PDBsum entry 3hg3

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Hydrolase PDB id
Protein chain
395 a.a. *
NAG ×3
2PE ×5
Waters ×893
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human alpha-galactosidase catalytic mechanism 2. Substrate b
Structure: Alpha-galactosidase a. Chain: a, b. Synonym: alpha-d-galactoside galactohydrolase, alpha-d-gala a, melibiase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: gla. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
1.90Å     R-factor:   0.167     R-free:   0.197
Authors: A.I.Guce,N.E.Clark,S.C.Garman
Key ref: A.I.Guce et al. (2010). Catalytic mechanism of human alpha-galactosidase. J Biol Chem, 285, 3625-3632. PubMed id: 19940122
13-May-09     Release date:   24-Nov-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P06280  (AGAL_HUMAN) -  Alpha-galactosidase A
429 a.a.
395 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Alpha-galactosidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Melibiose + H2O = galactose + glucose

      Cofactor: Mg(2+); NAD(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     metabolic process   11 terms 
  Biochemical function     catalytic activity     10 terms  


J Biol Chem 285:3625-3632 (2010)
PubMed id: 19940122  
Catalytic mechanism of human alpha-galactosidase.
A.I.Guce, N.E.Clark, E.N.Salgado, D.R.Ivanen, A.A.Kulminskaya, H.Brumer, S.C.Garman.
The enzyme alpha-galactosidase (alpha-GAL, also known as alpha-GAL A; E.C. is responsible for the breakdown of alpha-galactosides in the lysosome. Defects in human alpha-GAL lead to the development of Fabry disease, a lysosomal storage disorder characterized by the buildup of alpha-galactosylated substrates in the tissues. alpha-GAL is an active target of clinical research: there are currently two treatment options for Fabry disease, recombinant enzyme replacement therapy (approved in the United States in 2003) and pharmacological chaperone therapy (currently in clinical trials). Previously, we have reported the structure of human alpha-GAL, which revealed the overall structure of the enzyme and established the locations of hundreds of mutations that lead to the development of Fabry disease. Here, we describe the catalytic mechanism of the enzyme derived from x-ray crystal structures of each of the four stages of the double displacement reaction mechanism. Use of a difluoro-alpha-galactopyranoside allowed trapping of a covalent intermediate. The ensemble of structures reveals distortion of the ligand into a (1)S(3) skew (or twist) boat conformation in the middle of the reaction cycle. The high resolution structures of each step in the catalytic cycle will allow for improved drug design efforts on alpha-GAL and other glycoside hydrolase family 27 enzymes by developing ligands that specifically target different states of the catalytic cycle. Additionally, the structures revealed a second ligand-binding site suitable for targeting by novel pharmacological chaperones.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21092187 D.P.Germain (2010).
Fabry disease.
  Orphanet J Rare Dis, 5, 30.  
21138548 G.Andreotti, M.R.Guarracino, M.Cammisa, A.Correra, and M.V.Cubellis (2010).
Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study.
  Orphanet J Rare Dis, 5, 36.  
20681989 H.Nakai, M.J.Baumann, B.O.Petersen, Y.Westphal, M.A.Hachem, A.Dilokpimol, J...Duus, H.A.Schols, and B.Svensson (2010).
Aspergillus nidulans alpha-galactosidase of glycoside hydrolase family 36 catalyses the formation of alpha-galacto-oligosaccharides by transglycosylation.
  FEBS J, 277, 3538-3551.  
20552664 T.V.Vuong, and D.B.Wilson (2010).
Glycoside hydrolases: catalytic base/nucleophile diversity.
  Biotechnol Bioeng, 107, 195-205.  
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