide bond; Glycoprotein; Glycosidase;
KW   Glycosyltransferase; Hydrolase; Lipid metabolism; Lysosome; Membrane;
KW   Reference proteome; Signal; Sphingolipid metabolism; Steroid metabolism;
KW   Sterol metabolism; Transferase.
FT   SIGNAL          1..39
FT                   /evidence="ECO:0000250"
FT   CHAIN           40..536
FT                   /note="Lysosomal acid glucosylceramidase"
FT                   /id="PRO_0000012179"
FT   ACT_SITE        274
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        379
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        58
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        98
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        185
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        309
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        501
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        43..55
FT                   /evidence="ECO:0000250|UniProtKB:P04062"
FT   DISULFID        57..62
FT                   /evidence="ECO:0000250|UniProtKB:P04062"
SQ   SEQUENCE   536 AA;  59664 MW;  E1A61BF380FF1888 CRC64;
     MEFSSPSREE CPKPSGRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT
     YCDSFDPPTF PALGTFSRYE STRSGRRMEL SMGTIQANHT GTGLLLTLQP EQKFQKVKGF
     GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV PMASCDFSIR TYTYADTPDD
     FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP
     GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA
     RDLGPTLANS THHNVRLLML DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK
     ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM QYSHSIITNL LYHVVGWTDW
     NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK
     NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ
//