Glucose-6-phosphate dehydrogenase

 

Glucose-6-phosphate dehydrogenase (G6PDH) is a ubiquitous protein, present in bacteria and all eukaryotic cell types. The enzyme catalyses the the first step in the pentose pathway: the conversion of glucose-6-phosphate to gluconolactone 6-phosphate in the presence of NADP, producing NADPH. The ubiquitous expression of the enzyme gives it a major role in the production of NADPH for the many NADPH-mediated reductive processes in all cells. Deficiency of G6PDH is a common genetic abnormality affecting millions of people worldwide. Many sequence variants, most caused by single point mutations, are known, exhibiting a wide variety of phenotypes.

 

Reference Protein and Structure

Sequence
P11411 UniProt (1.1.1.363) IPR001282 (Sequence Homologues) (PDB Homologues)
Biological species
Leuconostoc mesenteroides (Bacteria) Uniprot
PDB
1dpg - GLUCOSE 6-PHOSPHATE DEHYDROGENASE FROM LEUCONOSTOC MESENTEROIDES (2.0 Å) PDBe PDBsum 1dpg
Catalytic CATH Domains
3.30.360.10 CATHdb (see all for 1dpg)
Click To Show Structure

Enzyme Reaction (EC:1.1.1.49)

D-glucopyranose 6-phosphate(2-)
CHEBI:61548ChEBI
+
NADP(3-)
CHEBI:58349ChEBI
→
6-O-phosphonato-D-glucono-1,5-lactone(2-)
CHEBI:57955ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADPH(4-)
CHEBI:57783ChEBI
Alternative enzyme names: 6-phosphoglucose dehydrogenase, D-glucose 6-phosphate dehydrogenase, Entner-Doudoroff enzyme, NADP-dependent glucose 6-phosphate dehydrogenase, NADP-glucose-6-phosphate dehydrogenase, Zwischenferment, Glucose 6-phosphate dehydrogenase (NADP), G6PD, G6PDH, GPD, Glucose-6-phosphate 1-dehydrogenase, Glucose-6-phosphate dehydrogenase,

Enzyme Mechanism

Introduction

The oxidation of glucose 6-phosphate by G6PD involves general base (His240) abstraction of a proton from the C1−OH, thereby allowing transfer of the hydride from C1 to the C4 position of the nicotinamide ring of the coenzyme.

Catalytic Residues Roles

UniProt PDB* (1dpg)
His179 His178A Binds the phosphate group of the substrate and helps stabilise the transition state. transition state stabiliser
Asp178 Asp177A Hydrogen bonds with His240, lowering it's pKa to enable it to act as a general acid/base. modifies pKa
His241 His240A Acts as a general acid/base. Its Nδ1 is hydrogen bonded to Asp177 Oδ1 while Nϵ2 is within hydrogen–bonding distance of two waters in each subunit of the unliganded enzyme. proton acceptor, proton donor
*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

hydride transfer, proton transfer, overall product formed, overall reactant used, inferred reaction step, native state of enzyme regenerated

References

  1. Cosgrove MS et al. (1998), Biochemistry, 37, 2759-2767. On the mechanism of the reaction catalyzed by glucose 6-phosphate dehydrogenase. DOI:10.1021/bi972069y. PMID:9485426.
  2. Cosgrove MS et al. (2002), Biochemistry, 41, 6939-6945. The Catalytic Mechanism of Glucose 6-Phosphate Dehydrogenases:  Assignment and1H NMR Spectroscopy pH Titration of the Catalytic Histidine Residue in the 109 kDaLeuconostoc mesenteroidesEnzyme†. DOI:10.1021/bi0255219.
  3. Cosgrove MS et al. (2000), Biochemistry, 39, 15002-15011. An Examination of the Role of Asp-177 in the His-Asp Catalytic Dyad ofLeuconostoc mesenteroidesGlucose 6-Phosphate Dehydrogenase:  X-ray Structure and pH Dependence of Kinetic Parameters of the D177N Mutant Enzyme†,‡. DOI:10.1021/bi0014608.
  4. Vought V et al. (2000), Biochemistry, 39, 15012-15021. Delineation of the Roles of Amino Acids Involved in the Catalytic Functions ofLeuconostoc mesenteroidesGlucose 6-Phosphate Dehydrogenase†. DOI:10.1021/bi0014610.
  5. Rowland P et al. (1994), Structure, 2, 1073-1087. The three–dimensional structure of glucose 6–phosphate dehydrogenase from Leuconostoc mesenteroides refined at 2.0 Å resolution. DOI:10.1016/s0969-2126(94)00110-3. PMID:7881907.

Step 1. His240 abstracts a proton from the substrate, eliminating a hydride that is added to NAD(P).

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Catalytic Residues Roles

Residue Roles
Asp177A modifies pKa
His178A transition state stabiliser
His240A proton acceptor

Chemical Components

hydride transfer, proton transfer, overall product formed, overall reactant used

Step 2. Inferred return step to deprotonate His240, ready for another reaction cycle.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp177A modifies pKa
His240A proton donor

Chemical Components

inferred reaction step, native state of enzyme regenerated, proton transfer
Download: Image, Marvin File

Step 1. His240 abstracts a proton from the substrate, eliminating a hydride that is added to NAD(P).

Step 2. Inferred return step to deprotonate His240, ready for another reaction cycle.

Products.

Contributors

James W. Murray, Craig Porter, Gemma L. Holliday