Homoserine kinase

 

Homoserine kinase (HSK) belongs to a large superfamily of GHMP kinases. It catalyses the phosphorylation of L-homoserine to O-phospho-L-homoserine, the first reaction after the branching-point to methionine in the bacterial threonine biosynthetic pathway. Mevalonate kinase, Galactokinase and Phosphomevalonate kinase are also members of the GHMP kinase superfamily but have a different mechanism proposed involving an aspartate acting as an initiating general base. HSK lacks this catalytic aspartate so is proposed to proceed with direct phosphorylation.

 

Reference Protein and Structure

Sequence
Q58504 UniProt (2.7.1.39) IPR000870 (Sequence Homologues) (PDB Homologues)
Biological species
Methanocaldococcus jannaschii DSM 2661 (Archaea) Uniprot
PDB
1fwk - CRYSTAL STRUCTURE OF HOMOSERINE KINASE COMPLEXED WITH ADP (2.1 Å) PDBe PDBsum 1fwk
Catalytic CATH Domains
3.30.70.890 CATHdb 3.30.230.10 CATHdb (see all for 1fwk)
Cofactors
Magnesium(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:2.7.1.39)

ATP(4-)
CHEBI:30616ChEBI
+
L-homoserine zwitterion
CHEBI:57476ChEBI
→
O-phosphonato-L-homoserine(2-)
CHEBI:57590ChEBI
+
ADP(3-)
CHEBI:456216ChEBI
+
hydron
CHEBI:15378ChEBI
Alternative enzyme names: HSK, Homoserine kinase (phosphorylating),

Enzyme Mechanism

Introduction

A transition state stabilisation mechanism which does not involved a catalytic base is the currently accepted proposal for HSK. Substrate binding induces conformational changes at the active site to promote the catalysis and transition state stabilisation. Mg2+ ion coordinates with the beta and gamma-phosphate of ATP and also Glu126. It activates the gamma-phosphate to deprotonate the delta-OH group of Hse and hence mediating the direct attack of the delta-OH group on the gamma-phosphate of ATP. The transition state is stabilised by Mg2+ ion and Thr179, which interacts with the beta-phosphate.

Catalytic Residues Roles

UniProt PDB* (1fwk)
Thr179 Thr183(179)C Threonine coordinates with the beta-phosphate of ATP to stabilise the transition state. electrostatic stabiliser, polar interaction
Glu126 Glu130(126)C Glutamate coordinates to the Mg2+ ion that in turn binds to the beta and gamma phosphate groups on ATP. metal ligand
*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

overall product formed, proton transfer, bimolecular nucleophilic substitution, overall reactant used

References

  1. Krishna SS et al. (2001), Biochemistry, 40, 10810-10818. Structural Basis for the Catalysis and Substrate Specificity of Homoserine Kinase†. DOI:10.1021/bi010851z. PMID:11535056.
  2. Huang M et al. (2013), Biochemistry, 52, 4858-4868. Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies. DOI:10.1021/bi400228e. PMID:23786354.
  3. Zhou T et al. (2000), Structure, 8, 1247-1257. Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily. PMID:11188689.

Step 1. Direct nucleophilic attack by homoserine's hydroxyl group on the gamma phosphate on ATP. Proton transfer from hydroxyl to gamma phosphate O atom.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu130(126)C metal ligand
Thr183(179)C electrostatic stabiliser, polar interaction

Chemical Components

overall product formed, proton transfer, ingold: bimolecular nucleophilic substitution, overall reactant used
Download: Image, Marvin File

Step 1. Direct nucleophilic attack by homoserine's hydroxyl group on the gamma phosphate on ATP. Proton transfer from hydroxyl to gamma phosphate O atom.

Products.

Contributors

Mei Leung, Gemma L. Holliday, Morwenna Hall