|
|
| CATH domain | Related DB codes (homologues) |
|---|
| 2.60.40.1180 | M00113,T00307,D00165,D00176,D00664,D00665,D00863,M00112,M00193,M00314,T00057,T00062,T00067 | | 3.20.20.80 | S00202,S00210,S00748,S00906,S00907,S00911,S00912,S00915,M00134,M00160,D00479,S00204,S00205,S00206,S00207,S00203,S00208,S00209,S00211,S00213,S00214,M00113,T00307,D00165,D00166,D00169,D00176,D00501,D00502,D00503,D00844,D00861,M00026,M00112,M00193,M00346,T00057,T00062,T00063,T00066,T00067 |
| Enzyme Name | | Swiss-prot | KEGG |
|---|
| Q9BDT0 | P04062 |
|---|
| Protein name | Glucosylceramidase | Glucosylceramidase | GlucosylceramidasePsychosine hydrolaseGlucosphingosine glucosylhydrolaseGlcCer-beta-glucosidasebeta-D-GlucocerebrosidaseGlucosylcerebrosidasebeta-GlucosylceramidaseCeramide glucosidaseGlucocerebrosidaseGlucosylsphingosine beta-glucosidaseGlucosylsphingosine beta-D-glucosidase |
|---|
| Synonyms | EC 3.2.1.45Beta-glucocerebrosidaseAcid beta-glucosidaseD-glucosyl-N-acylsphingosine glucohydrolase | EC 3.2.1.45Beta-glucocerebrosidaseAcid beta-glucosidaseD-glucosyl-N-acylsphingosine glucohydrolaseAlgluceraseImiglucerase |
|---|
| KEGG pathways | | MAP code | Pathways |
|---|
| MAP00600 | Sphingolipid metabolism | | MAP01032 | Glycan structures - degradation |
| Swiss-prot:Accession Number | Q9BDT0 | P04062 |
|---|
| Entry name | GLCM_PANTR | GLCM_HUMAN |
|---|
| Activity | D-glucosyl-N-acylsphingosine + H(2)O = D-glucose + N-acylsphingosine. | D-glucosyl-N-acylsphingosine + H(2)O = D-glucose + N-acylsphingosine. |
|---|
| Subunit | Interacts with SCARB2 (By similarity). | Interacts with saposin-C. |
|---|
| Subcellular location | Lysosome membrane, Peripheral membrane protein (By similarity). Note=Targeting to lysosomes occurs through an alternative MPR-independent mechanism via SCARB2 (By similarity). | Lysosome membrane, Peripheral membrane protein, Lumenal side. Note=Interaction with saposin-C promotes membrane association. |
|---|
| Cofactor |
|
|
|---|
| References for Catalytic Mechanism | | References | Sections | No. of steps in catalysis |
|---|
| [3] | Fig.1, p.886, p.890 |
| | [6] | Fig.1, p.853 |
| | [12] | p.4242 |
| | [14] | Fig.6, p.29055-29057 |
|
| references | | [1] |
|---|
| PubMed ID | 3927728 |
|---|
| Journal | Am J Med Genet |
|---|
| Year | 1985 |
|---|
| Volume | 21 |
|---|
| Pages | 529-49 |
|---|
| Authors | Grabowski GA, Goldblatt J, Dinur T, Kruse J, Svennerholm L, Gatt S, Desnick RJ |
|---|
| Title | Genetic heterogeneity in Gaucher disease: physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients. |
|---|
| [2] |
|---|
| PubMed ID | 1714449 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 1991 |
|---|
| Volume | 266 |
|---|
| Pages | 15021-7 |
|---|
| Authors | Fabbro D, Grabowski GA |
|---|
| Title | Human acid beta-glucosidase. Use of inhibitory and activating monoclonal antibodies to investigate the enzyme's catalytic mechanism and saposin A and C binding sites. |
|---|
| [3] |
|---|
| PubMed ID | 7712292 |
|---|
| Journal | Curr Opin Struct Biol |
|---|
| Year | 1994 |
|---|
| Volume | 4 |
|---|
| Pages | 885-92 |
|---|
| Authors | McCarter JD, Withers SG |
|---|
| Title | Mechanisms of enzymatic glycoside hydrolysis. |
|---|
| [4] |
|---|
| PubMed ID | 8294487 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 1994 |
|---|
| Volume | 269 |
|---|
| Pages | 2283-91 |
|---|
| Authors | Grace ME, Newman KM, Scheinker V, Berg-Fussman A, Grabowski GA |
|---|
| Title | Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. |
|---|
| [5] |
|---|
| PubMed ID | 7908905 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 1994 |
|---|
| Volume | 269 |
|---|
| Pages | 10975-8 |
|---|
| Authors | Miao S, McCarter JD, Grace ME, Grabowski GA, Aebersold R, Withers SG |
|---|
| Title | Identification of Glu340 as the active-site nucleophile in human glucocerebrosidase by use of electrospray tandem mass spectrometry. |
|---|
| Related Swiss-prot | P04062 |
|---|
| [6] |
|---|
| PubMed ID | 8535779 |
|---|
| Journal | Structure |
|---|
| Year | 1995 |
|---|
| Volume | 3 |
|---|
| Pages | 853-9 |
|---|
| Authors | Davies G, Henrissat B |
|---|
| Title | Structures and mechanisms of glycosyl hydrolases. |
|---|
| [7] |
|---|
| PubMed ID | 11087714 |
|---|
| Journal | Glycobiology |
|---|
| Year | 2000 |
|---|
| Volume | 10 |
|---|
| Pages | 1217-24 |
|---|
| Authors | Fabrega S, Durand P, Codogno P, Bauvy C, Delomenie C, Henrissat B, Martin BM, McKinney C, Ginns EI, Mornon JP, Lehn P |
|---|
| Title | Human glucocerebrosidase: heterologous expression of active site mutants in murine null cells. |
|---|
| [8] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 40-536, GLYCOSYLATION AT ASN-58, AND DISULFIDE BONDS. |
|---|
| PubMed ID | 12792654 |
|---|
| Journal | EMBO Rep |
|---|
| Year | 2003 |
|---|
| Volume | 4 |
|---|
| Pages | 704-9 |
|---|
| Authors | Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, Sussman JL |
|---|
| Title | X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. |
|---|
| Related PDB | 1ogs |
|---|
| Related Swiss-prot | P04062 |
|---|
| [9] |
|---|
| PubMed ID | 15019270 |
|---|
| Journal | Trends Pharmacol Sci |
|---|
| Year | 2004 |
|---|
| Volume | 25 |
|---|
| Pages | 147-51 |
|---|
| Authors | Futerman AH, Sussman JL, Horowitz M, Silman I, Zimran A |
|---|
| Title | New directions in the treatment of Gaucher disease. |
|---|
| [10] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 40-536 IN COMPLEX WITH SYNTHETIC INHIBITOR, ACTIVE SITE. |
|---|
| PubMed ID | 15817452 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 2005 |
|---|
| Volume | 280 |
|---|
| Pages | 23815-9 |
|---|
| Authors | Premkumar L, Sawkar AR, Boldin-Adamsky S, Toker L, Silman I, Kelly JW, Futerman AH, Sussman JL |
|---|
| Title | X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease. |
|---|
| Related PDB | 1y7v |
|---|
| Related Swiss-prot | P04062 |
|---|
| [11] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 40-536, AND GLYCOSYLATION AT ASN-58; ASN-98 AND ASN-185. |
|---|
| PubMed ID | 17139081 |
|---|
| Journal | Acta Crystallogr D Biol Crystallogr |
|---|
| Year | 2006 |
|---|
| Volume | 62 |
|---|
| Pages | 1458-65 |
|---|
| Authors | Brumshtein B, Wormald MR, Silman I, Futerman AH, Sussman JL |
|---|
| Title | Structural comparison of differently glycosylated forms of acid-beta-glucosidase, the defective enzyme in Gaucher disease. |
|---|
| Related PDB | 2j25 |
|---|
| Related Swiss-prot | P04062 |
|---|
| [12] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 40-536, CHARACTERIZATION OF GD VARIANTS SER-55; GLN-87; ASN-118; GLN-159; LEU-161; VAL-162; VAL-166; ASN-200; PHE-213; PHE-224; GLU-232; GLU-237; LEU-298; ILE-303; CYS-343; ILE-362; LYS-365; GLY-381; LYS-388; TRP-392; CYS-402; SER-409; VAL-410; HIS-419; LYS-421; ARG-429; LEU-433; SER-436; ASN-438; HIS-448; VAL-455; PRO-483; PRO-500 AND PRO-502, AND MUTAGENESIS OF CYS-43; CYS-57 AND CYS-62. |
|---|
| PubMed ID | 16293621 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 2006 |
|---|
| Volume | 281 |
|---|
| Pages | 4242-53 |
|---|
| Authors | Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, Grabowski GA |
|---|
| Title | Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. |
|---|
| Related PDB | 2f61 |
|---|
| Related Swiss-prot | P04062 |
|---|
| [13] |
|---|
| PubMed ID | 17894779 |
|---|
| Journal | FEBS J |
|---|
| Year | 2007 |
|---|
| Volume | 274 |
|---|
| Pages | 4944-50 |
|---|
| Authors | Yu Z, Sawkar AR, Kelly JW |
|---|
| Title | Pharmacologic chaperoning as a strategy to treat Gaucher disease. |
|---|
| [14] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY |
|---|
| PubMed ID | 17666401 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 2007 |
|---|
| Volume | 282 |
|---|
| Pages | 29052-8 |
|---|
| Authors | Brumshtein B, Greenblatt HM, Butters TD, Shaaltiel Y, Aviezer D, Silman I, Futerman AH, Sussman JL |
|---|
| Title | Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease. |
|---|
| Related PDB | 2v3e,2v3d |
|---|
| [15] |
|---|
| PubMed ID | 17713797 |
|---|
| Journal | J Mol Model |
|---|
| Year | 2007 |
|---|
| Volume | 13 |
|---|
| Pages | 1133-9 |
|---|
| Authors | Zubrzycki IZ, Borcz A, Wiacek M, Hagner W |
|---|
| Title | The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-beta-glucosidase. |
|---|
| [16] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 40-536 IN COMPLEXES WITH ISOFAGOMINE, AND SUBCELLULAR LOCATION. |
|---|
| PubMed ID | 17187079 |
|---|
| Journal | Nat Chem Biol |
|---|
| Year | 2007 |
|---|
| Volume | 3 |
|---|
| Pages | 101-7 |
|---|
| Authors | Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA |
|---|
| Title | Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. |
|---|
| Related PDB | 2nt0,2nt1,2nsx |
|---|
| Related Swiss-prot | P04062 |
|---|
| [17] |
|---|
| Comments | X-RAY CRYSTALLOGRAPHY |
|---|
| PubMed ID | 17524049 |
|---|
| Journal | Plant Biotechnol J |
|---|
| Year | 2007 |
|---|
| Volume | 5 |
|---|
| Pages | 579-90 |
|---|
| Authors | Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D |
|---|
| Title | Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. |
|---|
| Related PDB | 2v3f |
|---|
| [18] |
|---|
| PubMed ID | 18783340 |
|---|
| Journal | Biol Chem |
|---|
| Year | 2008 |
|---|
| Volume | 389 |
|---|
| Pages | 1361-9 |
|---|
| Authors | Kacher Y, Brumshtein B, Boldin-Adamsky S, Toker L, Shainskaya A, Silman I, Sussman JL, Futerman AH |
|---|
| Title | Acid beta-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy. |
|---|
| Related PDB | 2vt0 |
|---|
| [19] |
|---|
| PubMed ID | 19374450 |
|---|
| Journal | Biochemistry |
|---|
| Year | 2009 |
|---|
| Volume | 48 |
|---|
| Pages | 4816-27 |
|---|
| Authors | Lieberman RL, D'aquino JA, Ringe D, Petsko GA |
|---|
| Title | Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. |
|---|
| Related PDB | 3gxd,3gxf,3gxi,3gxm |
|---|
| [20] |
|---|
| PubMed ID | 19437524 |
|---|
| Journal | Chembiochem |
|---|
| Year | 2009 |
|---|
| Volume | 10 |
|---|
| Pages | 1480-5 |
|---|
| Authors | Brumshtein B, Aguilar-Moncayo M, Garc?a-Moreno MI, Ortiz Mellet C, Garc?a Fern?ndez JM, Silman I, Shaaltiel Y, Aviezer D, Sussman JL, Futerman AH |
|---|
| Title | 6-Amino-6-deoxy-5,6-di-N-(N'-octyliminomethylidene)nojirimycin: synthesis, biological evaluation, and crystal structure in complex with acid beta-glucosidase. |
|---|
| Related PDB | 2wcg |
|---|
| [21] |
|---|
| PubMed ID | 20980263 |
|---|
| Journal | J Biol Chem |
|---|
| Year | 2011 |
|---|
| Volume | 286 |
|---|
| Pages | 299-308 |
|---|
| Authors | Wei RR, Hughes H, Boucher S, Bird JJ, Guziewicz N, Van Patten SM, Qiu H, Pan CQ, Edmunds T |
|---|
| Title | X-ray and biochemical analysis of N370S mutant human acid ??-glucosidase. |
|---|
| Related PDB | 3ke0,3keh |
|---|
| [22] |
|---|
| PubMed ID | 21483943 |
|---|
| Journal | Org Biomol Chem |
|---|
| Year | 2011 |
|---|
| Volume | 9 |
|---|
| Pages | 4160-7 |
|---|
| Authors | Brumshtein B, Aguilar-Moncayo M, Benito JM, Garc?a Fernandez JM, Silman I, Shaaltiel Y, Aviezer D, Sussman JL, Futerman AH, Ortiz Mellet C |
|---|
| Title | Cyclodextrin-mediated crystallization of acid ??-glucosidase in complex with amphiphilic bicyclic nojirimycin analogues. |
|---|
| Related PDB | 2xwd,2xwe |
|---|
| comments | This enzyme belongs to glycosidase family-30, with a retaining mechanism.
This enzyme seems to be distantly related to beta-xylosidase (EC 3.2.1.37; D00844 in EzCatDB) from glycosidase family-39, and the catalytic residues of the counterpart enzyme can be superimposed with the corresponding residues. According to the literature [14], [16] and [18], these residues are located at the active site, along with the nucleophilic residue, Glu340, and general acid-base, Glu235.
The reaction may proceeds as follows:
(0) Arg120 and Tyr313 may modulate the activity of catalytic nucleophile, Glu340, whereas His311 may modulate the activity of a general acid-base, Glu235.
(1) Glu235 acts as a general acid to protonate the leaving oxygen, O4 atom at subsite +1, forming an oxocarbenium-ion-like transition-state. The transition-state is stabilized by Asn234 and Tyr313 through hydrogen bonding to the oxygen atoms of glucosyl group. (SN1-like reaction)
(2) Glu340 makes a nucleophilic attack on C1 atom of substrate, glucose, to form a covalent intermediate with the glucose unit.
(3) Glu235 acts as a general base to deprotonate a water molecule, to activate it.
(4) The activated water makes a nucleophilic attack on the C1 atom of the covalent intermediate. Thus, the substitution reaction completes.
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| created | updated |
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| 2008-05-13 | 2012-02-14 |
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