1. Pyruvate Dehydrogenase Kinase Pyruvate Dehydrogenase Kinase Marshall Law Oct. 23, 2014

2. Biochemical Pathway

3. Pyruvate Dehydrogenase Kinase PDK1: found in heart, pancreatic islets, and skeletal muscles PDK2: found in all tissues; low abundance in spleen and lung cells PDK3: found in testes, kidney, and pancreatic islets PDK4: found in heart, skeletal muscle, kidney, and pancreatic islets.

4. Sequence Alignment Gly284 Gly286Asp282

5. Sequence Alignment(Cont.) Gly319 Asn247

6. Monomeric Structure Dimer; each 12 alpha-helixes and 7 beta strands N-terminal and C-terminal domains are stabilized relative to each other 1)by hydrogen bondings between B1 & B7 2)by non-hydrophobic interaction between side chains from a4/a5/a6 and a11 Large cavity between the two domains for binding to lipoyl domain of PDH complex.

7. Dimeric Structure Catalytic site is situated in the interface of two subunits. Pdb: 1JM6

8. Catalytic Mechanism Examination of  -phosphate binding site has shown no candidate for nucleophilic attack on the ATP. General base catalysis by Glu-234 to activate serine residue from lipoyl domain (L2) of E1 for direct attack on the  -phosphate. His-239 increases the basicity of Glu-234.

9. ATP binding site

10. Lipoyl binding domain

11. Residues interacting with L2 Pdb: 3CRK

12. Disease Relevance Hyperglycaemia due to overexpression of PDK4

13. References Holness, M., Sugden, M. (2003) Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem. Soc. T. 31, 1143- 1151. Kato, M., Li, J., Chuang, J., Chuang, D. (2007) Distinct structucal mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 15, 992-1004. Bowker-Kinley, M., Popov, K. Evidence that pyruvate dehydrogenase kinase belongs to the ATpase/kinase superfamily. Biochem. J. 344, 47-53.