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Glycoside Hydrolase Family 63

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Glycoside Hydrolase Family GH63
Clan GH-G
Mechanism inverting
Active site residues Inferred
CAZy DB link

Substrate specificities

Glycoside hydrolases of GH63 are exo-acting α-glucosidases. Eukaryotic members of this family are processing α-glucosidase I enzymes (mannosyl-oligosaccharide glucosidase, EC, which specifically hydrolyze the terminal α-1,2-glucosidic linkage in the N-linked oligosaccharide precursor, Glc3Man9GlcNAc2, to produce β-glucose and Glc2Man9GlcNAc2. Processing α-glucosidase I thus plays a critical role in the maturation of eukaryotic N-glycans. The enzymatic properties of Cwh41p, a processing α-glucosidase I from Saccharomyces cerevisiae, have been intensively studied [1] (also reviewed in [2]).

Genes encoding GH63 enzymes have also been found in archaea and bacteria, but their natural substrates are still unclear, as these organisms are not known to produce eukaryotic N-linked oligosacharides. A bacterial GH63 enzyme, Escherichia coli YgjK, demonstrated the highest activity toward the α-1,3-glucosidic linkage of nigerose (Glc-α-1,3-Glc) among the commercially available sugars tested, but the Km value for nigerose was substantially higher than that for other typical α-glucosidases [3]. In 2013, the substrates of GH63 enzymes from Thermus thermophilus HB27 and Rubrobacter radiotolerans RSPS-4 have been identified as α-D-mannopyranosyl-1,2-D-glycerate (mannosylglycerate) and α-D-glucopyranosyl-1,2-D-glycerate (glucosylglycerate) [4].

Kinetics and Mechanism

Family GH63 enzymes are inverting enzymes, as first shown by NMR on a processing α-glucosidase I from S. cerevisiae [5].

Catalytic Residues

The catalytic residues were inferred by comparing the catalytic (α/α)6 barrel domain of the GH63 enzyme, E. coli YgjK, with those of GH15 and GH37 enzymes. In the case of GH37 and GH63, both of which belong to clan GH-G, the catalytic general acid is predicted as an Asp residue (Asp501 in E. coli YgjK), and the general base is considered to be a Glu residue (Glu727 in E. coli YgjK) [3]. Although both of the corresponding residues of GH15, which belongs to clan GH-L, are identified as Glu residues, the positions of the catalytic residues of GH15, GH37, and GH63 are highly conserved [3, 6].

Three-dimensional structures

The crystal structures of the bacterial GH63 proteins, E. coli YgjK [3] (multiple PDB entries) and Thermus thermophilus uncharacterised protein TTHA0978 (PDB 2z07), have been reported. The catalytic domain consists of an (α/α)6 barrel fold. The main chain of the (α/α)6 barrel domain shares high structural similarity with those of GH15, GH37, GH65, and GH94 [3, 6]. This similarity had been predicted on the basis of sequence comparison, before their crystal structures were available [7]. The first crystal structure of the eukaryotic processing α-glucosidase I (PDB 4j5t) has been reported in 2013 [8].

Family Firsts

First gene cloning
Human processing α-glucosidase I [9].
First stereochemistry determination
Processing α-glucosidase I from Saccharomyces cerevisiae (Cwh41p) [5].
First general acid residue identification
Inferred from structural comparison [3].
First general base residue identification
Inferred from structural comparison [3].
First 3-D structure
Escherichia coli YgjK, an enzyme showing the highest activity for the α-1,3-glucosidic linkage of nigerose [3].
First 3-D structure of a eukaryotic GH63 enzyme
A transmembrane-deleted form of processing α-glucosidase I from Saccharomyces cerevisiae [8].


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  1. Error fetching PMID 11971867: [Dhanawansa2002]
  2. Error fetching PMID 9878780: [Herscovics1999]
  3. Error fetching PMID 18586271: [Kurakata2008]
  4. Error fetching PMID 23273275: [Alarico2013]
  5. Error fetching PMID 10619707: [Palcic1999]
  6. Gibson RP, Gloster TM, Roberts S, Warren RA, Storch de Gracia I, GarcĂ­a A, Chiara JL, and Davies GJ. (2007) Molecular basis for trehalase inhibition revealed by the structure of trehalase in complex with potent inhibitors. Angew Chem Int Ed Engl. 46, 4115-9. DOI:10.1002/anie.200604825 | PubMed ID:17455176 | HubMed [Gibson2007]
  7. Error fetching PMID 16226731: [Stam2005]
  8. Error fetching PMID 23536181: [Barker2013]
  9. Error fetching PMID 7635146: [Kalz-Fuller1995]
All Medline abstracts: PubMed | HubMed