Pyruvate carboxylase control mechanisms

Most pyruvate carboxylases of animal and of yeast are allosterically activated by acetyl-CoA, but those of bacteria are usually not. The enzyme from chicken liver has almost no activity in the absence of acetyl-CoA, which appears to increase greatly the rate of formation of carboxyphosphate and to slow the side reaction by which carboxyphosphate is hydrolyzed to bicarbonate and phosphate.70 The acetyl-CoA carboxylases of rat or chicken liver aggregate in the presence of citrate to form 8000-kDa rods. Citrate is an allosteric activator for this enzyme but it acts only on a phosphorylated form and the primary control mechanism.7172 This enzyme in plants is a target for a group of herbicides that are selectively toxic to grasses.73... 

The first partial reaction of pyruvate carboxylase, the formation of carboxybiotin, depends on the presence of acetyl CoA. Biotin is not carboxylated unless acetyl CoA is bound to the enzyme. Acetyl CoA has no effect on the second partial reaction. The allosteric activation of pyruvate carboxylase by acetyl CoA is an important physiological control mechanism that will be discussed in Section 17.3.1. 

Utter, M. F., and Fung, C. H., 1971, Possible control mechanisms of liver pyruvate carboxylase, in Regulation of Gluconeogenesis (H. D. Soling and B. Willms, eds.), pp. 1-10, Academic Press, New York. 

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

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