Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enz
yme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloa
cetate. 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 ins
ulin secretion by pancreatic islets. The reaction catalysed by PC and the p
hysical properties of the enzyme have been studied extensively. Although no
high-resolution three dimensional structure has yet been determined by X-r
ay crystallography, structural studies of PC have been conducted by electro
n microscopy, by limited proteolysis, and by cloning and sequencing of gene
s 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 domai
n. Different physiological conditions, including diabetes, hyperthyroidism,
genetic obesity and postnatal development, increase the level of PC expres
sion 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, nam
ely Val(345) --> Ala, Arg(451) --> CYs, Ala(610) --> Thr and Met(743) --> T
hr.