Structure, Function and Regulation of the Mammalian Pyruvate Dehydrogenase Complex

Abstract

The mammalian pyruvate dehydrogenase complex is organized about a core of dihydrolipoyl transacetylase, to which are bound pyruvate dehydrogenase, dihydrolipoyl dehydrogenase, and two regulatory enzymes — a kinase and a phosphatase. Association of these enzymes into a complex alters the kinetic and regulatory properties of some, and possibly all, of the enzymes. The pyruvate dehydrogenase component has the subunit composition α₂β₂. The kinase, in a MgATP²⁻-dependent reaction, phosphorylates a seryl residue in one of the α-chains of pyruvate dehydrogenase, and thereby inactivates the tetramer. The phosphatase, which dephosphorylates and activates pyruvate dehydrogenase phosphate, requires Mg²⁺ and Ca²⁺ ions. Ca²⁺ ions increase binding of phosphatase to the transacetylase, thereby lowering the apparent K_m of the phosphatase for pyruvate dehydrogenase phosphate. The kinase is inhibited by pyruvate and by ADP. It appears that its activity may be regulated by the intramitochondrial concentration of pyruvate and by the ATP/ADP ratio. The ATP/ADP ratio may also regulate the activity of the phosphatase by determiningg at least in part, the intramitochondrial concentrations of uncomplexed Mg²⁺ and Ca²⁺ ions. It appears that the kinase and phosphatase maintain steady state levels of activity of the complex and that these levels are modulated through the actions on the kinase and phosphatase of the factors mentioned and possibly by other factors yet to be determined.

Supported in part by Grant GM06590 from the U. S. Public Health Service.