Regulation of the activity of the pyruvate dehydrogenase complex

Robert A. Harris, Melissa M. Bowker-Kinley, Boli Huang, Pengfei Wu

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

The pyruvate dehydrogenase complex is a major source of acetyl-CoA for citric acid cycle activity. In this capacity the pyruvate dehydrogenase complex plays a key role in energy production in every cell of the body that have mitochondria. Although a critically important reaction for this purpose, the rate of pyruvate decarboxylation has to be carefully controlled to match the overall energy need of the body to avoid over consumption of glucose as well as three carbon compounds that can be converted back to glucose. This is particularly true when the body should be living primarily off its stored fat and thereby conserving glucose for use by the brain. Mechanisms have therefore evolved to inactivate the pyruvate dehydrogenase complex when glucose becomes scarce. These include allosteric effector control (direct inhibition of the complex and activation of the kinases by acetyl-CoA and NADH), covalent modification (inactivation by phosphorylation of its Elα subunits), and altered expression of the regulatory proteins (kinases and phosphatases) responsible for covalent modification of the complex. Our focus has been on the latter where we find increased expression of PDK2 and PDK4 along with decreased expression of PDP2 result in hyperphosphorylation and therefore inactivation of the pyruvate dehydrogenase complex. Factors involved in regulation of PDK4 expression include glucocorticoids and free fatty acids, which have positive effects, and insulin, which has a negative effect. PDK2 expression is also down regulated by insulin. Factors that regulate PDP2 expression remain to be identified.

Original languageEnglish (US)
Pages (from-to)249-259
Number of pages11
JournalAdvances in Enzyme Regulation
Volume42
DOIs
StatePublished - Sep 27 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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