GBA2_HUMAN
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 03-AUG-2022, entry version 153.
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},
GN SPG46 {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 beta-D-glucosyl-
CC (1->3)-O-lithocholate (PubMed:9111029). kcat is 1300 min(-1) for the
CC hydrolysis of beta-D-glucosyl-(1->3)-O-chenodeoxycholate
CC (PubMed:9111029). kcat is 4700 min(-1) for the hydrolysis of 4-
CC methylumbelliferyl beta-D-glucoside (PubMed:9111029).
CC {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 ---------------------------------------------------------------------------
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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. [Q9HCG7-3]
DR AlphaFoldDB; Q9HCG7; -.
DR SMR; Q9HCG7; -.
DR BioGRID; 121728; 29.
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 BioMuta; GBA2; -.
DR DMDM; 143018392; -.
DR EPD; Q9HCG7; -.
DR jPOST; Q9HCG7; -.
DR MassIVE; Q9HCG7; -.
DR MaxQB; Q9HCG7; -.
DR PaxDb; Q9HCG7; -.
DR PeptideAtlas; Q9HCG7; -.
DR PRIDE; Q9HCG7; -.
DR ProteomicsDB; 81709; -. [Q9HCG7-1]
DR ProteomicsDB; 81710; -. [Q9HCG7-2]
DR ProteomicsDB; 81711; -. [Q9HCG7-3]
DR Antibodypedia; 11711; 111 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 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; 207392at2759; -.
DR PhylomeDB; Q9HCG7; -.
DR TreeFam; TF313888; -.
DR BRENDA; 3.2.1.45; 2681.
DR PathwayCommons; Q9HCG7; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR SABIO-RK; Q9HCG7; -.
DR SignaLink; Q9HCG7; -.
DR UniPathway; UPA00222; -.
DR UniPathway; UPA00296; -.
DR BioGRID-ORCS; 57704; 10 hits in 1078 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 173 other tissues.
DR ExpressionAtlas; Q9HCG7; baseline and differential.
DR Genevisible; Q9HCG7; HS.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0042406; C:extrinsic component of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0090498; C:extrinsic component of Golgi membrane; ISS:UniProtKB.
DR GO; GO:0019898; C:extrinsic component of membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of 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:0006687; P:glycosphingolipid metabolic 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 Pfam; PF04685; DUF608; 1.
DR Pfam; PF12215; Glyco_hydr_116N; 1.
DR PIRSF; PIRSF028944; Beta_gluc_GBA2; 1.
DR SUPFAM; SSF48208; SSF48208; 1.
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
