Phosphoglycerate mutase (2,3-diphosphoglycerate-dependent)

 

Phosphoglycerate mutase (EC:5.4.2.11) from vertebrates, platyhelminths, mollusks, annelids, crustaceans, insects, algae, fungi, yeast and some bacteria (particularly Gram-negative) interconverts 2-phosphoglycerate and 3-phosphoglycerate via a transiently phosphorylated active site histidine. This histidine is phosphorylated by a 2,3-diphosphoglyerate cofactor. The enzyme has no requirement for metal ions and also catalyses, slowly, the reactions of EC 5.4.2.4, bisphosphoglycerate mutase.

 

Reference Protein and Structure

Sequence
P00950 UniProt (5.4.2.11) IPR005952 (Sequence Homologues) (PDB Homologues)
Biological species
Saccharomyces cerevisiae S288c (Baker's yeast) Uniprot
PDB
1qhf - YEAST PHOSPHOGLYCERATE MUTASE-3PG COMPLEX STRUCTURE TO 1.7 A (1.7 Å) PDBe PDBsum 1qhf
Catalytic CATH Domains
3.40.50.1240 CATHdb (see all for 1qhf)
Cofactors
(2r)-2,3-diphosphoglyceric acid (1), Water (1)
Click To Show Structure

Enzyme Reaction (EC:5.4.2.11)

2-phosphonato-D-glycerate(3-)
CHEBI:58289ChEBI
→
3-phosphonato-D-glycerate(3-)
CHEBI:58272ChEBI
Alternative enzyme names: GriP mutase, MPGM, PGA mutase, PGAM, PGAM-d, PGM, Glycerate phosphomutase (diphosphoglycerate cofactor), Monophosphoglycerate mutase, Monophosphoglyceromutase, Phosphoglycerate phosphomutase, Phosphoglyceromutase, 2,3-diphosphoglycerate dependent phosphoglycerate mutase, Cofactor dependent phosphoglycerate mutase, DPGM,

Enzyme Mechanism

Introduction

The substrate/cofactor initially binds with its phospho group favorably hydrogen bonded by His8, Arg59. The phosphohistidine intermediate would result from the nucleophilic attack of His8 on the phospho group, with accompanying transfer of a proton from Glu86 to the dephosphorylated product. This proton transfer is likely water-mediated. Formation of the catalytically active, protonated form of Glu86 would be promoted by the proximity of the substrate's phospho group. The phosphohistidine intermediate would be stabilised through hydrogen bonding interactions with Arg59. Dephosphorylation of this intermediate would be ccomplished through a water-mediated nucleophilic attack of the now deprotonated Glu86

Catalytic Residues Roles

UniProt PDB* (1qhf)
His9 His8A Forms a tele-phosphohistidine intermediate. covalent catalysis
Glu87 Glu86A Acts as a general acid/base. proton shuttle (general acid/base), proton donor
Arg60, His182 Arg59A, His181A Acts to stabilise the reactive intermediates and transition states. 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

  1. Bond CS et al. (2002), J Mol Biol, 316, 1071-1081. Mechanistic implications for Escherichia coli cofactor-dependent phosphoglycerate mutase based on the high-resolution crystal structure of a vanadate complex. DOI:10.1006/jmbi.2002.5418. PMID:11884145.
  2. Wang Y et al. (2006), J Biol Chem, 281, 39642-39648. Seeing the Process of Histidine Phosphorylation in Human Bisphosphoglycerate Mutase. DOI:10.1074/jbc.m606421200. PMID:17052986.
  3. Wang Y et al. (2005), Biochem Biophys Res Commun, 331, 1207-1215. Crystal structure of human B-type phosphoglycerate mutase bound with citrate. DOI:10.1016/j.bbrc.2005.03.243. PMID:15883004.
  4. Wang Y et al. (2004), J Biol Chem, 279, 39132-39138. Crystal Structure of Human Bisphosphoglycerate Mutase. DOI:10.1074/jbc.m405982200. PMID:15258155.
  5. Rigden DJ et al. (2002), J Mol Biol, 315, 1129-1143. Structure and mechanism of action of a cofactor-dependent phosphoglycerate mutase homolog from Bacillus stearothermophilus with broad specificity phosphatase activity. DOI:10.1006/jmbi.2001.5290. PMID:11827481.
  6. Rigden DJ et al. (1999), J Mol Biol, 286, 1507-1517. Sulphate ions observed in the 2.12 Å structure of a new crystal form of S. cerevisiae phosphoglycerate mutase provide insights into understanding the catalytic mechanism. DOI:10.1006/jmbi.1999.2566. PMID:10064712.
  7. White MF et al. (1992), Eur J Biochem, 207, 709-714. Development of a mutagenesis, expression and purification system for yeast phosphoglycerate mutase. Investigation of the role of active-site His181. PMID:1386023.

Step 1. His8 initiates a nucleophilic attack on the 2,3-BPG cofactor, which eliminates 2-phosphoglycerate, which is protonated via a proton relay through a water molecule and Glu86.

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Catalytic Residues Roles

Residue Roles
Glu86A proton shuttle (general acid/base)
His8A covalent catalysis
Arg59A electrostatic stabiliser
His181A electrostatic stabiliser
Glu86A proton donor

Chemical Components

Step 1. His8 initiates a nucleophilic attack on the 2,3-BPG cofactor, which eliminates 2-phosphoglycerate, which is protonated via a proton relay through a water molecule and Glu86.

Contributors

Alex Gutteridge, Craig Porter, Gemma L. Holliday