Downloads:   GraphML   SVG   CellDesigner  

Contributors

Alexander Mazein¹

Affiliations

1. ¹Department of Cancer Research, Luxembourg Institute of Health, Strassen, Luxembourg

Reactome-Recon connection

The connection was chosen from the Reactome-Recon lists: proteins of the Recon2 metabolic reconstruction that take part in Reactome signalling processes. The PDH complex is in the lists through the Reactome processes PDK isozymes phosphorylate PDHC subunit E1 (R-HSA-203946) and PDP1,2 dephosphorylate p-lipo-PDH (R-HSA-204169).

Description

The pyruvate dehydrogenase complex (PDH) converts pyruvate, CoA and NAD+ into acetyl-CoA, CO2 and NADH, the irreversible step that decides whether carbon from glucose is oxidised in mitochondria. Pyruvate dehydrogenase kinases (PDK1-4) inactivate PDH by phosphorylating its PDHA1 subunit, and the phosphatases PDP1 and PDP2 reactivate it. The products acetyl-CoA and NADH stimulate PDK, while pyruvate inhibits it; Ca2+ stimulates PDP1, linking PDH activation to muscle contraction. The drug dichloroacetate inhibits PDK and lowers blood lactate in congenital lactic acidosis.

References

1. Baker JC, Yan X, Peng T, Kasten S, Roche TE. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. J Biol Chem. 2000 May 26;275(21):15773-81. doi: 10.1074/jbc.M909488199. PMID: 10748134.
2. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998 Jan 1;329(Pt 1):191-6. doi: 10.1042/bj3290191. PMID: 9405293.
3. Denton RM, Randle PJ, Martin BR. Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem J. 1972 Jun;128(1):161-3. doi: 10.1042/bj1280161. PMID: 4343661.
4. Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM. Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation. J Biol Chem. 1998 Jul 10;273(28):17680-8. doi: 10.1074/jbc.273.28.17680. PMID: 9651365.
5. Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry. 2006 Jan 17;45(2):402-15. doi: 10.1021/bi051402s. PMID: 16401071.
6. Korotchkina LG, Patel MS. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem. 2001 Oct 5;276(40):37223-9. doi: 10.1074/jbc.M103069200. PMID: 11486000.
7. Linn TC, Pettit FH, Reed LJ. Alpha-keto acid dehydrogenase complexes. X. Regulation of the activity of the pyruvate dehydrogenase complex from beef kidney mitochondria by phosphorylation and dephosphorylation. Proc Natl Acad Sci U S A. 1969 Jan;62(1):234-41. doi: 10.1073/pnas.62.1.234. PMID: 4306045.
8. Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014 Jun 13;289(24):16615-23. doi: 10.1074/jbc.R114.563148. PMID: 24798336.
9. Pettit FH, Pelley JW, Reed LJ. Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios. Biochem Biophys Res Commun. 1975 Jul 22;65(2):575-82. doi: 10.1016/s0006-291x(75)80185-9. PMID: 167775.
10. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O’Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW, Valenstein E. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006 May;117(5):1519-31. doi: 10.1542/peds.2005-1226. PMID: 16651305.
11. Whitehouse S, Cooper RH, Randle PJ. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J. 1974 Sep;141(3):761-74. doi: 10.1042/bj1410761. PMID: 4478069.