Pyruvate Carboxylase - Structure

Structure

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 a single biotin moiety acting as a swinging arm to transport carbon dioxide to the catalytic site that is formed at the interface between adjacent monomers. Each subunit of the functional tetramer contains four domains: the biotin carboxylation (BC) domain, the transcarboxylation (CT) domain, the biotin carboxyl carrier (BCCP) domain and the recently termed PC tetramerization (PT) domain. From the two most complete crystal structures available, an asymmetric and symmetric form of the protein have been visualized. The Staphylococcus aureus tetramer in complex with the activator Coenzyme A is highly symmetric, possessing 222 symmetry, and has been confirmed by Cryo-EM studies. In contrast the Rhizobium etli, tetramer in complex with ethyl-CoA, a non-hydrolyzable analog of Acetyl-CoA, possesses only one line of symmetry.

Staphylococcus aureus

Pyruvate carboxylase uses a covalently attached Biotin cofactor which is used to catalyze the ATP– dependent carboxylation of pyruvate to oxaloacetate in two steps. Biotin is initially carboxylated at the BC active site by ATP and bicarbonate. The carboxyl group is subsequently transferred by carboxybiotin to a second active site in the CT domain, where pyruvate is carboxylated to generate oxaloacetate. The BCCP domain transfers the tethered cofactor between the two remote active sites. The allosteric binding site in PC offers a target for modifiers of activity that may be useful in the treatment of obesity or type II diabetes, and the mechanistic insights gained from the complete structural description of RePC (R. etli) permit detailed investigations into the individual catalytic and regulatory sites of the enzyme.

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