title: Structure, function and regulation of pyruvate carboxylase.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Jitrapakdee
authors.forename: J C
authors.initials: JC
authors.lastname: Wallace
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008055:Lipids; D011770:Pyruvate Kinase