Pyruvate dehydrogenase complex regulation

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. 

See also Pyruvate Oxidation, Pyruvate Dehydrogenase Complex Regulation... 

This chapter focuses on the developmental regulation of the pyruvate dehydrogenase complex (PDC). The PDC plays diverse and pivotal roles in the entry of glycolytically generated carbon into the TCA cycle in aerobic stages and the metabolism of mitochondrially generated pyruvate in anaerobic stages (Fig. 14.1). 

Fig. 14.2. Regulation of the pyruvate dehydrogenase complex (PDC) from adult A suum muscle. PDC, pyruvate dehydrogenase complex E1, pyruvate dehydrogenase subunit of the PDC PDK, pyruvate dehydrogenase kinase PDP, pyruvate dehydrogenase phosphatase.

Bowker-Kinley, M.M., Davis, W.I., Wu, P., Harris, R.A. and Popov, KM. (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Bio chemicalfournal 329, 191-196. 

The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose 543... 

Patel, M.S., Nalk, S., Wexler, I.D., Kerr, D.S. (1995) Gene regulation and genetic defects in the pyruvate dehydrogenase complex. J. Nutr. 125, 1753S-1757S. 

Production of Acetyl-CoA by the Pyruvate Dehydrogenase Complex Is Regulated by Allosteric and Covalent Mechanisms... 

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). 

The pyruvate dehydrogenase complex may have been regulated by phosphorylation of any one of the three different enzymes in the complex, yet regulation occurs on the first enzyme of the complex. How is regulation of the complex consistent with the regulation observed in metabolic pathways whose enzymes are not physically associated ... 

Holness MJ, Sugden MC Regulation of pyruvate dehydrogenase complex activity by reversible... 

Czerniecki J and Czygier M (2001) Cooperation of divalent ions and thiamin diphosphate in regulation of the function of pig heart pyruvate dehydrogenase complex. Joumai of Nutritionai Scence and Vitaminoiogy (Tokyo) 47,385-6. 

The Pyruvate Dehydrogenase Complex Is Regulated Allosterically and by Reversible Phosphorylation... 

Figure 17.17. Regulation of the Pyruvate Dehydrogenase Complex. The complex is inhibited by its immediate products, NADH and acetyl CoA. The pyruvate dehydrogenase component is also regulated by covalent modification. A specific kinase phosphorylates and inactivates pyruvate dehydrogenase, and a phosphatase actives the dehydrogenase by removing the phosphoryl. The kinase and the phosphatase also are highly regulated enzymes.

A fourth fate of pyruvate is its oxidative decarboxylation to acetyl CoA. This irreversible reaction inside mitochondria is a decisive reaction in metabolism it commits the carbon atoms of carbohydrates and amino acids to oxidation by the citric acid cycle or to the synthesis of lipids. The pyruvate dehydrogenase complex, which catalyzes this irreversible funneling, is stringently regulated by multiple allosteric interactions and covalent modifications. Pyruvate is rapidly converted into acetyl CoA only if ATP is needed or if two-carbon fragments are required for the synthesis of lipids. 

Regulation of metabolic processes can be accomplished by other methods. One is the use of a multienzyme complex (e.g., pyruvate dehydrogenase complex or fatty acid synthase complex) in which various enzymes are organized such that the product of one becomes the substrate for an adjacent enzyme. A single polypeptide chain may contain multiple catalytic centers that carry out a sequence of transformations (e.g., the mammalian fatty acid synthase see Chapter 18). Such multifunctional polypeptides increase catalytic efficiency by abolishing the accumulation of free intermediates and by maintaining a stoichiometry of 1 1 between catalytic centers. 

The pyruvate dehydrogenase complex catalyzes an irreversible reaction that is the entry point of pyruvate into the TCA cycle (see below) and is under complex regulation by allosteric and covalent modification of the pyruvate dehydrogenase component of the complex. The end products of the overall reaction (NADH and acetyl-CoA) are potent allosteric inhibitors of the pyruvate dehydrogenase... 

TCA cycle substrates oxaloacetate and acetyl-CoA and the product NADH are the critical regulators. The availability of acetyl-CoA is regulated by pyruvate dehydrogenase complex. The TCA cycle enzymes citrate synthase. 

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