Regulation of the Mammalian Pyruvate Dehydrogenase Complex: Physiological Aspects and Characterization of PDH-Phosphatase from Pig Heart

Abstract

Studies on intact rats as well as on perfused rat liver and rat heart indicate that the PDH-complex underlies reversible interconversion by phosphorylation and dephosphorylation, in vivo. With the exception of the brain the proportion of the a and b-forms is low under situations of an increased supply of fatty acid, and vice versa. These changes are in accordance with the expected change of pyruvate utilization under these conditions. However, as indicated from heart perfusion experiments with labeled pyruvate feedback control of PDH most probably by acetyl-CoA has to be considered as an important control mechanism beyond PDH interconversion.

Insulin which stimulates conversion of carbohydrate to fatty acids in liver and adipose tissue also leads to increased PDHa-formation in these tissues. Although other mechanisms cannot definitely be excluded there is evidence that in liver the effect is due to the lowering of free fatty acid levels resulting from the antilipolytic action of the hormone. Whether insulin acts on PDH-interconversion by some other mechanism, especially in adipose tissue, remains to be clarified. Inorganic pyrophosphate, in vitro, is a powerful inhibitor of ATP-dependent inactivation of purified heart muscle PDH exceeding the effectiveness of ADP or pyruvate. The physiological significance of this finding remains to be established.

PDH phosphatase was purified over 8000-fold from pig heart muscle and some of the properties of the enzyme are presented. From studies with chelating agents it is suggested that beyond Mg⁺⁺, another metal, probably Ca⁺⁺ is essential for phosphatase activity.