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PYRUVATE CARBOXYLASE

Pyruvate carboxylase is an enzyme of the ligase class that catalyzes the irreversible carboxylation of pyruvate to form oxaloacetate. The enzyme is a mitochondrial protein containing a biotin prosthetic group, requiring magnesium or manganese and acetyl CoA, and occurs in liver but not in muscle.

At present my suspicion is that pyruvate carboxylase may be an important intermediate in the metabolic pathway from deficiencies of biotin, magnesium, and manganese to some of the characteristic symptoms seen in hyperthyroidism.

 

Int J Biochem Cell Biol 1998 Jan;30(1):1-5

Pyruvate carboxylase.

Wallace JC, Jitrapakdee S, Chapman-Smith A

Department of Biochemistry, University of Adelaide, Australia. jwallace@biochem.adelaide.edu.au

Pyruvate carboxylase [EC 6.4.1.1] is a member of the family of biotin-dependent carboxylases and is found widely among eukaryotic tissues and in many prokaryotic species. It catalyses the ATP-dependent carboxylation of pyruvate to form oxaloacetate which may be utilised in the synthesis of glucose, fat, some amino acids or their derivatives and several neurotransmitters. Diabetes and hyperthyroidism increase the level of expression of pyruvate carboxylase in the long term, while its activity in the short term is controlled by the intramitochondrial concentrations of acetyl-CoA and pyruvate. Many details of this enzyme's regulation are yet to be described in molecular terms. However, progress towards this goal and towards understanding the relationship of pyruvate carboxylase structure to its catalytic reaction mechanism, has been enormously enhanced recently by the cloning and sequencing of genes and cDNAs encoding the approximately 130 kDa subunit of this homotetramer. Defects in the expression or biotinylation of pyruvate carboxylase in humans almost invariably results in early death or at best a severely debilitating psychomotor retardation, clearly reflecting the vital role it plays in intermediary metabolism in many tissues including the brain.

 

Biochem J 1999 May 15;340 ( Pt 1):1-16

Structure, function and regulation of pyruvate carboxylase.

Jitrapakdee S, Wallace JC

Department of Biochemistry, University of Adelaide, Adelaide, South Australia 5005, Australia.

Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145-->Ala, Arg451-->Cys, Ala610-->Thr and Met743-->Thr.