{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9HCG7","secondaryAccessions":["D3DRP2","Q5TCV6","Q96A51","Q96LY1","Q96SJ2","Q9H2L8"],"uniProtkbId":"GBA2_HUMAN","entryAudit":{"firstPublicDate":"2007-04-03","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2007-04-03","entryVersion":171,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Non-lysosomal glucosylceramidase"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"30308956"}],"value":"NLGase"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17080196"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30308956"}],"value":"3.2.1.45"}]},"alternativeNames":[{"fullName":{"value":"Beta-glucocerebrosidase 2"},"shortNames":[{"value":"Beta-glucosidase 2"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9111029"}],"value":"Bile acid beta-glucosidase GBA2"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"9111029"}],"value":"Bile acid glucosyl transferase GBA2"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Cholesterol glucosyltransferase GBA2"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"2.4.1.-"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Cholesteryl-beta-glucosidase GBA2"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"3.2.1.-"}]},{"fullName":{"value":"Glucosylceramidase 2"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Non-lysosomal cholesterol glycosyltransferase"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Non-lysosomal galactosylceramidase"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}],"value":"3.2.1.46"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Non-lysosomal glycosylceramidase"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:18986"}],"value":"GBA2"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000312","source":"EMBL","id":"BAB13431.1"}],"value":"KIAA1605"},{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:18986"}],"value":"SPG46"}],"orfNames":[{"value":"AD035"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17080196"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17105727"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30308956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}],"value":"Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine) (PubMed:17105727, PubMed:30308956, PubMed:32144204). GlcCers are membrane glycosphingolipids that have a wide intracellular distribution (By similarity). They are the main precursors of more complex glycosphingolipids that play a role in cellular growth, differentiation, adhesion, signaling, cytoskeletal dynamics and membrane properties (By similarity). Involved in the transglucosylation of cholesterol, transfers glucose from GlcCer to cholesterol, thereby modifying its water solubility and biological properties (PubMed:32144204). Under specific conditions, may catalyze the reverse reaction, transferring glucose from cholesteryl-3-beta-D-glucoside to ceramide (such as N-acylsphing-4-enine) (Probable). May play a role in the metabolism of bile acids (PubMed:11489889, PubMed:17080196, PubMed:9111029). Able to hydrolyze bile acid 3-O-glucosides as well as to produce bile acid-glucose conjugates thanks to a bile acid glucosyl transferase activity (PubMed:11489889, PubMed:17080196, PubMed:9111029). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the galactosyl transfer between GalCers and cholesterol in vitro with lower activity compared with their activity against GlcCers (PubMed:32144204)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + 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D-glucose","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:58340"},{"database":"ChEBI","id":"CHEBI:4167"},{"database":"ChEBI","id":"CHEBI:15377"},{"database":"ChEBI","id":"CHEBI:36234"},{"database":"ChEBI","id":"CHEBI:142610"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:58341"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"9111029"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a di-trans,poly-cis-dolichyl beta-D-glucosyl phosphate + chenodeoxycholate = beta-D-glucosyl-(1->3)-O-chenodeoxycholate + a di-trans,poly-cis-dolichyl phosphate + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:59104"},{"database":"Rhea","id":"RHEA-COMP:19498"},{"database":"Rhea","id":"RHEA-COMP:19502"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:36234"},{"database":"ChEBI","id":"CHEBI:57525"},{"database":"ChEBI","id":"CHEBI:57683"},{"database":"ChEBI","id":"CHEBI:142610"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:59105"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"9111029"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"octyl beta-D-glucose + chenodeoxycholate = beta-D-glucosyl-(1->3)-O-chenodeoxycholate + 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N-acylsphing-4-enine","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:58264"},{"database":"ChEBI","id":"CHEBI:16113"},{"database":"ChEBI","id":"CHEBI:17495"},{"database":"ChEBI","id":"CHEBI:22801"},{"database":"ChEBI","id":"CHEBI:52639"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:58265"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:58266"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine + cholesterol = N-(9Z-octadecenoyl)-sphing-4-enine + cholesteryl 3-beta-D-glucoside","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:58324"},{"database":"ChEBI","id":"CHEBI:16113"},{"database":"ChEBI","id":"CHEBI:17495"},{"database":"ChEBI","id":"CHEBI:77996"},{"database":"ChEBI","id":"CHEBI:139140"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:58325"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:58326"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + an N-acylsphing-4-enine","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:70235"},{"database":"ChEBI","id":"CHEBI:16113"},{"database":"ChEBI","id":"CHEBI:18390"},{"database":"ChEBI","id":"CHEBI:52639"},{"database":"ChEBI","id":"CHEBI:189066"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:70236"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:70237"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:70255"},{"database":"ChEBI","id":"CHEBI:16113"},{"database":"ChEBI","id":"CHEBI:72956"},{"database":"ChEBI","id":"CHEBI:73432"},{"database":"ChEBI","id":"CHEBI:189066"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:70256"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32144204"}]},{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:70257"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30308956"}],"value":"Inhibited by AMP-DMN/N -((5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (PubMed:11489889, PubMed:30308956). Activated by Mn(2+), Co(2+) and Mg(2+) and inhibited by Zn(2+) (PubMed:11489889). Enzymatic activity is dependent on membrane association and requires the presence of lipids (PubMed:11489889). The membrane-associated enzyme is not inhibited by condutiriol B epoxide and bromocondutiriol B epoxide (PubMed:11489889)"}],"commentType":"ACTIVITY REGULATION"},{"commentType":"BIOPHYSICOCHEMICAL PROPERTIES","kineticParameters":{"michaelisConstants":[{"constant":1.7,"unit":"uM","substrate":"beta-D-glucosyl-(1->3)-O-lithocholate","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}]},{"constant":6.2,"unit":"uM","substrate":"beta-D-glucosyl-(1->3)-O-chenodeoxycholate","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}]},{"constant":210.0,"unit":"uM","substrate":"4-methylumbelliferyl beta-D-glucoside","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}]}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}],"value":"kcat is 2500 min(-1) for the hydrolysis of beta-D-glucosyl-(1->3)-O-lithocholate (PubMed:9111029). kcat is 1300 min(-1) for the hydrolysis of beta-D-glucosyl-(1->3)-O-chenodeoxycholate (PubMed:9111029). kcat is 4700 min(-1) for the hydrolysis of 4-methylumbelliferyl beta-D-glucoside (PubMed:9111029)."}]}},"phDependence":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9111029"}],"value":"Optimum pH is 5.0 for the hydrolysis of bile acid glucosides."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17080196"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30308956"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}],"value":"Lipid metabolism; sphingolipid metabolism"}],"commentType":"PATHWAY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32144204"}],"value":"Steroid metabolism; cholesterol metabolism"}],"commentType":"PATHWAY"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17105727"}],"value":"Localization to the plasma membrane and alternative topologies have also been reported"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Endoplasmic reticulum membrane","id":"SL-0097"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"}],"value":"Peripheral membrane protein","id":"SL-9903"},"orientation":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Cytoplasmic side","id":"SL-9910"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Golgi apparatus membrane","id":"SL-0134"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"}],"value":"Peripheral membrane protein","id":"SL-9903"},"orientation":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q69ZF3"}],"value":"Cytoplasmic side","id":"SL-9910"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q9HCG7-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q9HCG7-2"],"sequenceIds":["VSP_024384"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["Q9HCG7-3"],"sequenceIds":["VSP_024383"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11489889"}],"value":"Widely expressed (PubMed:11489889). Mainly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower levels in liver, spleen, small intestine and lung (PubMed:11489889). Detectable in colon, thymus and peripheral blood leukocytes (PubMed:11489889)"}],"commentType":"TISSUE SPECIFICITY"},{"commentType":"DISEASE","disease":{"diseaseId":"Spastic paraplegia 46, autosomal recessive","diseaseAccession":"DI-03745","acronym":"SPG46","description":"A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging.","diseaseCrossReference":{"database":"MIM","id":"614409"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23332916"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23332917"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24252062"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26220345"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30308956"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the non-lysosomal glucosylceramidase family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Frameshift","sequence":"AAG44660.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAB13431.1","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":927,"modifier":"EXACT"}},"description":"Non-lysosomal glucosylceramidase","featureId":"PRO_0000283758"},{"type":"Region","location":{"start":{"value":32,"modifier":"EXACT"},"end":{"value":62,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Compositional bias","location":{"start":{"value":46,"modifier":"EXACT"},"end":{"value":58,"modifier":"EXACT"}},"description":"Basic and acidic residues","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Alternative sequence","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":287,"modifier":"EXACT"}},"description":"in isoform 3","evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.8"}],"featureId":"VSP_024383","alternativeSequence":{}},{"type":"Alternative sequence","location":{"start":{"value":836,"modifier":"EXACT"},"end":{"value":927,"modifier":"EXACT"}},"description":"in isoform 2","evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"10997877"}],"featureId":"VSP_024384","alternativeSequence":{"originalSequence":"GLTWEGFQTAEGCYRTVWERLGLAFQTPEAYCQQRVFRSLAYMRPLSIWAMQLALQQQQHKKASWPKVKQGTGLRTGPMFGPKEAMANLSPE","alternativeSequences":["LLPSGFCLWVIVISSTCWELLEGKDSTASIYPVEVALQRVPS"]}},{"type":"Natural variant","location":{"start":{"value":121,"modifier":"EXACT"},"end":{"value":927,"modifier":"EXACT"}},"description":"in SPG46; 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