The Architecture and Specificity of Acyl-CoA Carboxylase Beta Subunit.

DIACOVICH L., KHOSLA C., GRAMAJO H., TSAI S.C.

Kimball Union Academy, Meriden, NH, USA.

Conferencia; Enzymes, Coenzymes & Metabolic Pathways, Gordon Research Conferences.; 2003

Gordon Research Conferences.

Acyl-coenzyme A carboxylases (ACC), such as acetyl-CoA carboxylase (AcCC) or propionyl-CoA carboxylase (PCC), catalyze the carboxylation of acetyl- and propionyl-CoA to provide malonyl- and methylmalonyl-CoA. This carboxylation reaction is one of the most important metabolic regulation checkpoints by committing acyl-CoA to the biosynthesis of fatty acids and polyketides. ACC and PCC are therefore targeted for therapeutics against obesity and diabetes, as well as herbicides and antibiotics. ACC and PCC in Streptomyces ceolicolor are 1 MDa multienzyme complexes containing at least 18 polypeptide chains. The core catalytic beta subunits, PccB and AccB, are 360 kDa homo-hexamers, catalyzing the transcarboxylation between biotin and acyl-CoA. Apo and substrate-bound crystal structures of PccB hexamer were solved to 2.0 – 2.4 A. Overall, the hexamer assembly of the core 360 kD beta subunit forms a large ring-shaped complex as two stacks of trimers related by two-fold symmetry. In the active site, oxyanion hole and hydrogen-bonding network were identified. The structural studies shed light on the molecular basis of substrate recognition and the nature of the assembly. The hexameric structure also helps visualize different oligomeric architectures of ACC and PCC from different organisms, as well as the identification of future drug design targets.