Α‑glucosidase maltase-glucoamylase

 

α‑Glucosidase Maltase- Glucoamylase catalyses the digestion of starch. α‑Glucosidase inhibitors have been efficient in delaying glucose production, which is crucial for regulating postprandial blood glucose levels and can be used for therapeutic purposes to reduce the damage and complications in diabetics and obesity.

 

Reference Protein and Structure

Sequence
O43451 UniProt (3.2.1.3, 3.2.1.20) IPR000322 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
2qmj - Crystral Structure of the N-terminal Subunit of Human Maltase-Glucoamylase in Complex with Acarbose (1.9 Å) PDBe PDBsum 2qmj
Catalytic CATH Domains
2.60.40.1760 CATHdb 3.20.20.80 CATHdb (see all for 2qmj)
Click To Show Structure

Enzyme Reaction (EC:3.2.1.20)

maltose
CHEBI:17306ChEBI
+
water
CHEBI:15377ChEBI
→
D-glucose
CHEBI:17634ChEBI
Alternative enzyme names: Alpha-1,4-glucosidase, Alpha-D-glucosidase, Alpha-glucopyranosidase, Alpha-glucoside hydrolase, Glucoinvertase, Glucosidoinvertase, Glucosidosucrase, Maltase, Maltase-glucoamylase, Lysosomal alpha-glucosidase, Acid maltase,

Enzyme Mechanism

Introduction

The mechanism involves cleavage of the maltose molecule with net retention of anomeric configuration. Asp443 performs a nucleophilic attack on the anomeric carbon of the maltose molecule and then attack of a water molecule forms the second glucose product. Asp542 acts as a general acid/base catalyst.

Catalytic Residues Roles

UniProt PDB* (2qmj)
Asp628 Asp542A General acid/base catalyst. proton acceptor, proton donor
Asp529 Asp443A Asp443 stabilises and modulates the pKa throughout the glycosylation step of the reaction by forming a water-mediated hydrogen bond with Asp366. nucleophile
Asp452 Asp366A Asp366 stabilises and modulates the pKa throughout the glycosylation step of the reaction by forming a water-mediated hydrogen bond with Asp443. modifies pKa
Met530 Met444A Steric role. steric role
Tyr300 Tyr214A Stacking interaction with the sugar rings helps with the position of the substrate in the active site. modifies pKa, pi-pi interaction
Trp492, Trp625 Trp406A, Trp539A Bulky residues, contribute to stacking interactions that properly orient the maltose rings. pi-pi interaction
His686, Asp529, Arg612, Asp413 His600A, Asp443A, Arg526A, Asp327A Contribute to the orientation of the sugars by forming hydrogen bonds with the hydroxyl group of the sugar rings. steric role
*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

acidic bimolecular nucleophilic substitution, proton transfer

References

  1. Brás NF et al. (2018), J Phys Chem B, 122, 3889-3899. Mechanistic Pathway on Human α-Glucosidase Maltase-Glucoamylase Unveiled by QM/MM Calculations. DOI:10.1021/acs.jpcb.8b01321. PMID:29548257.

Step 1. Asp443 performs a nucleophilic attack on the anomeric carbon of the maltose molecule, while Asp542 acts as a general acid/base and protonates the glyosidic oxygen atom.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp443A nucleophile
Asp542A proton donor
Asp327A steric role
His600A steric role
Tyr214A pi-pi interaction
Trp406A pi-pi interaction
Trp539A pi-pi interaction
Asp366A modifies pKa
Tyr214A modifies pKa
Arg526A steric role
Met444A steric role

Chemical Components

ingold: acidic bimolecular nucleophilic substitution, proton transfer

Step 2. Asp542 deprotonates the water molecule which in turn attacks the anomeric carbon and forms a covalent bond.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp542A proton acceptor

Chemical Components

ingold: acidic bimolecular nucleophilic substitution

Step 3. Products. Two glucose molecules are formed.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles

Chemical Components

Step 1. Asp443 performs a nucleophilic attack on the anomeric carbon of the maltose molecule, while Asp542 acts as a general acid/base and protonates the glyosidic oxygen atom.

Step 2. Asp542 deprotonates the water molecule which in turn attacks the anomeric carbon and forms a covalent bond.

Step 3. Products. Two glucose molecules are formed.

Contributors

Yordanos Abeje, Noa Marson