[pyruvate dehydrogenase (acetyl-transferring)] kinase

 

Mitochondrial Pyruvate Dehydrogenase kinase (PDK) regulates the activity of Pyruvate dehydrogenase complex (PDC) by phosphorylating a serine residue at the E1 subunit and thus inactivating it. Mitochondrial PDK is in a family of serine protein kinases that lacks sequence similarity with all other eukaryotic protein kinase but show similarity with key motifs of prokaryotic histidine protein kinases and a family of eukaryotic ATPases. In mammals, 4 isozymes of PDK have been found, PDK1, PDK2, PDK3, PDK4. PDK2 is found in many tissues but is low in amount in lung and spleen. It only phosphorylates site 2 and 3 serine residue of the E1 subunit.

 

Reference Protein and Structure

Sequence
Q64536 UniProt (2.7.11.2) IPR003594 (Sequence Homologues) (PDB Homologues)
Biological species
Rattus norvegicus (Norway rat) Uniprot
PDB
1jm6 - Pyruvate dehydrogenase kinase, isozyme 2, containing ADP (2.5 Å) PDBe PDBsum 1jm6
Catalytic CATH Domains
3.30.565.10 CATHdb (see all for 1jm6)
Cofactors
Magnesium(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:2.7.11.2)

L-serine residue
CHEBI:29999ChEBI
+
ATP(4-)
CHEBI:30616ChEBI
→
ADP(2-)
CHEBI:87518ChEBI
+
O-phospho-L-serine(2-) residue
CHEBI:83421ChEBI
Alternative enzyme names: Pyruvate dehydrogenase kinase, Pyruvate dehydrogenase kinase (phosphorylating), PDH kinase, PDHK, PDK, PDK1, PDK2, PDK3, PDK4, Pyruvate dehydrogenase kinase activator protein, STK1,

Enzyme Mechanism

Introduction

One proposed mechanism is a general base mechanism. Glu251 deprotonates the targeted serine residue of the pyruvate dehydrogenase E1 subunit and promotes its nucleophilic attack on the terminal phosphate of ATP. His247 polarises Glu243 to allow deprotonation. Magnesium ion coordinated to Asp helps in positioning of the ATP and promotes the nucleophilic attack. There is also evidence to suggest Glu251 alongside Asn255 and Lys254 in fact coordinates to a magnesium ion while His247 is the base catalyst. Therefore, it is still unclear of the exact mechanism pyruvate dehydrogenase kinase has.

Catalytic Residues Roles

UniProt PDB* (1jm6)
Lys254, Asn255 Lys1246(254)A, Asn1247(255)A Proposed to coordinate to a magnesium ion. metal ligand
Glu251 Glu1243(251)A A general base to deprotonate the hydroxyl group of the target E1-alpha Serine residue and promotes the nucleophilic attack of the terminal phosphate of ATP or is proposed to coordinate to a magnesium ion. proton shuttle (general acid/base), metal ligand
His247 His1239(247)A It is proposed to either polarise Glu251 for deprotonation or act as a general base catalyst. 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. Steussy CN et al. (2001), J Biol Chem, 276, 37443-37450. Structure of Pyruvate Dehydrogenase Kinase: NOVEL FOLDING PATTERN FOR A SERINE PROTEIN KINASE. DOI:10.1074/jbc.m104285200. PMID:11483605.
  2. Tovar-Méndez A et al. (2005), Arch Biochem Biophys, 434, 159-168. Analysis of the catalytic mechanism of pyruvate dehydrogenase kinase. DOI:10.1016/j.abb.2004.10.017. PMID:15629119.
  3. Tuganova A et al. (2001), J Biol Chem, 276, 17994-17999. An Essential Role of Glu-243 and His-239 in the Phosphotransfer Reaction Catalyzed by Pyruvate Dehydrogenase Kinase. DOI:10.1074/jbc.m009327200. PMID:11278487.

Step 1.

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Catalytic Residues Roles

Residue Roles
His1239(247)A electrostatic stabiliser
Glu1243(251)A proton shuttle (general acid/base)
Asn1247(255)A metal ligand
Lys1246(254)A metal ligand
Glu1243(251)A metal ligand

Chemical Components

Step 1.

Contributors

Mei Leung, Gemma L. Holliday, Morwenna Hall