Pyruvate dehydrogenase activity regulation

Hoshi, M. Takashima, A. Noguchi, K. Murayama, M. Sato, M. Kondo, S. Saitoh, Y. Ishiguro, K. Hoshino, T. Imahori, K. Regulation of mitochondrial pyruvate dehydrogenase activity by r protein kinase I/glycogen synthase kinase 3/1 in brain. Proc. Natl. Acad. Sci. USA, 93, 2719-2723 (1996)... 

Regulation of Pyruvate Dehydrogenase Activity Pyruvate dehydrogenase is the key enzyme that commits pyruvate (and hence the products of carbohydrate metabolism) to complete oxidation (via the tricarboxyUc acid cycle) or lipogenesis. It is subject to regulation by both product inhibition and a phosphorylation/dephosphorylation mechanism. Acetyl CoA and NADH are both inhibitors, competing with coenzyme A and NAD+. 

Kolobova E,Tuganova A, BoulatnikovI, and Popov KM (2001) Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Biochemical Journal 358, 69-77. 

The activity of pyruvate dehydrogenase is regulated by two mechanisms product inhibition and covalent modification (Section 6.5). The enzyme complex is allosterically activated by NAD+, CoASH, and AMP. It is inhibited by high concentrations of ATP and the reaction products acetyl-CoA and NADH. In vertebrates these molecules also activate a kinase, which converts the active pyruvate dehydrogenase complex to an inactive phosphorylated form. High concentrations of the substrates pyruvate, CoASH, and NAD+ inhibit the activity of the kinase. The pyruvate dehydrogenase complex is reactivated by a dephosphorylation reaction catalyzed by a phosphoprotein phosphatase. The phosphoprotein phosphatase is activated when the mitochondrial ATP concentration is low. 

L. G. Korotchkina M. S. Patel, Pyruvate Dehydrogenase Complex Regulation and Lipoic Acid. In Lipoic Acid Energy Production, Antioxidant Activity and Health Effects L. Packer, M. S. Patel, Eds. CRC Press Boca Raton, 2008. 

Zhou Q, Lam PY, Han D, Cadenas E (2007) c-Jun N-temiinal kinase regulates mitochondrial bioenergetics by modulating pyruvate dehydrogenase activity in primary cortical neurons. J Neurochem 104(2) 325-335... 

Rutter GA, Burnett P, Rizzuto R et al (1996) SubceUular imaging of intramitochondrial Ca with recombinant targeted aequorin significance for the regulation of pyruvate dehydrogenase activity. Proceedings of the National Academy of Science, USA 93 5489-5494. 

Severson. D. L., Denton, R. M., Bridges, B. J., and Randle, P. J., 1976, Exchangeable and total calcium pools in mitochondria of rat epidid3nnal fat pads and isolated fat cells. Role in the regulation of pyruvate dehydrogenase activity. Biochem. ]. 154 209. 

Figure 17-6. Regulation of pyruvate dehydrogenase (PDH). Arrows with wavy shafts indicate allosteric effects. A Regulation by end-product inhibition. B Regulation by interconversion of active and inactive forms.

Control of pymvate dehydrogenase activity is via covalent modification a specific kinase causes inactivation of the PDH by phosphorylation of three serine residues located in the pyruvate decarboxylase/dehydrogenase component whilst a phosphatase activates PDH by removing the phosphates. The kinase and phosphatase enzymes are non-covalently associated with the transacetylase unit of the complex. Here again we have an example of simultaneous but opposite control of enzyme activity, that is, reciprocal regulation. 

Covalent interconversion of enzymes is well established as a fundamental theme in metabolic regulation. The prototypic reversible interconverting systems include the sequence of phosphorylation/dephosphorylation steps in the activation of mammalian glycogen phosphorylase and pyruvate dehydrogenase as well as the nucleotidyla-tion/denucleotidylation using UTP and ATP in the bacterial glutamine synthetase cascade (see Fig. 1.). 

Regulation of the activity of the pyruvate dehydrogenase complex. Adv. Enzyme Regul. 42, 249-259. 

Regulation of the Pyruvate Dehydrogenase Complex In animal tissues, the rate of conversion of pyruvate to acetyl-CoA is regulated by the ratio of active, phosphory-lated to inactive, unphosphorylated PDH complex. Determine what happens to the rate of this reaction when a preparation of rabbit muscle mitochondria containing the PDH complex is treated with (a) pyruvate dehydrogenase kinase, ATP, and NADH (b) pyruvate dehydrogenase phosphatase and Ca2+ (c) malonate. 

Experiments with rats have shown that the branched-chain a-keto acid dehydrogenase complex is regulated by covalent modification in response to the content of branched-chain amino acids in the diet. With little or no excess dietary intake of branched-chain amino acids, the enzyme complex is phosphorylated and thereby inactivated by a protein kinase. Addition of excess branched-chain amino acids to the diet results in dephosphoiylation and consequent activation of the enzyme. Recall that the pyruvate dehydrogenase complex is subject to similar regulation by phosphorylation and dephosphorylation (p. 621). 

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