Beta-glucuronidase
Catalyses the stepwise degradation of beta-D-glucuronic acid residues from the non-reducing termini of glycosaminoglycans (hyaluronic acid, heparan sulfate, dermatan sulfate, and chondroitin srulfate) to yield their respective glycosidase and hydrolysis results in release of alcohols and free glucuronic acid.
Reference Protein and Structure
- Sequence
-
P08236
(3.2.1.31)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Homo sapiens (Human)
- PDB
-
1bhg
- HUMAN BETA-GLUCURONIDASE AT 2.6 A RESOLUTION
(2.53 Å)
- Catalytic CATH Domains
-
2.60.120.260
3.20.20.80
(see all for 1bhg)
Enzyme Reaction (EC:3.2.1.31)
+
→
+
Alternative enzyme names: Beta-glucuronide glucuronohydrolase, Exo-beta-D-glucuronidase, Glucuronidase, Ketodase,
Enzyme Mechanism
Introduction
In this retaining mechanism, Glu540 acts as the catalytic nucleophile, forming an enzyme-substrate complex eliminating the alcohol product. Glu451 then abstracts a proton from the catalytic water, which cleaves the intermediate from the enzyme, regenerating the active site.
Catalytic Residues Roles
| UniProt | PDB* (1bhg) | ||
| Glu451 | Glu451(431)A | Acts as a general acid/base. | proton shuttle (general acid/base) |
| Glu540 | Glu540(520)A | Acts as the catalytic nucleophile. | covalent catalysis |
| Tyr504, Asp207 | Tyr504(484)A, Asp207(187)A | Acts as electrostatic stabilisers. | electrostatic stabiliser |
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file;
y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain;
C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.
Chemical Components
References
- Islam MR et al. (1999), J Biol Chem, 274, 23451-23455. Active Site Residues of Human -Glucuronidase: EVIDENCE FOR GLU540 AS THE NUCLEOPHILE AND GLU451 AS THE ACID-BASE RESIDUE. DOI:10.1074/jbc.274.33.23451. PMID:10438523.
- Khan FI et al. (2016), Gene, 576, 36-44. Large scale analysis of the mutational landscape in β-glucuronidase: A major player of mucopolysaccharidosis type VII. DOI:10.1016/j.gene.2015.09.062. PMID:26415878.
- Khan KM et al. (2014), J Comput Aided Mol Des, 28, 577-585. Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors. DOI:10.1007/s10822-014-9745-z. PMID:24771145.
- Khan KM et al. (2014), Bioorg Med Chem Lett, 24, 1825-1829. Evaluation of bisindole as potent β-glucuronidase inhibitors: Synthesis and in silico based studies. DOI:10.1016/j.bmcl.2014.02.015. PMID:24602903.
- Hassan MI et al. (2013), PLoS One, 8, e79687-. High Resolution Crystal Structure of Human β-Glucuronidase Reveals Structural Basis of Lysosome Targeting. DOI:10.1371/journal.pone.0079687. PMID:24260279.
- Khan KM et al. (2011), Bioorg Med Chem, 19, 4286-4294. Synthesis of novel inhibitors of β-glucuronidase based on benzothiazole skeleton and study of their binding affinity by molecular docking. DOI:10.1016/j.bmc.2011.05.052. PMID:21684753.
- Wong AW et al. (1998), J Biol Chem, 273, 34057-34062. Identification of Glu-540 as the Catalytic Nucleophile of Human beta -Glucuronidase Using Electrospray Mass Spectrometry. DOI:10.1074/jbc.273.51.34057. PMID:9852062.
- Jain S et al. (1996), Nat Struct Biol, 3, 375-381. Structure of human β-glucuronidase reveals candidate lysosomal targeting and active-site motifs. DOI:10.1038/nsb0496-375. PMID:8599764.
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Glu540(520)A | covalent catalysis |
| Glu451(431)A | proton shuttle (general acid/base) |
| Tyr504(484)A | electrostatic stabiliser |
| Asp207(187)A | electrostatic stabiliser |