Q9H227 (GBA3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cytosolic beta-glucosidase
EC=3.2.1.21

Alternative name(s):
Cytosolic beta-glucosidase-like protein 1

Gene names

Name:	GBA3
Synonyms:	CBG, CBGL1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	469 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Glycosidase probably involved in the intestinal absorption and metabolism of dietary flavonoid glycosides. Able to hydrolyze a broad variety of glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens. Possesses beta-glycosylceramidase activity and may be involved in a nonlysosomal catabolic pathway of glycosylceramide. Ref.3 Ref.8 Ref.9
Catalytic activity	Hydrolysis of terminal, non-reducing beta-D-glucosyl residues with release of beta-D-glucose.
Enzyme regulation	Inhibited by 2,4-dinitrophenyl-2-fluoro-2-deoxy-beta-D-glucopyranoside and sodium taurocholate. Ref.2 Ref.3
Subcellular location	Cytoplasm › cytosol Ref.8 Ref.9.
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. Ref.1 Ref.8
Post-translational modification	The N-terminus is blocked.
Sequence similarities	Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.
Biophysicochemical properties	Kinetic parameters: KM=40 µM for 4-methylumbelliferyl-beta-D-glucopyranoside Ref.2 Ref.3 KM=50 µM for 4-methylumbelliferyl-beta-D-galactopyranoside KM=370 µM for 4-nitrophenyl-beta-D-fucopyranoside KM=570 µM for 4-nitrophenyl-alpha-D-arabinopyranoside KM=1.76 mM for 4-nitrophenyl-beta-D-glucopyranoside KM=3.14 mM for 4-nitrophenyl-beta-D-galactopyranoside KM=1.58 mM for 4-nitrophenyl-beta-D-xylopyranoside KM=52.6 mM for 4-nitrophenyl-beta-L-arabinopyranoside KM=35 µM for genistein-7-glucoside KM=118 µM for daidzein-7-glucoside KM=31.8 µM for quercetin-4'-glucoside KM=42.2 µM for quercetin-7-glucoside KM=21.5 µM for apigenin-7-glucoside KM=10 µM for luteolin-4'-glucoside KM=50 µM for luteolin-7-glucoside KM=432 µM for naringenin-7-glucoside KM=253 µM for eriodictyol-7-glucoside Vmax=10 µmol/min/mg enzyme toward 4-nitrophenyl-beta-D-glucopyranoside Vmax=1.73 µmol/min/mg enzyme toward genistein-7-glucoside Vmax=2.75 µmol/min/mg enzyme toward daidzein-7-glucoside Vmax=1.19 µmol/min/mg enzyme toward quercetin-4'-glucoside Vmax=0.77 µmol/min/mg enzyme toward quercetin-7-glucoside Vmax=1.30 µmol/min/mg enzyme toward apigenin-7-glucoside Vmax=1.30 µmol/min/mg enzyme toward luteolin-4'-glucoside Vmax=2.85 µmol/min/mg enzyme toward luteolin-7-glucoside Vmax=0.93 µmol/min/mg enzyme toward naringenin-7-glucoside Vmax=0.90 µmol/min/mg enzyme toward eriodictyol-7-glucoside pH dependence: Optimum pH is 6.5. Active from pH 5 to 7.5. Activity decreases sharply with increasing acidity and is less than 4% at pH 4. Temperature dependence: Optimum temperature is 50 degrees Celsius. Stable more than 24 hours at 37 degrees Celsius. Loses activity at 58 degrees Celsius.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Molecular function	Glycosidase Hydrolase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	carbohydrate metabolic process Inferred from electronic annotation. Source: InterPro glycoside catabolic process Inferred from direct assay Ref.2. Source: UniProtKB glycosylceramide catabolic process Inferred from mutant phenotype Ref.9. Source: UniProtKB phospholipid metabolic process Traceable author statement. Source: Reactome small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	beta-galactosidase activity Inferred from direct assay Ref.2Ref.9. Source: UniProtKB beta-glucosidase activity Inferred from direct assay Ref.9. Source: UniProtKB glycosylceramidase activity Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: 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.

Isoform 2 (identifier: Q9H227-2)

The sequence of this isoform differs from the canonical sequence as follows:
     95-401: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 469

469

Cytosolic beta-glucosidase

PRO_0000063908

Regions

Region

424 – 425

2

Substrate binding By similarity

Sites

Active site

165

1

Proton donor Potential

Active site

373

1

Nucleophile Potential

Binding site

17

1

Substrate

Binding site

120

1

Substrate

Binding site

164

1

Substrate

Binding site

309

1

Substrate

Binding site

417

1

Substrate

Natural variations

Alternative sequence

95 – 401

307

Missing in isoform 2.

VSP_015835

Natural variant

106

1

D → N Rare polymorphism. Ref.12

VAR_023587

Natural variant

172

1

M → I.
Corresponds to variant rs36090352 [ dbSNP | Ensembl ].

VAR_049298

Natural variant

213

1

R → P.
Corresponds to variant rs17612341 [ dbSNP | Ensembl ].

VAR_023588

Natural variant

354

1

C → R.
Corresponds to variant rs16873108 [ dbSNP | Ensembl ].

VAR_023589

Experimental info

Mutagenesis

165

1

E → D: Reduces catalytic activity 2-fold. Ref.9 Ref.11

Mutagenesis

165

1

E → Q: Loss of catalytic activity. Ref.9 Ref.11

Mutagenesis

168

1

V → Y: No change in temperature or pH dependence. Decrease in specific activity. Ref.7

Mutagenesis

225

1

F → S: Decrease in specific activity. Ref.7

Mutagenesis

308

1

Y → F or A: Decrease in specific activity. Ref.7

Mutagenesis

373

1

E → D: Reduces catalytic activity 2-fold. Ref.9

Mutagenesis

373

1

E → Q: Loss of catalytic activity. Ref.9

Sequence conflict

29

1

P → L in AAH70188. Ref.6

Sequence conflict

134

1

L → W in AAG39217. Ref.3

Sequence conflict

309

1

Y → C in BAD96683. Ref.5

Sequence conflict

321

1

K → R in BAD96683. Ref.5

Sequence conflict

326

1

I → T in CAC08178. Ref.2

Secondary structure

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469

Helix Strand Turn

Details...

Beta strand

8 – 12

5

Helix

15 – 18

4

Helix

24 – 26

3

Helix

31 – 38

8

Beta strand

40 – 43

4

Helix

44 – 46

3

Beta strand

49 – 51

3

Turn

55 – 57

3

Helix

59 – 69

11

Beta strand

72 – 77

6

Helix

80 – 83

4

Helix

94 – 109

16

Beta strand

113 – 121

9

Helix

125 – 129

5

Helix

132 – 134

3

Helix

138 – 153

16

Turn

154 – 156

3

Beta strand

159 – 164

6

Helix

166 – 174

9

Turn

186 – 188

3

Helix

189 – 211

23

Helix

213 – 216

4

Beta strand

219 – 221

3

Beta strand

223 – 233

11

Helix

237 – 250

14

Helix

252 – 259

8

Helix

266 – 278

13

Helix

291 – 297

7

Beta strand

302 – 316

15

Helix

326 – 330

5

Beta strand

332 – 335

4

Helix

351 – 363

13

Beta strand

369 – 374

6

Beta strand

378 – 381

4

Helix

387 – 405

19

Beta strand

411 – 417

7

Helix

425 – 430

6

Beta strand

435 – 438

4

Beta strand

442 – 444

3

Beta strand

447 – 449

3

Helix

451 – 462

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 11, 2005. Version 2. Checksum: 9036455485CE2E2F	FASTA	469	53,696
	10 20 30 40 50 60 MAFPAGFGWA AATAAYQVEG GWDADGKGPC VWDTFTHQGG ERVFKNQTGD VACGSYTLWE 70 80 90 100 110 120 EDLKCIKQLG LTHYRFSLSW SRLLPDGTTG FINQKGIDYY NKIIDDLLKN GVTPIVTLYH 130 140 150 160 170 180 FDLPQTLEDQ GGWLSEAIIE SFDKYAQFCF STFGDRVKQW ITINEANVLS VMSYDLGMFP 190 200 210 220 230 240 PGIPHFGTGG YQAAHNLIKA HARSWHSYDS LFRKKQKGMV SLSLFAVWLE PADPNSVSDQ 250 260 270 280 290 300 EAAKRAITFH LDLFAKPIFI DGDYPEVVKS QIASMSQKQG YPSSRLPEFT EEEKKMIKGT 310 320 330 340 350 360 ADFFAVQYYT TRLIKYQENK KGELGILQDA EIEFFPDPSW KNVDWIYVVP WGVCKLLKYI 370 380 390 400 410 420 KDTYNNPVIY ITENGFPQSD PAPLDDTQRW EYFRQTFQEL FKAIQLDKVN LQVYCAWSLL 430 440 450 460 DNFEWNQGYS SRFGLFHVDF EDPARPRVPY TSAKEYAKII RNNGLEAHL
	Isoform 2 [UniParc]. Checksum: AC2A05DB957E6997	FASTA	162	18,265
	10 20 30 40 50 60 MAFPAGFGWA AATAAYQVEG GWDADGKGPC VWDTFTHQGG ERVFKNQTGD VACGSYTLWE 70 80 90 100 110 120 EDLKCIKQLG LTHYRFSLSW SRLLPDGTTG FINQKAIQLD KVNLQVYCAW SLLDNFEWNQ 130 140 150 160 GYSSRFGLFH VDFEDPARPR VPYTSAKEYA KIIRNNGLEA HL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and expression of a novel klotho-related protein." Yahata K., Mori K., Arai H., Koide S., Ogawa Y., Mukoyama M., Sugawara A., Ozaki S., Tanaka I., Nabeshima Y., Nakao K. J. Mol. Med. 78:389-394(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Fetal liver.
[2]	"Cloning and characterization of human liver cytosolic beta-glycosidase." de Graaf M., van Veen I.C., van der Meulen-Muileman I.H., Gerritsen W.R., Pinedo H.M., Haisma H.J. Biochem. J. 356:907-910(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES. Tissue: Liver.
[3]	"Functional expression of human liver cytosolic beta-glucosidase in Pichia pastoris. Insights into its role in the metabolism of dietary glucosides." Berrin J.-G., McLauchlan W.R., Needs P., Williamson G., Puigserver A., Kroon P.A., Juge N. Eur. J. Biochem. 269:249-258(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, BLOCKAGE OF N-TERMINUS, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES. Tissue: Liver.
[4]	Hays W.S., VanderJagt D.J., Glew R.H., Johnston D.E. Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Liver.
[5]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Small intestine.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Kidney and Liver.
[7]	"Substrate (aglycone) specificity of human cytosolic beta-glucosidase." Berrin J.-G., Czjzek M., Kroon P.A., McLauchlan W.R., Puigserver A., Williamson G., Juge N. Biochem. J. 373:41-48(2003) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF VAL-168; PHE-225 AND TYR-308.
[8]	"Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans." Nemeth K., Plumb G.W., Berrin J.-G., Juge N., Jacob R., Naim H.Y., Williamson G., Swallow D.M., Kroon P.A. Eur. J. Nutr. 42:29-42(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[9]	"Klotho-related protein is a novel cytosolic neutral beta-glycosylceramidase." Hayashi Y., Okino N., Kakuta Y., Shikanai T., Tani M., Narimatsu H., Ito M. J. Biol. Chem. 282:30889-30900(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH GLUCOSE AND GALACTOSE, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF GLU-165 AND GLU-373.
[10]	"The crystal structure of human cytosolic beta-glucosidase unravels the substrate aglycone specificity of a family 1 glycoside hydrolase." Tribolo S., Berrin J.G., Kroon P.A., Czjzek M., Juge N. J. Mol. Biol. 370:964-975(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
[11]	"Crystal structure of the covalent intermediate of human cytosolic beta-glucosidase." Noguchi J., Hayashi Y., Baba Y., Okino N., Kimura M., Ito M., Kakuta Y. Biochem. Biophys. Res. Commun. 374:549-552(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH GLUCOSE, MUTAGENESIS OF GLU-165.
[12]	"Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease." Beutler E., Beutler L., West C. J. Lab. Clin. Med. 144:65-68(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ASN-106.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB017913 mRNA. Translation: BAB18741.1.
AJ278964 mRNA. Translation: CAC08178.1.
AF317840 mRNA. Translation: AAG39217.1.
AF323990 mRNA. Translation: AAL37305.1.
AK222963 mRNA. Translation: BAD96683.1.
BC029362 mRNA. Translation: AAH29362.1.
BC070188 mRNA. Translation: AAH70188.1.
BC101829 mRNA. Translation: AAI01830.1.
BC109377 mRNA. Translation: AAI09378.1.

IPI

IPI00300622.
IPI00651709.

RefSeq

NP_001121904.1. NM_001128432.1.
NP_066024.1. NM_020973.3.

UniGene

Hs.653107.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2E9L	X-ray	1.60	A	1-469	[»]
2E9M	X-ray	1.80	A	1-469	[»]
2JFE	X-ray	2.70	X	1-469	[»]
2ZOX	X-ray	1.90	A	1-469	[»]
3VKK	X-ray	2.00	A	1-469	[»]

ProteinModelPortal

Q9H227.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9H227. 1 interaction.

Protein family/group databases

CAZy

GH1. Glycoside Hydrolase Family 1.

PTM databases

PhosphoSite

Q9H227.

Polymorphism databases

DMDM

77416427.

Proteomic databases

PRIDE

Q9H227.

Protocols and materials databases

DNASU

57733.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

57733.

KEGG

hsa:57733.

UCSC

uc003gqp.4. human.
uc010iep.3. human.

Organism-specific databases

CTD

57733.

GeneCards

GC04P022694.

HGNC

HGNC:19069. GBA3.

MIM

606619. gene.

neXtProt

NX_Q9H227.

PharmGKB

PA134861643.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

HBG053101.

InParanoid

Q9H227.

KO

K05350.

OrthoDB

EOG4WDDBM.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

Q9H227.

Gene expression databases

CleanEx

HS_GBA3.

Genevestigator

Q9H227.

GermOnline

ENSG00000176201. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.80. 1 hit.

InterPro

IPR001360. Glyco_hydro_1.
IPR018120. Glyco_hydro_1_AS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
[Graphical view]

PANTHER

PTHR10353. PTHR10353. 1 hit.

Pfam

PF00232. Glyco_hydro_1. 1 hit.
[Graphical view]

PRINTS

PR00131. GLHYDRLASE1.

SUPFAM

SSF51445. Glyco_hydro_cat. 1 hit.

PROSITE

PS00572. GLYCOSYL_HYDROL_F1_1. False negative.
PS00653. GLYCOSYL_HYDROL_F1_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q9H227.

ChEMBL

CHEMBL3865.

EvolutionaryTrace

Q9H227.

GenomeRNAi

57733.

NextBio

64698.

SOURCE

Search...

Entry information

Entry name

GBA3_HUMAN

Accession

Primary (citable) accession number: Q9H227
Secondary accession number(s): Q32LY7 , Q3MIH4, Q53GG8, Q6NSF4, Q8NHT8, Q9H3T4, Q9H4C6

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	October 11, 2005
Last modified:	May 1, 2013
This is version 106 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.