Q9H227 · GBA3_HUMAN
- ProteinCytosolic beta-glucosidase
- GeneGBA3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids469 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Neutral cytosolic beta-glycosidase with a broad substrate specificity that could play a role in the catabolism of glycosylceramides (PubMed:11389701, PubMed:11784319, PubMed:17595169, PubMed:20728381, PubMed:26724485, PubMed:33361282).
Has a significant glucosylceramidase activity in vitro (PubMed:17595169, PubMed:26724485).
However, that activity is relatively low and its significance in vivo is not clear (PubMed:17595169, PubMed:20728381, PubMed:26724485).
Hydrolyzes galactosylceramides/GalCers, glucosylsphingosines/GlcSphs and galactosylsphingosines/GalSphs (PubMed:17595169).
However, the in vivo relevance of these activities is unclear (PubMed:17595169).
It can also hydrolyze a broad variety of dietary glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens in vitro and could therefore play a role in the metabolism of xenobiotics (PubMed:11784319).
Possesses transxylosylase activity in vitro using xylosylated ceramides/XylCers (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) as xylosyl donors and cholesterol as acceptor (PubMed:33361282).
Could also play a role in the catabolism of cytosolic sialyl free N-glycans (PubMed:26193330).
Has a significant glucosylceramidase activity in vitro (PubMed:17595169, PubMed:26724485).
However, that activity is relatively low and its significance in vivo is not clear (PubMed:17595169, PubMed:20728381, PubMed:26724485).
Hydrolyzes galactosylceramides/GalCers, glucosylsphingosines/GlcSphs and galactosylsphingosines/GalSphs (PubMed:17595169).
However, the in vivo relevance of these activities is unclear (PubMed:17595169).
It can also hydrolyze a broad variety of dietary glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens in vitro and could therefore play a role in the metabolism of xenobiotics (PubMed:11784319).
Possesses transxylosylase activity in vitro using xylosylated ceramides/XylCers (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) as xylosyl donors and cholesterol as acceptor (PubMed:33361282).
Could also play a role in the catabolism of cytosolic sialyl free N-glycans (PubMed:26193330).
Catalytic activity
- a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + D-glucoseThis reaction proceeds in the forward direction.
- beta-D-glucosyl-(1<->1)-sphing-4-enine + H2O = D-glucose + sphing-4-enineThis reaction proceeds in the forward direction.
- beta-D-glucosyl-(1<->1)-N-octadecanoylsphing-4-enine + H2O = D-glucose + N-octadecanoylsphing-4-enineThis reaction proceeds in the forward direction.
- beta-D-galactosyl-(1<->1)-sphing-4-enine + H2O = D-galactose + sphing-4-enineThis reaction proceeds in the forward direction.
- beta-D-galactosyl-(1<->1')-N-octadecanoylsphing-4-enine + H2O = D-galactose + N-octadecanoylsphing-4-enineThis reaction proceeds in the forward direction.
- a beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine + cholesterol = an N-acylsphing-4-enine + cholesteryl 3-beta-D-xylosideThis reaction proceeds in the forward and the backward directions.
Activity regulation
Inhibited by 2,4-dinitrophenyl-2-fluoro-2-deoxy-beta-D-glucopyranoside (PubMed:11784319).
Inhibited by sodium taurocholate (PubMed:11389701).
Inhibited by alpha-1-C-nonyl-DIX/AnDIX (PubMed:20728381).
The glucosylceramidase activity is slightly inhibited by conduritol B epoxide/CBE while the galactosylceramidase activity is not (PubMed:17595169).
Inhibited by sodium taurocholate (PubMed:11389701).
Inhibited by alpha-1-C-nonyl-DIX/AnDIX (PubMed:20728381).
The glucosylceramidase activity is slightly inhibited by conduritol B epoxide/CBE while the galactosylceramidase activity is not (PubMed:17595169).
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
13.67 μM | glucosylceramide | 6.0 | 37 | |||
9.24 μM | galactosylceramide | 6.0 | 37 | |||
4.64 μM | C6-NBD-glucosylceramide | 6.0 | 37 | |||
2.04 μM | C6-NBD-galactosylceramide | 6.0 | 37 | |||
40 μM | 4-methylumbelliferyl-beta-D-glucopyranoside | 5.5 | 37 | |||
49.28 μM | 4-methylumbelliferyl-beta-D-glucopyranoside | 6.0 | 37 | |||
50 μM | 4-methylumbelliferyl-beta-D-galactopyranoside | 5.5 | 37 | |||
144.49 μM | 4-methylumbelliferyl-beta-D-galactopyranoside | 6.0 | 37 | |||
370 μM | 4-nitrophenyl-beta-D-fucopyranoside | |||||
570 μM | 4-nitrophenyl-alpha-L-arabinopyranoside | |||||
1.76 mM | 4-nitrophenyl-beta-D-glucopyranoside | |||||
3.14 mM | 4-nitrophenyl-beta-D-galactopyranoside | |||||
1.58 mM | 4-nitrophenyl-beta-D-xylopyranoside | |||||
52.6 mM | 4-nitrophenyl-beta-L-arabinopyranoside | |||||
35 μM | genistein-7-glucoside | |||||
118 μM | daidzein-7-glucoside | |||||
31.8 μM | quercetin-4'-glucoside | |||||
42.2 μM | quercetin-7-glucoside | |||||
21.5 μM | apigenin-7-glucoside | |||||
10 μM | luteolin-4'-glucoside | |||||
50 μM | luteolin-7-glucoside | |||||
432 μM | naringenin-7-glucoside | |||||
253 μM | eriodictyol-7-glucoside |
Vmax | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|
280 μmol/h/mg | toward 4-methylumbelliferyl-beta-D-glucopyranoside | ||||
10 μmol/min/mg | toward 4-nitrophenyl-beta-D-glucopyranoside | ||||
1.73 μmol/min/mg | toward genistein-7-glucoside | ||||
2.75 μmol/min/mg | toward daidzein-7-glucoside | ||||
1.19 μmol/min/mg | toward quercetin-4'-glucoside | ||||
0.77 μmol/min/mg | toward quercetin-7-glucoside | ||||
1.3 μmol/min/mg | toward apigenin-7-glucoside | ||||
1.3 μmol/min/mg | toward luteolin-4'-glucoside | ||||
2.85 μmol/min/mg | toward luteolin-7-glucoside | ||||
0.93 μmol/min/mg | toward naringenin-7-glucoside | ||||
0.9 μmol/min/mg | toward eriodictyol-7-glucoside |
kcat is 0.43 min-1 for the hydrolysis of glucosylceramide (PubMed:17595169).
kcat<0.01 min-1 for the hydrolysis of galactosylceramide (PubMed:17595169).
kcat is 7.26 min-1 for the hydrolysis of C6-NBD-glucosylceramide (PubMed:17595169).
kcat is 1.53 min-1 for the hydrolysis of C6-NBD-galactosylceramide (PubMed:17595169).
kcat is 73.75 min-1 for the hydrolysis of 4-methylumbelliferyl-beta-D-glucopyranoside (PubMed:17595169).
kcat is 94.35 min-1 for the hydrolysis of 4-methylumbelliferyl-beta-D-galactopyranoside (PubMed:17595169).
kcat is 10.7 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-fucopyranoside (PubMed:11784319).
kcat is 5.97 sec-1 for the hydrolysis of 4-nitrophenyl-alpha-L-arabinopyranoside (PubMed:11784319).
kcat is 12.1 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-glucopyranoside (PubMed:11784319).
kcat is 17.6 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-galactopyranoside (PubMed:11784319).
kcat is 0.75 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-xylopyranoside (PubMed:11784319).
kcat is 0.66 sec-1 for the hydrolysis of 4-nitrophenyl-beta-L-arabinopyranoside (PubMed:11784319).
kcat<0.01 min-1 for the hydrolysis of galactosylceramide (PubMed:17595169).
kcat is 7.26 min-1 for the hydrolysis of C6-NBD-glucosylceramide (PubMed:17595169).
kcat is 1.53 min-1 for the hydrolysis of C6-NBD-galactosylceramide (PubMed:17595169).
kcat is 73.75 min-1 for the hydrolysis of 4-methylumbelliferyl-beta-D-glucopyranoside (PubMed:17595169).
kcat is 94.35 min-1 for the hydrolysis of 4-methylumbelliferyl-beta-D-galactopyranoside (PubMed:17595169).
kcat is 10.7 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-fucopyranoside (PubMed:11784319).
kcat is 5.97 sec-1 for the hydrolysis of 4-nitrophenyl-alpha-L-arabinopyranoside (PubMed:11784319).
kcat is 12.1 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-glucopyranoside (PubMed:11784319).
kcat is 17.6 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-galactopyranoside (PubMed:11784319).
kcat is 0.75 sec-1 for the hydrolysis of 4-nitrophenyl-beta-D-xylopyranoside (PubMed:11784319).
kcat is 0.66 sec-1 for the hydrolysis of 4-nitrophenyl-beta-L-arabinopyranoside (PubMed:11784319).
pH Dependence
Optimum pH is 6.0-7.0 for the glucosylceramidase activity (PubMed:11784319, PubMed:17595169).
Optimum pH is 6.0 for the hydrolysis of 4-methylumbelliferyl-beta-D-glucopyranoside (PubMed:20728381).
Activity decreases sharply with increasing acidity and is less than 4% at pH 4 (PubMed:11784319).
Optimum pH is 6.0 for the hydrolysis of 4-methylumbelliferyl-beta-D-glucopyranoside (PubMed:20728381).
Activity decreases sharply with increasing acidity and is less than 4% at pH 4 (PubMed:11784319).
Temperature Dependence
Optimum temperature is 50 degrees Celsius (PubMed:11784319).
Stable more than 24 hours at 37 degrees Celsius (PubMed:11784319).
Loses activity at 58 degrees Celsius (PubMed:11784319).
Stable more than 24 hours at 37 degrees Celsius (PubMed:11784319).
Loses activity at 58 degrees Celsius (PubMed:11784319).
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 17 | substrate | ||||
Sequence: Q | ||||||
Binding site | 120 | substrate | ||||
Sequence: H | ||||||
Binding site | 164 | substrate | ||||
Sequence: N | ||||||
Active site | 165 | Proton donor | ||||
Sequence: E | ||||||
Binding site | 309 | substrate | ||||
Sequence: Y | ||||||
Active site | 373 | Nucleophile | ||||
Sequence: E | ||||||
Binding site | 417 | substrate | ||||
Sequence: W | ||||||
Binding site | 424-425 | substrate | ||||
Sequence: EW |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | catalytic complex | |
Cellular Component | cytosol | |
Molecular Function | beta-galactosidase activity | |
Molecular Function | beta-glucosidase activity | |
Molecular Function | galactosylceramidase activity | |
Molecular Function | glucosylceramidase activity | |
Molecular Function | glycosylceramidase activity | |
Molecular Function | scopolin beta-glucosidase activity | |
Biological Process | beta-glucoside catabolic process | |
Biological Process | galactosylceramide catabolic process | |
Biological Process | glucosylceramide catabolic process | |
Biological Process | glycoside catabolic process | |
Biological Process | glycosphingolipid catabolic process | |
Biological Process | glycosylceramide catabolic process | |
Biological Process | oligosaccharide catabolic process | |
Biological Process | positive regulation of exo-alpha-sialidase activity | |
Biological Process | protein stabilization |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Chemistry
Names & Taxonomy
Protein names
- Recommended nameCytosolic beta-glucosidase
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9H227
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_023587 | 106 | ||||
Sequence: D → N | ||||||
Mutagenesis | 165 | 2-fold decreased glucosylceramidase activity. | ||||
Sequence: E → D | ||||||
Mutagenesis | 165 | Loss of glucosylceramidase activity. | ||||
Sequence: E → Q | ||||||
Mutagenesis | 168 | No change in temperature or pH dependence. Decreased glucosidase activity. | ||||
Sequence: V → Y | ||||||
Natural variant | VAR_049298 | 172 | in dbSNP:rs36090352 | |||
Sequence: M → I | ||||||
Natural variant | VAR_023588 | 213 | in dbSNP:rs17612341 | |||
Sequence: R → P | ||||||
Mutagenesis | 225 | Decreased glucosidase activity. | ||||
Sequence: F → S | ||||||
Mutagenesis | 308 | Decreased glucosidase activity. | ||||
Sequence: Y → F or A | ||||||
Natural variant | VAR_023589 | 354 | in dbSNP:rs16873108 | |||
Sequence: C → R | ||||||
Mutagenesis | 373 | 2-fold decreased glucosylceramidase activity. | ||||
Sequence: E → D | ||||||
Mutagenesis | 373 | Loss of glucosylceramidase activity. | ||||
Sequence: E → Q | ||||||
Natural variant | VAR_081439 | 456-469 | loss of glucosidase activity toward the artificial substrate 4-methylumbelliferyl-beta-D-glucopyranoside | |||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 5 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000063908 | 1-469 | Cytosolic beta-glucosidase | |||
Sequence: MAFPAGFGWAAATAAYQVEGGWDADGKGPCVWDTFTHQGGERVFKNQTGDVACGSYTLWEEDLKCIKQLGLTHYRFSLSWSRLLPDGTTGFINQKGIDYYNKIIDDLLKNGVTPIVTLYHFDLPQTLEDQGGWLSEAIIESFDKYAQFCFSTFGDRVKQWITINEANVLSVMSYDLGMFPPGIPHFGTGGYQAAHNLIKAHARSWHSYDSLFRKKQKGMVSLSLFAVWLEPADPNSVSDQEAAKRAITFHLDLFAKPIFIDGDYPEVVKSQIASMSQKQGYPSSRLPEFTEEEKKMIKGTADFFAVQYYTTRLIKYQENKKGELGILQDAEIEFFPDPSWKNVDWIYVVPWGVCKLLKYIKDTYNNPVIYITENGFPQSDPAPLDDTQRWEYFRQTFQELFKAIQLDKVNLQVYCAWSLLDNFEWNQGYSSRFGLFHVDFEDPARPRVPYTSAKEYAKIIRNNGLEAHL |
Post-translational modification
The N-terminus is blocked.
Proteomic databases
PTM databases
Expression
Tissue specificity
Present in small intestine (at protein level). Expressed in liver, small intestine, colon, spleen and kidney. Down-regulated in renal cell carcinomas and hepatocellular carcinomas.
Structure
Family & Domains
Sequence similarities
Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9H227-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length469
- Mass (Da)53,696
- Last updated2005-10-11 v2
- Checksum9036455485CE2E2F
Q9H227-2
- Name2
- Differences from canonical
- 95-401: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0AAG2UVJ5 | A0AAG2UVJ5_HUMAN | GBA3 | 298 |
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 29 | in Ref. 7; AAH70188 | ||||
Sequence: P → L | ||||||
Alternative sequence | VSP_015835 | 95-401 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 134 | in Ref. 3; AAG39217 | ||||
Sequence: L → W | ||||||
Sequence conflict | 309 | in Ref. 5; BAD96683 | ||||
Sequence: Y → C | ||||||
Sequence conflict | 321 | in Ref. 5; BAD96683 | ||||
Sequence: K → R | ||||||
Sequence conflict | 326 | in Ref. 2; CAC08178 | ||||
Sequence: I → T |
Polymorphism
The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 456 in the reference genome, leading to the synthesis of a truncated protein lacking enzymatic activity in vitro. The sequence shown in this entry is that of variant p.Ter456Tyr, which has a frequency of about 88% in the human population according to the Genome Aggregation Database (gnomAD v3.1.2) and gives rise to a fully active beta-glucosidase.
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AB017913 EMBL· GenBank· DDBJ | BAB18741.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ278964 EMBL· GenBank· DDBJ | CAC08178.1 EMBL· GenBank· DDBJ | mRNA | ||
AF317840 EMBL· GenBank· DDBJ | AAG39217.1 EMBL· GenBank· DDBJ | mRNA | ||
AF323990 EMBL· GenBank· DDBJ | AAL37305.1 EMBL· GenBank· DDBJ | mRNA | ||
AK222963 EMBL· GenBank· DDBJ | BAD96683.1 EMBL· GenBank· DDBJ | mRNA | ||
AC093917 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC029362 EMBL· GenBank· DDBJ | AAH29362.1 EMBL· GenBank· DDBJ | mRNA | ||
BC070188 EMBL· GenBank· DDBJ | AAH70188.1 EMBL· GenBank· DDBJ | mRNA | ||
BC101829 EMBL· GenBank· DDBJ | AAI01830.1 EMBL· GenBank· DDBJ | mRNA | ||
BC109377 EMBL· GenBank· DDBJ | AAI09378.1 EMBL· GenBank· DDBJ | mRNA |