HGNC Approved Gene Symbol: PDK1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:172,555,373-172,724,312 (from NCBI)
PDK1 belongs to the family of pyruvate dehydrogenase (PDH) kinases (EC 2.7.11.2), which reversibly inactivate the mitochondrial PDH complex by ATP-dependent serine phosphorylation of the alpha subunit of the complex's E1 component (see 300502) (summary by Korotchkina and Patel, 2001).
By screening a human liver cDNA library with rat Pdk1, Gudi et al. (1995) cloned PDK1. The deduced 436-amino acid protein, with a calculated molecular mass of 49.2 kD, has a putative mitochondrial protein kinase catalytic domain with 5 characteristic subdomains. The human and rat proteins share 93% identity. Northern blot analysis detected variable expression of an over 4.5-kb PDK1 transcript in all 8 human tissues examined, with highest expression in heart, followed by skeletal muscle.
Gudi et al. (1995) noted that the products of the PDH reaction stimulate the kinase activity of PDKs, whereas the substrates are inhibitory. ADP also acts synergistically with pyruvate to inhibit PDK kinase activity. Using kinase-depleted PDH complexes isolated from rat heart as substrate, they found that recombinant human PDK1, PDK2 (602525), and PDK3 (300906) inactivated PDH in an ATP-dependent manner. PDK3 showed the highest kinase activity, and PDK2 the lowest. However, the products of the PDH reaction, NADH and acetyl-CoA, increased the ability of PDK2 to inhibit PDH.
Each of the 2 E1 alpha subunits of PDH contains 3 serines that are phosphorylated by PDKs. Using recombinant enzymes expressed in E. coli and double site mutants of human E1, Korotchkina and Patel (2001) found that rat Pdk1, Pdk2, and Pdk4 (602527), and human PDK3, showed unique specificity and activity toward each of these serines. Only Pdk1 had detectable activity with site 3, which the authors called ser203. Each kinase also showed unique activity in the presence or absence of the E2 subunit (DLAT; 608770) in complex with its binding partner E3BP (PDHX; 608769), and unique sensitivity to the redox and/or acetylation state of the lipoyl moieties of E2, and the buffer system employed.
Boulatnikov and Popov (2003) found that rat Pdk1 and Pdk2 could form homodimers when expressed singly, or heterodimers when expressed together, in E. coli. The heterodimeric kinase was catalytically active, with kinetic parameters, site specificity, and regulation clearly distinct from those of homodimeric Pdk1 or Pdk2. The Pdk1-Pdk2 heterodimers catalyzed phosphorylation of all 3 serine sites. Homodimers of Pdk1 or Pdk2 and the Pdk1-Pdk2 heterodimer also readily bound the isolated E2 component of PDH as well as the E2-E3BP subcomplex. Interactions were strengthened by the presence of the lipoate prosthetic groups in E2.
Hartz (2013) mapped the PDK1 gene to chromosome 2q31.1 based on an alignment of the PDK1 sequence (GenBank BC039158) with the genomic sequence (GRCh37).
Boulatnikov, I., Popov, K. M. Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Biochim. Biophys. Acta 1645: 183-192, 2003. [PubMed: 12573248] [Full Text: https://doi.org/10.1016/s1570-9639(02)00542-3]
Gudi, R., Bowker-Kinley, M. M., Kedishvili, N. Y., Zhao, Y., Popov, K. M. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J. Biol. Chem. 270: 28989-28994, 1995. Note: Erratum: J. Biol. Chem. 271: 1250 only, 1996. [PubMed: 7499431] [Full Text: https://doi.org/10.1074/jbc.270.48.28989]
Hartz, P. A. Personal Communication. Baltimore, Md. 8/19/2013.
Korotchkina, L. G., Patel, M. S. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J. Biol. Chem. 276: 37223-37229, 2001. [PubMed: 11486000] [Full Text: https://doi.org/10.1074/jbc.M103069200]