ID GBA2_HUMAN Reviewed; 927 AA. AC Q9HCG7; D3DRP2; Q5TCV6; Q96A51; Q96LY1; Q96SJ2; Q9H2L8; DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot. DT 03-APR-2007, sequence version 2. DT 27-MAR-2024, entry version 161. DE RecName: Full=Non-lysosomal glucosylceramidase {ECO:0000305}; DE Short=NLGase {ECO:0000303|PubMed:30308956}; DE EC=3.2.1.45 {ECO:0000269|PubMed:17080196, ECO:0000269|PubMed:30308956}; DE AltName: Full=Beta-glucocerebrosidase 2; DE Short=Beta-glucosidase 2; DE AltName: Full=Bile acid beta-glucosidase GBA2 {ECO:0000303|PubMed:9111029}; DE AltName: Full=Bile acid glucosyl transferase GBA2 {ECO:0000305|PubMed:9111029}; DE AltName: Full=Cholesterol glucosyltransferase GBA2 {ECO:0000250|UniProtKB:Q69ZF3}; DE EC=2.4.1.- {ECO:0000250|UniProtKB:Q69ZF3}; DE AltName: Full=Cholesteryl-beta-glucosidase GBA2 {ECO:0000250|UniProtKB:Q69ZF3}; DE EC=3.2.1.- {ECO:0000250|UniProtKB:Q69ZF3}; DE AltName: Full=Glucosylceramidase 2; DE AltName: Full=Non-lysosomal cholesterol glycosyltransferase {ECO:0000305}; DE AltName: Full=Non-lysosomal galactosylceramidase {ECO:0000305}; DE EC=3.2.1.46 {ECO:0000269|PubMed:32144204}; DE AltName: Full=Non-lysosomal glycosylceramidase {ECO:0000305}; GN Name=GBA2 {ECO:0000312|HGNC:HGNC:18986}; GN Synonyms=KIAA1605 {ECO:0000312|EMBL:BAB13431.1}, SPG46 GN {ECO:0000312|HGNC:HGNC:18986}; ORFNames=AD035; 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), PROTEIN SEQUENCE OF 39-46; 619-636 RP AND 919-927, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, TOPOLOGY, RP AND TISSUE SPECIFICITY. RC TISSUE=Liver; RX PubMed=11489889; DOI=10.1074/jbc.m104290200; RA Matern H., Boermans H., Lottspeich F., Matern S.; RT "Molecular cloning and expression of human bile acid beta -glucosidase."; RL J. Biol. Chem. 276:37929-37933(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=10997877; DOI=10.1093/dnares/7.4.271; RA Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XVIII. The RT complete sequences of 100 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 7:273-281(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Kidney, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Melanoma; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lymph; 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-780 (ISOFORM 3). RC TISSUE=Adrenal gland; RA Xu X., Yang Y., Gao G., Xiao H., Chen Z., Han Z.; RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases. RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=9111029; DOI=10.1074/jbc.272.17.11261; RA Matern H., Heinemann H., Legler G., Matern S.; RT "Purification and characterization of a microsomal bile acid beta- RT glucosidase from human liver."; RL J. Biol. Chem. 272:11261-11267(1997). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY. RX PubMed=17080196; DOI=10.1172/jci29224; RA Yildiz Y., Matern H., Thompson B., Allegood J.C., Warren R.L., RA Ramirez D.M.O., Hammer R.E., Hamra F.K., Matern S., Russell D.W.; RT "Mutation of beta-glucosidase 2 causes glycolipid storage disease and RT impaired male fertility."; RL J. Clin. Invest. 116:2985-2994(2006). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=17105727; DOI=10.1074/jbc.m610544200; RA Boot R.G., Verhoek M., Donker-Koopman W., Strijland A., van Marle J., RA Overkleeft H.S., Wennekes T., Aerts J.M.F.G.; RT "Identification of the non-lysosomal glucosylceramidase as beta-glucosidase RT 2."; RL J. Biol. Chem. 282:1305-1312(2007). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY. RX PubMed=32144204; DOI=10.1074/jbc.ra119.012502; RA Akiyama H., Ide M., Nagatsuka Y., Sayano T., Nakanishi E., Uemura N., RA Yuyama K., Yamaguchi Y., Kamiguchi H., Takahashi R., Aerts J.M.F.G., RA Greimel P., Hirabayashi Y.; RT "Glucocerebrosidases catalyze a transgalactosylation reaction that yields a RT newly-identified brain sterol metabolite, galactosylated cholesterol."; RL J. Biol. Chem. 295:5257-5277(2020). RN [13] RP VARIANTS SPG46 173-TRP--GLU-927 DEL; 234-ARG--GLU-927 DEL AND TRP-630. RX PubMed=23332916; DOI=10.1016/j.ajhg.2012.11.021; RA Martin E., Schuele R., Smets K., Rastetter A., Boukhris A., Loureiro J.L., RA Gonzalez M.A., Mundwiller E., Deconinck T., Wessner M., Jornea L., RA Oteyza A.C., Durr A., Martin J.J., Schoels L., Mhiri C., Lamari F., RA Zuechner S., De Jonghe P., Kabashi E., Brice A., Stevanin G.; RT "Loss of function of glucocerebrosidase GBA2 is responsible for motor RT neuron defects in hereditary spastic paraplegia."; RL Am. J. Hum. Genet. 92:238-244(2013). RN [14] RP CHARACTERIZATION OF VARIANTS SPG46 121-TYR--GLU-927 DEL; 173-TRP--GLU-927 RP DEL; 234-ARG--GLU-927 DEL; 340-ARG--GLU-927 DEL; TRP-630 AND HIS-873, AND RP MUTAGENESIS OF PHE-419. RX PubMed=26220345; DOI=10.1016/j.bbrc.2015.07.112; RA Sultana S., Reichbauer J., Schuele R., Mochel F., Synofzik M., RA van der Spoel A.C.; RT "Lack of enzyme activity in GBA2 mutants associated with hereditary spastic RT paraplegia/cerebellar ataxia (SPG46)."; RL Biochem. Biophys. Res. Commun. 465:35-40(2015). RN [15] RP VARIANTS SPG46 121-TYR--GLU-927 DEL; 340-ARG--GLU-927 DEL AND HIS-873. RX PubMed=23332917; DOI=10.1016/j.ajhg.2012.12.012; RA Hammer M.B., Eleuch-Fayache G., Schottlaender L.V., Nehdi H., Gibbs J.R., RA Arepalli S.K., Chong S.B., Hernandez D.G., Sailer A., Liu G., Mistry P.K., RA Cai H., Shrader G., Sassi C., Bouhlal Y., Houlden H., Hentati F., RA Amouri R., Singleton A.B.; RT "Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with RT spasticity."; RL Am. J. Hum. Genet. 92:245-251(2013). RN [16] RP VARIANT SPG46 HIS-594. RX PubMed=24252062; DOI=10.1111/ahg.12045; RA Votsi C., Zamba-Papanicolaou E., Middleton L.T., Pantzaris M., RA Christodoulou K.; RT "A novel GBA2 gene missense mutation in spastic ataxia."; RL Ann. Hum. Genet. 78:13-22(2014). RN [17] RP FUNCTION, PATHWAY, CHARACTERIZATION OF VARIANT SPG46 HIS-594, AND ACTIVITY RP REGULATION. RX PubMed=30308956; DOI=10.3390/ijms19103099; RA Malekkou A., Samarani M., Drousiotou A., Votsi C., Sonnino S., RA Pantzaris M., Chiricozzi E., Zamba-Papanicolaou E., Aureli M., Loberto N., RA Christodoulou K.; RT "Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in RT Lymphoblastoid Cells from Patients with Spastic Ataxia."; RL Int. J. Mol. Sci. 19:0-0(2018). CC -!- FUNCTION: Non-lysosomal glucosylceramidase that catalyzes the CC hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl- CC (1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as CC N-acylsphing-4-enine) (PubMed:17105727, PubMed:30308956, CC PubMed:32144204). GlcCers are membrane glycosphingolipids that have a CC wide intracellular distribution (By similarity). They are the main CC precursors of more complex glycosphingolipids that play a role in CC cellular growth, differentiation, adhesion, signaling, cytoskeletal CC dynamics and membrane properties (By similarity). Involved in the CC transglucosylation of cholesterol, transfers glucose from GlcCer to CC cholesterol, thereby modifying its water solubility and biological CC properties (PubMed:32144204). Under specific conditions, may catalyze CC the reverse reaction, transferring glucose from cholesteryl-3-beta-D- CC glucoside to ceramide (such as N-acylsphing-4-enine) (Probable). May CC play a role in the metabolism of bile acids (PubMed:11489889, CC PubMed:9111029, PubMed:17080196). Able to hydrolyze bile acid 3-O- CC glucosides as well as to produce bile acid-glucose conjugates thanks to CC a bile acid glucosyl transferase activity (PubMed:11489889, CC PubMed:9111029, PubMed:17080196). Catalyzes the hydrolysis of CC galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N- CC acylsphing-4-enine), as well as the galactosyl transfer between GalCers CC and cholesterol in vitro with lower activity compared with their CC activity against GlcCers (PubMed:32144204). CC {ECO:0000250|UniProtKB:Q69ZF3, ECO:0000269|PubMed:11489889, CC ECO:0000269|PubMed:17080196, ECO:0000269|PubMed:17105727, CC ECO:0000269|PubMed:30308956, ECO:0000269|PubMed:32144204, CC ECO:0000269|PubMed:9111029, ECO:0000305|PubMed:32144204}. 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:0000269|PubMed:17080196}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13270; CC Evidence={ECO:0000269|PubMed:17080196}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14298; CC Evidence={ECO:0000269|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1->3)-O-lithocholate + H2O = D-glucose + CC lithocholate; Xref=Rhea:RHEA:58344, ChEBI:CHEBI:4167, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:29744, ChEBI:CHEBI:142611; CC Evidence={ECO:0000269|PubMed:11489889, ECO:0000269|PubMed:17080196, CC ECO:0000269|PubMed:9111029}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58345; CC Evidence={ECO:0000305|PubMed:11489889, ECO:0000305|PubMed:17080196, CC ECO:0000305|PubMed:9111029}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1->3)-O-chenodeoxycholate + H2O = CC chenodeoxycholate + D-glucose; Xref=Rhea:RHEA:58340, CC ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, ChEBI:CHEBI:36234, CC ChEBI:CHEBI:142610; Evidence={ECO:0000269|PubMed:9111029}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58341; CC Evidence={ECO:0000305|PubMed:9111029}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a dolichyl beta-D-glucosyl phosphate + chenodeoxycholate = a CC dolichyl phosphate + beta-D-glucosyl-(1->3)-O-chenodeoxycholate + CC H(+); Xref=Rhea:RHEA:59104, Rhea:RHEA-COMP:9517, Rhea:RHEA-COMP:9528, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36234, ChEBI:CHEBI:57525, CC ChEBI:CHEBI:57683, ChEBI:CHEBI:142610; CC Evidence={ECO:0000269|PubMed:9111029}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59105; CC Evidence={ECO:0000305|PubMed:9111029}; CC -!- CATALYTIC ACTIVITY: CC Reaction=chenodeoxycholate + octyl beta-D-glucose = beta-D-glucosyl- CC (1->3)-O-chenodeoxycholate + octan-1-ol; Xref=Rhea:RHEA:59108, CC ChEBI:CHEBI:16188, ChEBI:CHEBI:36234, ChEBI:CHEBI:41128, CC ChEBI:CHEBI:142610; Evidence={ECO:0000269|PubMed:9111029}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59109; CC Evidence={ECO:0000305|PubMed:9111029}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11957; CC Evidence={ECO:0000269|PubMed:32144204}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58265; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58266; CC Evidence={ECO:0000305|PubMed:32144204}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58325; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58326; CC Evidence={ECO:0000305|PubMed:32144204}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70236; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70237; CC Evidence={ECO:0000305|PubMed:32144204}; 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:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70256; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70257; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- ACTIVITY REGULATION: Inhibited by AMP-DMN/N -((5-adamantane-1-yl- CC methoxy)pentyl)-deoxynojirimycin (PubMed:11489889, PubMed:30308956). CC Activated by Mn(2+), Co(2+) and Mg(2+) and inhibited by Zn(2+) CC (PubMed:11489889). Enzymatic activity is dependent on membrane CC association and requires the presence of lipids (PubMed:11489889). The CC membrane-associated enzyme is not inhibited by condutiriol B epoxide CC and bromocondutiriol B epoxide (PubMed:11489889). CC {ECO:0000269|PubMed:11489889, ECO:0000269|PubMed:30308956}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.7 uM for beta-D-glucosyl-(1->3)-O-lithocholate CC {ECO:0000269|PubMed:9111029}; CC KM=6.2 uM for beta-D-glucosyl-(1->3)-O-chenodeoxycholate CC {ECO:0000269|PubMed:9111029}; CC KM=210 uM for 4-methylumbelliferyl beta-D-glucoside CC {ECO:0000269|PubMed:9111029}; CC Note=kcat is 2500 min(-1) for the hydrolysis of CC beta-D-glucosyl-(1->3)-O-lithocholate (PubMed:9111029). kcat is 1300 CC min(-1) for the hydrolysis of CC beta-D-glucosyl-(1->3)-O-chenodeoxycholate (PubMed:9111029). kcat is CC 4700 min(-1) for the hydrolysis of 4-methylumbelliferyl CC beta-D-glucoside (PubMed:9111029). {ECO:0000269|PubMed:9111029}; CC pH dependence: CC Optimum pH is 5.0 for the hydrolysis of bile acid glucosides. CC {ECO:0000269|PubMed:9111029}; CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism. CC {ECO:0000269|PubMed:17080196, ECO:0000269|PubMed:30308956, CC ECO:0000305|PubMed:32144204}. CC -!- PATHWAY: Steroid metabolism; cholesterol metabolism. CC {ECO:0000305|PubMed:32144204}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q69ZF3}; Peripheral membrane protein CC {ECO:0000269|PubMed:11489889}; Cytoplasmic side CC {ECO:0000250|UniProtKB:Q69ZF3}. Golgi apparatus membrane CC {ECO:0000250|UniProtKB:Q69ZF3}; Peripheral membrane protein CC {ECO:0000269|PubMed:11489889}; Cytoplasmic side CC {ECO:0000250|UniProtKB:Q69ZF3}. Note=Localization to the plasma CC membrane and alternative topologies have also been reported. CC {ECO:0000269|PubMed:11489889, ECO:0000269|PubMed:17105727}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9HCG7-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9HCG7-2; Sequence=VSP_024384; CC Name=3; CC IsoId=Q9HCG7-3; Sequence=VSP_024383; CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:11489889). Mainly CC expressed in brain, heart, skeletal muscle, kidney and placenta and CC expressed at lower levels in liver, spleen, small intestine and lung CC (PubMed:11489889). Detectable in colon, thymus and peripheral blood CC leukocytes (PubMed:11489889). {ECO:0000269|PubMed:11489889}. CC -!- DISEASE: Spastic paraplegia 46, autosomal recessive (SPG46) CC [MIM:614409]: A neurodegenerative disorder characterized by onset in CC childhood of slowly progressive spastic paraplegia and cerebellar CC signs. Some patients have cognitive impairment, cataracts, and CC cerebral, cerebellar, and corpus callosum atrophy on brain imaging. CC {ECO:0000269|PubMed:23332916, ECO:0000269|PubMed:23332917, CC ECO:0000269|PubMed:24252062, ECO:0000269|PubMed:26220345, CC ECO:0000269|PubMed:30308956}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the non-lysosomal glucosylceramidase family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG44660.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAB13431.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ309567; CAC83792.1; -; mRNA. DR EMBL; AB046825; BAB13431.1; ALT_INIT; mRNA. DR EMBL; AK027884; BAB55430.1; -; mRNA. DR EMBL; AL834306; CAD38976.1; -; mRNA. DR EMBL; AL133410; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471071; EAW58348.1; -; Genomic_DNA. DR EMBL; CH471071; EAW58349.1; -; Genomic_DNA. DR EMBL; BC011363; AAH11363.1; -; mRNA. DR EMBL; AF258662; AAG44660.1; ALT_FRAME; mRNA. DR CCDS; CCDS6589.1; -. [Q9HCG7-1] DR CCDS; CCDS83363.1; -. [Q9HCG7-2] DR RefSeq; NP_001317589.1; NM_001330660.1. [Q9HCG7-2] DR RefSeq; NP_065995.1; NM_020944.2. [Q9HCG7-1] DR RefSeq; XP_016870435.1; XM_017014946.1. DR AlphaFoldDB; Q9HCG7; -. DR SMR; Q9HCG7; -. DR BioGRID; 121728; 32. DR IntAct; Q9HCG7; 12. DR STRING; 9606.ENSP00000367343; -. DR BindingDB; Q9HCG7; -. DR ChEMBL; CHEMBL3761; -. DR DrugCentral; Q9HCG7; -. DR SwissLipids; SLP:000001382; -. DR SwissLipids; SLP:000001932; -. [Q9HCG7-1] DR CAZy; GH116; Glycoside Hydrolase Family 116. DR iPTMnet; Q9HCG7; -. DR PhosphoSitePlus; Q9HCG7; -. DR SwissPalm; Q9HCG7; -. DR BioMuta; GBA2; -. DR DMDM; 143018392; -. DR EPD; Q9HCG7; -. DR jPOST; Q9HCG7; -. DR MassIVE; Q9HCG7; -. DR MaxQB; Q9HCG7; -. DR PaxDb; 9606-ENSP00000367343; -. DR PeptideAtlas; Q9HCG7; -. DR ProteomicsDB; 81709; -. [Q9HCG7-1] DR ProteomicsDB; 81710; -. [Q9HCG7-2] DR ProteomicsDB; 81711; -. [Q9HCG7-3] DR Antibodypedia; 11711; 134 antibodies from 18 providers. DR DNASU; 57704; -. DR Ensembl; ENST00000378094.4; ENSP00000367334.4; ENSG00000070610.14. [Q9HCG7-2] DR Ensembl; ENST00000378103.7; ENSP00000367343.3; ENSG00000070610.14. [Q9HCG7-1] DR GeneID; 57704; -. DR KEGG; hsa:57704; -. DR MANE-Select; ENST00000378103.7; ENSP00000367343.3; NM_020944.3; NP_065995.1. DR UCSC; uc003zxw.3; human. [Q9HCG7-1] DR AGR; HGNC:18986; -. DR CTD; 57704; -. DR DisGeNET; 57704; -. DR GeneCards; GBA2; -. DR HGNC; HGNC:18986; GBA2. DR HPA; ENSG00000070610; Low tissue specificity. DR MalaCards; GBA2; -. DR MIM; 609471; gene. DR MIM; 614409; phenotype. DR neXtProt; NX_Q9HCG7; -. DR OpenTargets; ENSG00000070610; -. DR Orphanet; 352641; Autosomal recessive cerebellar ataxia with late-onset spasticity. DR Orphanet; 320391; Autosomal recessive spastic paraplegia type 46. DR PharmGKB; PA38773; -. DR VEuPathDB; HostDB:ENSG00000070610; -. DR eggNOG; KOG2119; Eukaryota. DR GeneTree; ENSGT00390000010998; -. DR HOGENOM; CLU_006322_1_1_1; -. DR InParanoid; Q9HCG7; -. DR OMA; HDLGAPN; -. DR OrthoDB; 997839at2759; -. DR PhylomeDB; Q9HCG7; -. DR TreeFam; TF313888; -. DR BRENDA; 3.2.1.45; 2681. DR PathwayCommons; Q9HCG7; -. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SABIO-RK; Q9HCG7; -. DR SignaLink; Q9HCG7; -. DR UniPathway; UPA00222; -. DR UniPathway; UPA00296; -. DR BioGRID-ORCS; 57704; 11 hits in 1158 CRISPR screens. DR ChiTaRS; GBA2; human. DR GeneWiki; GBA2; -. DR GenomeRNAi; 57704; -. DR Pharos; Q9HCG7; Tchem. DR PRO; PR:Q9HCG7; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; Q9HCG7; Protein. DR Bgee; ENSG00000070610; Expressed in metanephros cortex and 175 other cell types or tissues. DR ExpressionAtlas; Q9HCG7; baseline and differential. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; ISS:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005790; C:smooth endoplasmic reticulum; TAS:UniProtKB. DR GO; GO:0008422; F:beta-glucosidase activity; IDA:UniProtKB. DR GO; GO:0004336; F:galactosylceramidase activity; IEA:RHEA. DR GO; GO:0004348; F:glucosylceramidase activity; IDA:UniProtKB. DR GO; GO:0046527; F:glucosyltransferase activity; ISS:UniProtKB. DR GO; GO:0050295; F:steryl-beta-glucosidase activity; ISS:UniProtKB. DR GO; GO:0008206; P:bile acid metabolic process; IDA:UniProtKB. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro. DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central. DR GO; GO:0021954; P:central nervous system neuron development; IMP:UniProtKB. DR GO; GO:0008203; P:cholesterol metabolic process; ISS:UniProtKB. DR GO; GO:0006680; P:glucosylceramide catabolic process; IDA:UniProtKB. DR GO; GO:0016139; P:glycoside catabolic process; IDA:UniProtKB. DR GO; GO:0046479; P:glycosphingolipid catabolic process; TAS:Reactome. DR GO; GO:0030259; P:lipid glycosylation; ISS:UniProtKB. DR GO; GO:0030833; P:regulation of actin filament polymerization; ISS:UniProtKB. DR GO; GO:0097035; P:regulation of membrane lipid distribution; ISS:UniProtKB. DR GO; GO:0031113; P:regulation of microtubule polymerization; ISS:UniProtKB. DR Gene3D; 1.50.10.10; -; 1. DR InterPro; IPR008928; 6-hairpin_glycosidase_sf. DR InterPro; IPR012341; 6hp_glycosidase-like_sf. DR InterPro; IPR014551; B_Glucosidase_GBA2-typ. DR InterPro; IPR006775; GH116_catalytic. DR InterPro; IPR024462; GH116_N. DR PANTHER; PTHR12654; BILE ACID BETA-GLUCOSIDASE-RELATED; 1. DR PANTHER; PTHR12654:SF0; NON-LYSOSOMAL GLUCOSYLCERAMIDASE; 1. DR Pfam; PF04685; DUF608; 1. DR Pfam; PF12215; Glyco_hydr_116N; 1. DR PIRSF; PIRSF028944; Beta_gluc_GBA2; 1. DR SUPFAM; SSF48208; Six-hairpin glycosidases; 1. DR Genevisible; Q9HCG7; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cholesterol metabolism; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Glycosidase; Glycosyltransferase; KW Golgi apparatus; Hereditary spastic paraplegia; Hydrolase; KW Lipid metabolism; Membrane; Neurodegeneration; Reference proteome; KW Sphingolipid metabolism; Steroid metabolism; Sterol metabolism; KW Transferase. FT CHAIN 1..927 FT /note="Non-lysosomal glucosylceramidase" FT /id="PRO_0000283758" FT REGION 32..62 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 43..59 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..287 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.8" FT /id="VSP_024383" FT VAR_SEQ 836..927 FT /note="GLTWEGFQTAEGCYRTVWERLGLAFQTPEAYCQQRVFRSLAYMRPLSIWAMQ FT LALQQQQHKKASWPKVKQGTGLRTGPMFGPKEAMANLSPE -> LLPSGFCLWVIVISS FT TCWELLEGKDSTASIYPVEVALQRVPS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10997877" FT /id="VSP_024384" FT VARIANT 121..927 FT /note="Missing (in SPG46; loss of glucosylceramide FT catabolic process)" FT /evidence="ECO:0000269|PubMed:23332917, FT ECO:0000305|PubMed:26220345" FT /id="VAR_081406" FT VARIANT 173..927 FT /note="Missing (in SPG46; loss of glucosylceramide FT catabolic process)" FT /evidence="ECO:0000269|PubMed:23332916, FT ECO:0000305|PubMed:26220345" FT /id="VAR_081407" FT VARIANT 234..927 FT /note="Missing (in SPG46; loss of glucosylceramide FT catabolic process)" FT /evidence="ECO:0000269|PubMed:23332916, FT ECO:0000305|PubMed:26220345" FT /id="VAR_081408" FT VARIANT 340..927 FT /note="Missing (in SPG46; loss of glucosylceramide FT catabolic process)" FT /evidence="ECO:0000269|PubMed:23332917, FT ECO:0000305|PubMed:26220345" FT /id="VAR_081409" FT VARIANT 594 FT /note="D -> H (in SPG46; loss of glucosylceramide catabolic FT process; dbSNP:rs398123064)" FT /evidence="ECO:0000269|PubMed:24252062" FT /id="VAR_081410" FT VARIANT 630 FT /note="R -> W (in SPG46; loss of glucosylceramide catabolic FT process; dbSNP:rs398123012)" FT /evidence="ECO:0000269|PubMed:23332916, FT ECO:0000305|PubMed:26220345" FT /id="VAR_069634" FT VARIANT 873 FT /note="R -> H (in SPG46; loss of glucosylceramide catabolic FT process; dbSNP:rs398123015)" FT /evidence="ECO:0000269|PubMed:23332917, FT ECO:0000305|PubMed:26220345" FT /id="VAR_069635" FT MUTAGEN 419 FT /note="F->V: Loss of glucosylceramide catabolic process." FT /evidence="ECO:0000305|PubMed:26220345" FT CONFLICT 60 FT /note="C -> Y (in Ref. 3; BAB55430)" FT /evidence="ECO:0000305" FT CONFLICT 222 FT /note="C -> R (in Ref. 3; BAB55430)" FT /evidence="ECO:0000305" FT CONFLICT 482 FT /note="N -> K (in Ref. 3; BAB55430)" FT /evidence="ECO:0000305" SQ SEQUENCE 927 AA; 104649 MW; 1F6879D6E20A2B1D CRC64; MGTQDPGNMG TGVPASEQIS CAKEDPQVYC PEETGGTKDV QVTDCKSPED SRPPKETDCC NPEDSGQLMV SYEGKAMGYQ VPPFGWRICL AHEFTEKRKP FQANNVSLSN MIKHIGMGLR YLQWWYRKTH VEKKTPFIDM INSVPLRQIY GCPLGGIGGG TITRGWRGQF CRWQLNPGMY QHRTVIADQF TVCLRREGQT VYQQVLSLER PSVLRSWNWG LCGYFAFYHA LYPRAWTVYQ LPGQNVTLTC RQITPILPHD YQDSSLPVGV FVWDVENEGD EALDVSIMFS MRNGLGGGDD APGGLWNEPF CLERSGETVR GLLLHHPTLP NPYTMAVAAR VTAATTVTHI TAFDPDSTGQ QVWQDLLQDG QLDSPTGQST PTQKGVGIAG AVCVSSKLRP RGQCRLEFSL AWDMPRIMFG AKGQVHYRRY TRFFGQDGDA APALSHYALC RYAEWEERIS AWQSPVLDDR SLPAWYKSAL FNELYFLADG GTVWLEVLED SLPEELGRNM CHLRPTLRDY GRFGYLEGQE YRMYNTYDVH FYASFALIML WPKLELSLQY DMALATLRED LTRRRYLMSG VMAPVKRRNV IPHDIGDPDD EPWLRVNAYL IHDTADWKDL NLKFVLQVYR DYYLTGDQNF LKDMWPVCLA VMESEMKFDK DHDGLIENGG YADQTYDGWV TTGPSAYCGG LWLAAVAVMV QMAALCGAQD IQDKFSSILS RGQEAYERLL WNGRYYNYDS SSRPQSRSVM SDQCAGQWFL KACGLGEGDT EVFPTQHVVR ALQTIFELNV QAFAGGAMGA VNGMQPHGVP DKSSVQSDEV WVGVVYGLAA TMIQEGLTWE GFQTAEGCYR TVWERLGLAF QTPEAYCQQR VFRSLAYMRP LSIWAMQLAL QQQQHKKASW PKVKQGTGLR TGPMFGPKEA MANLSPE //