GBA3_HUMAN
ID GBA3_HUMAN Reviewed; 469 AA.
AC Q9H227; Q32LY7; Q3MIH4; Q53GG8; Q6NSF4; Q8NHT8; Q9H3T4; Q9H4C6;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Cytosolic beta-glucosidase {ECO:0000305|PubMed:11389701};
DE EC=3.2.1.21 {ECO:0000269|PubMed:11389701, ECO:0000269|PubMed:11784319, ECO:0000269|PubMed:20728381};
DE AltName: Full=Cytosolic beta-glucosidase-like protein 1;
DE AltName: Full=Cytosolic galactosylceramidase {ECO:0000305};
DE EC=3.2.1.46 {ECO:0000269|PubMed:17595169};
DE AltName: Full=Cytosolic glucosylceramidase {ECO:0000305};
DE EC=3.2.1.45 {ECO:0000269|PubMed:17595169, ECO:0000269|PubMed:26724485};
DE AltName: Full=Cytosolic glycosylceramidase {ECO:0000303|PubMed:17595169};
DE Short=Cytosolic GCase {ECO:0000303|PubMed:17595169};
DE AltName: Full=Glucosidase beta acid 3 {ECO:0000312|HGNC:HGNC:19069};
DE AltName: Full=Glucosylceramidase beta 3 {ECO:0000312|HGNC:HGNC:19069};
DE AltName: Full=Klotho-related protein {ECO:0000303|PubMed:17595169};
DE Short=KLrP {ECO:0000303|PubMed:17595169};
GN Name=GBA3 {ECO:0000312|HGNC:HGNC:19069}; Synonyms=CBG, CBGL1;
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), AND TISSUE SPECIFICITY.
RC TISSUE=Fetal liver;
RX PubMed=11043382; DOI=10.1007/s001090000131;
RA Yahata K., Mori K., Arai H., Koide S., Ogawa Y., Mukoyama M., Sugawara A.,
RA Ozaki S., Tanaka I., Nabeshima Y., Nakao K.;
RT "Molecular cloning and expression of a novel klotho-related protein.";
RL J. Mol. Med. 78:389-394(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=11389701; DOI=10.1042/0264-6021:3560907;
RA de Graaf M., van Veen I.C., van der Meulen-Muileman I.H., Gerritsen W.R.,
RA Pinedo H.M., Haisma H.J.;
RT "Cloning and characterization of human liver cytosolic beta-glycosidase.";
RL Biochem. J. 356:907-910(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP BLOCKAGE OF N-TERMINUS, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RC TISSUE=Liver;
RX PubMed=11784319; DOI=10.1046/j.0014-2956.2001.02641.x;
RA Berrin J.-G., McLauchlan W.R., Needs P., Williamson G., Puigserver A.,
RA Kroon P.A., Juge N.;
RT "Functional expression of human liver cytosolic beta-glucosidase in Pichia
RT pastoris. Insights into its role in the metabolism of dietary glucosides.";
RL Eur. J. Biochem. 269:249-258(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Hays W.S., VanderJagt D.J., Glew R.H., Johnston D.E.;
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Small intestine;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney, and Liver;
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 [7]
RP MUTAGENESIS OF VAL-168; PHE-225 AND TYR-308.
RX PubMed=12667141; DOI=10.1042/bj20021876;
RA Berrin J.-G., Czjzek M., Kroon P.A., McLauchlan W.R., Puigserver A.,
RA Williamson G., Juge N.;
RT "Substrate (aglycone) specificity of human cytosolic beta-glucosidase.";
RL Biochem. J. 373:41-48(2003).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12594539; DOI=10.1007/s00394-003-0397-3;
RA Nemeth K., Plumb G.W., Berrin J.-G., Juge N., Jacob R., Naim H.Y.,
RA Williamson G., Swallow D.M., Kroon P.A.;
RT "Deglycosylation by small intestinal epithelial cell beta-glucosidases is a
RT critical step in the absorption and metabolism of dietary flavonoid
RT glycosides in humans.";
RL Eur. J. Nutr. 42:29-42(2003).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, CAUTION, AND VARIANT 456-TYR--LEU-469 DEL.
RX PubMed=20728381; DOI=10.1016/j.bcmd.2010.07.009;
RA Dekker N., Voorn-Brouwer T., Verhoek M., Wennekes T., Narayan R.S.,
RA Speijer D., Hollak C.E., Overkleeft H.S., Boot R.G., Aerts J.M.;
RT "The cytosolic beta-glucosidase GBA3 does not influence type 1 Gaucher
RT disease manifestation.";
RL Blood Cells Mol. Dis. 46:19-26(2011).
RN [10]
RP FUNCTION, AND INTERACTION WITH NEU2.
RX PubMed=26193330; DOI=10.3390/biom5031499;
RA Wang L., Seino J., Tomotake H., Funakoshi Y., Hirayama H., Suzuki T.;
RT "Co-Expression of NEU2 and GBA3 Causes a Drastic Reduction in Cytosolic
RT Sialyl Free N-glycans in Human MKN45 Stomach Cancer Cells-Evidence for the
RT Physical Interaction of NEU2 and GBA3.";
RL Biomolecules 5:1499-1514(2015).
RN [11]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=26724485; DOI=10.1194/jlr.m064923;
RA Marques A.R., Mirzaian M., Akiyama H., Wisse P., Ferraz M.J., Gaspar P.,
RA Ghauharali-van der Vlugt K., Meijer R., Giraldo P., Alfonso P., Irun P.,
RA Dahl M., Karlsson S., Pavlova E.V., Cox T.M., Scheij S., Verhoek M.,
RA Ottenhoff R., van Roomen C.P., Pannu N.S., van Eijk M., Dekker N.,
RA Boot R.G., Overkleeft H.S., Blommaart E., Hirabayashi Y., Aerts J.M.;
RT "Glucosylated cholesterol in mammalian cells and tissues: formation and
RT degradation by multiple cellular beta-glucosidases.";
RL J. Lipid Res. 57:451-463(2016).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=33361282; DOI=10.1194/jlr.ra120001043;
RA Boer D.E., Mirzaian M., Ferraz M.J., Zwiers K.C., Baks M.V., Hazeu M.D.,
RA Ottenhoff R., Marques A.R.A., Meijer R., Roos J.C.P., Cox T.M., Boot R.G.,
RA Pannu N., Overkleeft H.S., Artola M., Aerts J.M.;
RT "Human glucocerebrosidase mediates formation of xylosyl-cholesterol by
RT beta-xylosidase and transxylosidase reactions.";
RL J. Lipid Res. 62:100018-100018(2021).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH GLUCOSE AND
RP GALACTOSE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP GLU-165 AND GLU-373.
RX PubMed=17595169; DOI=10.1074/jbc.m700832200;
RA Hayashi Y., Okino N., Kakuta Y., Shikanai T., Tani M., Narimatsu H.,
RA Ito M.;
RT "Klotho-related protein is a novel cytosolic neutral beta-
RT glycosylceramidase.";
RL J. Biol. Chem. 282:30889-30900(2007).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
RX PubMed=17555766; DOI=10.1016/j.jmb.2007.05.034;
RA Tribolo S., Berrin J.G., Kroon P.A., Czjzek M., Juge N.;
RT "The crystal structure of human cytosolic beta-glucosidase unravels the
RT substrate aglycone specificity of a family 1 glycoside hydrolase.";
RL J. Mol. Biol. 370:964-975(2007).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH GLUCOSE, AND
RP MUTAGENESIS OF GLU-165.
RX PubMed=18662675; DOI=10.1016/j.bbrc.2008.07.089;
RA Noguchi J., Hayashi Y., Baba Y., Okino N., Kimura M., Ito M., Kakuta Y.;
RT "Crystal structure of the covalent intermediate of human cytosolic beta-
RT glucosidase.";
RL Biochem. Biophys. Res. Commun. 374:549-552(2008).
RN [16]
RP VARIANT ASN-106.
RX PubMed=15322500; DOI=10.1016/j.lab.2004.03.013;
RA Beutler E., Beutler L., West C.;
RT "Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher
RT disease.";
RL J. Lab. Clin. Med. 144:65-68(2004).
CC -!- FUNCTION: Neutral cytosolic beta-glycosidase with a broad substrate
CC specificity that could play a role in the catabolism of
CC glycosylceramides (PubMed:11389701, PubMed:11784319, PubMed:20728381,
CC PubMed:26724485, PubMed:17595169, PubMed:33361282). Has a significant
CC glucosylceramidase activity in vitro (PubMed:26724485,
CC PubMed:17595169). However, that activity is relatively low and its
CC significance in vivo is not clear (PubMed:26724485, PubMed:17595169,
CC PubMed:20728381). Hydrolyzes galactosylceramides/GalCers,
CC glucosylsphingosines/GlcSphs and galactosylsphingosines/GalSphs
CC (PubMed:17595169). However, the in vivo relevance of these activities
CC is unclear (PubMed:17595169). It can also hydrolyze a broad variety of
CC dietary glycosides including phytoestrogens, flavonols, flavones,
CC flavanones and cyanogens in vitro and could therefore play a role in
CC the metabolism of xenobiotics (PubMed:11784319). Possesses
CC transxylosylase activity in vitro using xylosylated ceramides/XylCers
CC (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) as xylosyl
CC donors and cholesterol as acceptor (PubMed:33361282). Could also play a
CC role in the catabolism of cytosolic sialyl free N-glycans
CC (PubMed:26193330). {ECO:0000269|PubMed:11389701,
CC ECO:0000269|PubMed:11784319, ECO:0000269|PubMed:17595169,
CC ECO:0000269|PubMed:20728381, ECO:0000269|PubMed:26193330,
CC ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:33361282}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of terminal, non-reducing beta-D-glucosyl residues
CC with release of beta-D-glucose.; EC=3.2.1.21;
CC Evidence={ECO:0000269|PubMed:11389701, ECO:0000269|PubMed:11784319,
CC ECO:0000269|PubMed:20728381};
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:17595169, ECO:0000269|PubMed:26724485};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13270;
CC Evidence={ECO:0000269|PubMed:17595169};
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:17595169};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14298;
CC Evidence={ECO:0000269|PubMed:17595169};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-glucosyl-(1<->1)-sphing-4-enine + H2O = D-glucose +
CC sphing-4-enine; Xref=Rhea:RHEA:59288, ChEBI:CHEBI:4167,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57756, ChEBI:CHEBI:83992;
CC Evidence={ECO:0000269|PubMed:17595169};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59289;
CC Evidence={ECO:0000269|PubMed:17595169};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-glucosyl-(1<->1)-N-octadecanoylsphing-4-enine + H2O =
CC D-glucose + N-octadecanoylsphing-4-enine; Xref=Rhea:RHEA:59284,
CC ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, ChEBI:CHEBI:72961,
CC ChEBI:CHEBI:84719; Evidence={ECO:0000269|PubMed:17595169};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59285;
CC Evidence={ECO:0000269|PubMed:17595169};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-galactosyl-(1<->1)-sphing-4-enine + H2O = D-galactose +
CC sphing-4-enine; Xref=Rhea:RHEA:43908, ChEBI:CHEBI:4139,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57756, ChEBI:CHEBI:57934;
CC Evidence={ECO:0000269|PubMed:17595169};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43909;
CC Evidence={ECO:0000269|PubMed:17595169};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-galactosyl-(1<->1')-N-octadecanoylsphing-4-enine + H2O
CC = D-galactose + N-octadecanoylsphing-4-enine; Xref=Rhea:RHEA:59292,
CC ChEBI:CHEBI:4139, ChEBI:CHEBI:15377, ChEBI:CHEBI:72961,
CC ChEBI:CHEBI:84720; Evidence={ECO:0000269|PubMed:17595169};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59293;
CC Evidence={ECO:0000269|PubMed:17595169};
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:0000305|PubMed:33361282};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70240;
CC Evidence={ECO:0000305|PubMed:33361282};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70241;
CC Evidence={ECO:0000305};
CC -!- ACTIVITY REGULATION: Inhibited by 2,4-dinitrophenyl-2-fluoro-2-deoxy-
CC beta-D-glucopyranoside (PubMed:11784319). Inhibited by sodium
CC taurocholate (PubMed:11389701). Inhibited by alpha-1-C-nonyl-DIX/AnDIX
CC (PubMed:20728381). The glucosylceramidase activity is slightly
CC inhibited by conduritol B epoxide/CBE while the galactosylceramidase
CC activity is not (PubMed:17595169). {ECO:0000269|PubMed:11389701,
CC ECO:0000269|PubMed:11784319, ECO:0000269|PubMed:17595169,
CC ECO:0000269|PubMed:20728381}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=13.67 uM for glucosylceramide (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:17595169};
CC KM=9.24 uM for galactosylceramide (at 37 degrees Celsius and pH 6.0)
CC {ECO:0000269|PubMed:17595169};
CC KM=4.64 uM for C6-NBD-glucosylceramide (at 37 degrees Celsius and pH
CC 6.0) {ECO:0000269|PubMed:17595169};
CC KM=2.04 uM for C6-NBD-galactosylceramide (at 37 degrees Celsius and
CC pH 6.0) {ECO:0000269|PubMed:17595169};
CC KM=40 uM for 4-methylumbelliferyl-beta-D-glucopyranoside (at 37
CC degrees Celsius and pH 5.5) {ECO:0000269|PubMed:11389701};
CC KM=49.28 uM for 4-methylumbelliferyl-beta-D-glucopyranoside (at 37
CC degrees Celsius and pH 6.0) {ECO:0000269|PubMed:17595169};
CC KM=50 uM for 4-methylumbelliferyl-beta-D-galactopyranoside (at 37
CC degrees Celsius and pH 5.5) {ECO:0000269|PubMed:11389701};
CC KM=144.49 uM for 4-methylumbelliferyl-beta-D-galactopyranoside (at 37
CC degrees Celsius and pH 6.0) {ECO:0000269|PubMed:17595169};
CC KM=370 uM for 4-nitrophenyl-beta-D-fucopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=570 uM for 4-nitrophenyl-alpha-L-arabinopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=1.76 mM for 4-nitrophenyl-beta-D-glucopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=3.14 mM for 4-nitrophenyl-beta-D-galactopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=1.58 mM for 4-nitrophenyl-beta-D-xylopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=52.6 mM for 4-nitrophenyl-beta-L-arabinopyranoside
CC {ECO:0000269|PubMed:11784319};
CC KM=35 uM for genistein-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=118 uM for daidzein-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=31.8 uM for quercetin-4'-glucoside {ECO:0000269|PubMed:11784319};
CC KM=42.2 uM for quercetin-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=21.5 uM for apigenin-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=10 uM for luteolin-4'-glucoside {ECO:0000269|PubMed:11784319};
CC KM=50 uM for luteolin-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=432 uM for naringenin-7-glucoside {ECO:0000269|PubMed:11784319};
CC KM=253 uM for eriodictyol-7-glucoside {ECO:0000269|PubMed:11784319};
CC Vmax=280 umol/h/mg enzyme toward 4-methylumbelliferyl-beta-D-
CC glucopyranoside {ECO:0000269|PubMed:20728381};
CC Vmax=10 umol/min/mg enzyme toward 4-nitrophenyl-beta-D-
CC glucopyranoside {ECO:0000269|PubMed:11784319};
CC Vmax=1.73 umol/min/mg enzyme toward genistein-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=2.75 umol/min/mg enzyme toward daidzein-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=1.19 umol/min/mg enzyme toward quercetin-4'-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=0.77 umol/min/mg enzyme toward quercetin-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=1.30 umol/min/mg enzyme toward apigenin-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=1.30 umol/min/mg enzyme toward luteolin-4'-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=2.85 umol/min/mg enzyme toward luteolin-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=0.93 umol/min/mg enzyme toward naringenin-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Vmax=0.90 umol/min/mg enzyme toward eriodictyol-7-glucoside
CC {ECO:0000269|PubMed:11784319};
CC Note=kcat is 0.43 min(-1) for the hydrolysis of glucosylceramide
CC (PubMed:17595169). kcat<0.01 min(-1) for the hydrolysis of
CC galactosylceramide (PubMed:17595169). kcat is 7.26 min(-1) for the
CC hydrolysis of C6-NBD-glucosylceramide (PubMed:17595169). kcat is 1.53
CC min(-1) for the hydrolysis of C6-NBD-galactosylceramide
CC (PubMed:17595169). kcat is 73.75 min(-1) for the hydrolysis of 4-
CC methylumbelliferyl-beta-D-glucopyranoside (PubMed:17595169). kcat is
CC 94.35 min(-1) for the hydrolysis of 4-methylumbelliferyl-beta-D-
CC galactopyranoside (PubMed:17595169). kcat is 10.7 sec(-1) for the
CC hydrolysis of 4-nitrophenyl-beta-D-fucopyranoside (PubMed:11784319).
CC kcat is 5.97 sec(-1) for the hydrolysis of 4-nitrophenyl-alpha-L-
CC arabinopyranoside (PubMed:11784319). kcat is 12.1 sec(-1) for the
CC hydrolysis of 4-nitrophenyl-beta-D-glucopyranoside (PubMed:11784319).
CC kcat is 17.6 sec(-1) for the hydrolysis of 4-nitrophenyl-beta-D-
CC galactopyranoside (PubMed:11784319). kcat is 0.75 sec(-1) for the
CC hydrolysis of 4-nitrophenyl-beta-D-xylopyranoside (PubMed:11784319).
CC kcat is 0.66 sec(-1) for the hydrolysis of 4-nitrophenyl-beta-L-
CC arabinopyranoside (PubMed:11784319). {ECO:0000269|PubMed:11784319,
CC ECO:0000269|PubMed:17595169};
CC pH dependence:
CC Optimum pH is 6.0-7.0 for the glucosylceramidase activity
CC (PubMed:11784319, PubMed:17595169). Optimum pH is 6.0 for the
CC hydrolysis of 4-methylumbelliferyl-beta-D-glucopyranoside
CC (PubMed:20728381). Activity decreases sharply with increasing acidity
CC and is less than 4% at pH 4 (PubMed:11784319).
CC {ECO:0000269|PubMed:11784319, ECO:0000269|PubMed:17595169,
CC ECO:0000269|PubMed:20728381};
CC Temperature dependence:
CC Optimum temperature is 50 degrees Celsius (PubMed:11784319). Stable
CC more than 24 hours at 37 degrees Celsius (PubMed:11784319). Loses
CC activity at 58 degrees Celsius (PubMed:11784319).
CC {ECO:0000269|PubMed:11784319};
CC -!- SUBUNIT: May interact with NEU2. {ECO:0000269|PubMed:26193330}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:12594539,
CC ECO:0000269|PubMed:17595169}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H227-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H227-2; Sequence=VSP_015835;
CC -!- TISSUE SPECIFICITY: Present in small intestine (at protein level).
CC Expressed in liver, small intestine, colon, spleen and kidney. Down-
CC regulated in renal cell carcinomas and hepatocellular carcinomas.
CC {ECO:0000269|PubMed:11043382, ECO:0000269|PubMed:12594539}.
CC -!- PTM: The N-terminus is blocked. {ECO:0000269|PubMed:11784319}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 1 family. Klotho
CC subfamily. {ECO:0000305}.
CC -!- CAUTION: GBA3 could be both a gene and a pseudogene in the human
CC population, its representation in the current reference genome assembly
CC corresponding to a non-functional allele with a stop codon at position
CC 456. The sequence shown here with a Tyr at position 456 corresponds to
CC the most frequent allele in the human population and encodes an active
CC beta-glucosidase while the truncated protein is inactive in vitro.
CC {ECO:0000305|PubMed:20728381}.
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DR EMBL; AB017913; BAB18741.1; -; mRNA.
DR EMBL; AJ278964; CAC08178.1; -; mRNA.
DR EMBL; AF317840; AAG39217.1; -; mRNA.
DR EMBL; AF323990; AAL37305.1; -; mRNA.
DR EMBL; AK222963; BAD96683.1; -; mRNA.
DR EMBL; BC029362; AAH29362.1; -; mRNA.
DR EMBL; BC070188; AAH70188.1; -; mRNA.
DR EMBL; BC101829; AAI01830.1; -; mRNA.
DR EMBL; BC109377; AAI09378.1; -; mRNA.
DR RefSeq; NP_001121904.1; NM_001128432.2. [Q9H227-2]
DR RefSeq; NP_001264154.1; NM_001277225.1.
DR RefSeq; NP_066024.1; NM_020973.4. [Q9H227-1]
DR PDB; 2E9L; X-ray; 1.60 A; A=1-469.
DR PDB; 2E9M; X-ray; 1.80 A; A=1-469.
DR PDB; 2JFE; X-ray; 2.70 A; X=1-469.
DR PDB; 2ZOX; X-ray; 1.90 A; A=1-469.
DR PDB; 3VKK; X-ray; 2.00 A; A=1-469.
DR PDBsum; 2E9L; -.
DR PDBsum; 2E9M; -.
DR PDBsum; 2JFE; -.
DR PDBsum; 2ZOX; -.
DR PDBsum; 3VKK; -.
DR AlphaFoldDB; Q9H227; -.
DR SMR; Q9H227; -.
DR BioGRID; 121753; 10.
DR IntAct; Q9H227; 2.
DR BindingDB; Q9H227; -.
DR ChEMBL; CHEMBL3865; -.
DR SwissLipids; SLP:000001931; -.
DR CAZy; GH1; Glycoside Hydrolase Family 1.
DR GlyGen; Q9H227; 2 sites.
DR iPTMnet; Q9H227; -.
DR PhosphoSitePlus; Q9H227; -.
DR BioMuta; GBA3; -.
DR DMDM; 77416427; -.
DR jPOST; Q9H227; -.
DR MassIVE; Q9H227; -.
DR PaxDb; Q9H227; -.
DR PeptideAtlas; Q9H227; -.
DR PRIDE; Q9H227; -.
DR ProteomicsDB; 80477; -. [Q9H227-1]
DR ProteomicsDB; 80478; -. [Q9H227-2]
DR DNASU; 57733; -.
DR GeneID; 57733; -.
DR KEGG; hsa:57733; -.
DR CTD; 57733; -.
DR DisGeNET; 57733; -.
DR GeneCards; GBA3; -.
DR HGNC; HGNC:19069; GBA3.
DR MIM; 606619; gene.
DR neXtProt; NX_Q9H227; -.
DR PharmGKB; PA134861643; -.
DR InParanoid; Q9H227; -.
DR PhylomeDB; Q9H227; -.
DR BioCyc; MetaCyc:HS11014-MON; -.
DR BRENDA; 3.2.1.21; 2681.
DR PathwayCommons; Q9H227; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR SABIO-RK; Q9H227; -.
DR SignaLink; Q9H227; -.
DR BioGRID-ORCS; 57733; 2 hits in 149 CRISPR screens.
DR ChiTaRS; GBA3; human.
DR EvolutionaryTrace; Q9H227; -.
DR GeneWiki; GBA3; -.
DR GenomeRNAi; 57733; -.
DR Pharos; Q9H227; Tbio.
DR PRO; PR:Q9H227; -.
DR Proteomes; UP000005640; Unplaced.
DR RNAct; Q9H227; protein.
DR GO; GO:1902494; C:catalytic complex; IDA:CAFA.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0004565; F:beta-galactosidase activity; IDA:UniProtKB.
DR GO; GO:0008422; F:beta-glucosidase activity; IDA:UniProtKB.
DR GO; GO:0004336; F:galactosylceramidase activity; IDA:UniProtKB.
DR GO; GO:0004348; F:glucosylceramidase activity; IDA:UniProtKB.
DR GO; GO:0017042; F:glycosylceramidase activity; IDA:UniProtKB.
DR GO; GO:0102483; F:scopolin beta-glucosidase activity; IEA:UniProtKB-EC.
DR GO; GO:1901805; P:beta-glucoside catabolic process; IDA:UniProtKB.
DR GO; GO:0051692; P:cellular oligosaccharide catabolic process; IDA:CAFA.
DR GO; GO:0006683; P:galactosylceramide catabolic process; IDA: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:0046477; P:glycosylceramide catabolic process; IBA:GO_Central.
DR GO; GO:1903017; P:positive regulation of exo-alpha-sialidase activity; IDA:CAFA.
DR GO; GO:0050821; P:protein stabilization; IDA:CAFA.
DR InterPro; IPR001360; Glyco_hydro_1.
DR InterPro; IPR033132; Glyco_hydro_1_N_CS.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR PANTHER; PTHR10353; PTHR10353; 1.
DR Pfam; PF00232; Glyco_hydro_1; 1.
DR PRINTS; PR00131; GLHYDRLASE1.
DR SUPFAM; SSF51445; SSF51445; 1.
DR PROSITE; PS00653; GLYCOSYL_HYDROL_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Glycosidase; Hydrolase;
KW Lipid metabolism; Reference proteome.
FT CHAIN 1..469
FT /note="Cytosolic beta-glucosidase"
FT /id="PRO_0000063908"
FT ACT_SITE 165
FT /note="Proton donor"
FT /evidence="ECO:0000255"
FT ACT_SITE 373
FT /note="Nucleophile"
FT /evidence="ECO:0000255"
FT BINDING 17
FT /ligand="substrate"
FT BINDING 120
FT /ligand="substrate"
FT BINDING 164
FT /ligand="substrate"
FT BINDING 309
FT /ligand="substrate"
FT BINDING 417
FT /ligand="substrate"
FT BINDING 424..425
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT VAR_SEQ 95..401
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_015835"
FT VARIANT 106
FT /note="D -> N"
FT /evidence="ECO:0000269|PubMed:15322500"
FT /id="VAR_023587"
FT VARIANT 172
FT /note="M -> I (in dbSNP:rs36090352)"
FT /id="VAR_049298"
FT VARIANT 213
FT /note="R -> P (in dbSNP:rs17612341)"
FT /id="VAR_023588"
FT VARIANT 354
FT /note="C -> R (in dbSNP:rs16873108)"
FT /id="VAR_023589"
FT VARIANT 456..469
FT /note="Missing (loss of glucosidase activity toward 4-
FT methylumbelliferyl-beta-D-glucopyranoside)"
FT /evidence="ECO:0000269|PubMed:20728381"
FT /id="VAR_081439"
FT MUTAGEN 165
FT /note="E->D: 2-fold decreased glucosylceramidase activity."
FT /evidence="ECO:0000269|PubMed:17595169,
FT ECO:0000269|PubMed:18662675"
FT MUTAGEN 165
FT /note="E->Q: Loss of glucosylceramidase activity."
FT /evidence="ECO:0000269|PubMed:17595169,
FT ECO:0000269|PubMed:18662675"
FT MUTAGEN 168
FT /note="V->Y: No change in temperature or pH dependence.
FT Decreased glucosidase activity."
FT /evidence="ECO:0000269|PubMed:12667141"
FT MUTAGEN 225
FT /note="F->S: Decreased glucosidase activity."
FT /evidence="ECO:0000269|PubMed:12667141"
FT MUTAGEN 308
FT /note="Y->F,A: Decreased glucosidase activity."
FT /evidence="ECO:0000269|PubMed:12667141"
FT MUTAGEN 373
FT /note="E->D: 2-fold decreased glucosylceramidase activity."
FT /evidence="ECO:0000269|PubMed:17595169"
FT MUTAGEN 373
FT /note="E->Q: Loss of glucosylceramidase activity."
FT /evidence="ECO:0000269|PubMed:17595169"
FT CONFLICT 29
FT /note="P -> L (in Ref. 6; AAH70188)"
FT /evidence="ECO:0000305"
FT CONFLICT 134
FT /note="L -> W (in Ref. 3; AAG39217)"
FT /evidence="ECO:0000305"
FT CONFLICT 309
FT /note="Y -> C (in Ref. 5; BAD96683)"
FT /evidence="ECO:0000305"
FT CONFLICT 321
FT /note="K -> R (in Ref. 5; BAD96683)"
FT /evidence="ECO:0000305"
FT CONFLICT 326
FT /note="I -> T (in Ref. 2; CAC08178)"
FT /evidence="ECO:0000305"
FT STRAND 8..12
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 15..18
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 24..26
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 31..38
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 40..43
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 44..46
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 49..51
FT /evidence="ECO:0007829|PDB:2E9L"
FT TURN 55..57
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 59..69
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 72..77
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 80..83
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 94..109
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 113..121
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 125..129
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 132..134
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 138..153
FT /evidence="ECO:0007829|PDB:2E9L"
FT TURN 154..156
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 159..164
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 166..174
FT /evidence="ECO:0007829|PDB:2E9L"
FT TURN 186..188
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 189..211
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 213..216
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 223..233
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 237..250
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 252..259
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 266..278
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 291..297
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 302..316
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 326..330
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 332..335
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 351..363
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 369..374
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 378..381
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 387..405
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 411..417
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 425..430
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 435..438
FT /evidence="ECO:0007829|PDB:2E9L"
FT STRAND 442..444
FT /evidence="ECO:0007829|PDB:2JFE"
FT STRAND 447..449
FT /evidence="ECO:0007829|PDB:2E9L"
FT HELIX 451..462
FT /evidence="ECO:0007829|PDB:2E9L"
SQ SEQUENCE 469 AA; 53696 MW; 9036455485CE2E2F CRC64;
MAFPAGFGWA AATAAYQVEG GWDADGKGPC VWDTFTHQGG ERVFKNQTGD VACGSYTLWE
EDLKCIKQLG LTHYRFSLSW SRLLPDGTTG FINQKGIDYY NKIIDDLLKN GVTPIVTLYH
FDLPQTLEDQ GGWLSEAIIE SFDKYAQFCF STFGDRVKQW ITINEANVLS VMSYDLGMFP
PGIPHFGTGG YQAAHNLIKA HARSWHSYDS LFRKKQKGMV SLSLFAVWLE PADPNSVSDQ
EAAKRAITFH LDLFAKPIFI DGDYPEVVKS QIASMSQKQG YPSSRLPEFT EEEKKMIKGT
ADFFAVQYYT TRLIKYQENK KGELGILQDA EIEFFPDPSW KNVDWIYVVP WGVCKLLKYI
KDTYNNPVIY ITENGFPQSD PAPLDDTQRW EYFRQTFQEL FKAIQLDKVN LQVYCAWSLL
DNFEWNQGYS SRFGLFHVDF EDPARPRVPY TSAKEYAKII RNNGLEAHL
