Pyruvate regulation

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Pyruvate Dehydrogenase Is Regulated by End-Product Inhibition Covalent Modification... 

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.

Glycolysis is regulated by three enzymes catalyzing nonequilibrium reactions hexokinase, phosphoffuc-tokinase, and pyruvate kinase. 

Behai RH et al Regulation of the pyruvate dehydrogenase multienzyme complex. Annu Rev Nutr 1993 13 497. 

M15. Mattevi, A., Bolognesi, M and Valentini, G., The allosteric regulation of pyruvate kinase. FEBS Lett. 389, 15-19(1996). 

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.

Similarly, the regulation of PDK activity is modified in adult muscle PDC. For example, PDK activity is inhibited by pyruvate and propionate (metabolites elevated during anaerobic metabolism) and is less sensitive to stimulation by elevated NADH/NAD+ and acetyl CoA/CoA ratios (Fig. 14.2) (Thissen et al, 1986 Chen et al, 1998). The effects of NADH and acetyl CoA on PDK activity are mediated by the degree of E3-catalysed oxidation and E2-catalysed acetylation of the inner lipoyl domain of E2 (Roche and Cate, 1977 Rahmatullah and Roche, 1985, 1987 Ravindran et al, 1996 Yang et al, 1998), so that the regulation of this phenomenon is complex and involves multiple interacting components. 

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