Pyruvate dehydrogenase kinase family members (PDK1, 2, 3 and 4) are serine kinases that catalyze phosphorylation of the E1α subunit of the pyruvate dehydrogenase complex (PDC). PDC activity is controlled through phosphorylation and dephosphorylation of the E1α subunit, which leads to inactivation and reactivation, respectively. PDK3 binding to a free lipoyl domain (L2) in dihydrolypoyl acetyltransferase (E2), which comprises the core of PDC, leads to a large increase in E1α phosphorylation. Upregulation of PDK isoenzymes occurs during starvation conditions, where acetyl-CoA is alternatively generated through fatty acid oxidation. PDKs contain five conserved regions and are mechanistically similar to bacterial His-kinases, in that both require histidine residues for activity. In mammals, transcripts for PDK3 are most abundant in testis and are moderately expressed in heart and skeletal muscle.