Synthetic chemistry and chemical precedents for understanding the structure and function of acetyl coenzyme A synthase

Acetyl coenzyme A synthase (ACS), found in acetogenic and methanogenic organisms, is responsible for the synthesis and breakdown of acetate. The mechanism by which methylcob(III)alamin, CO and coenzyme A are assembled/disassembled at the active-site A-cluster involves a number of biologically unprecedented intermediates. In the past two years, two protein crystal structures have significantly enhanced the understanding of the structure of the active-site A-cluster, responsible for catalysis. The structure reports spawned a number of important questions regarding the metal ion constitution of the active enzyme, the structure(s) of the spectroscopically identified states and the details of the catalytic mechanism. This Commentary addresses these issues in the framework of existing synthetic and chemical precedent studies aimed at developing rational structure–function correlations and presents structural and reactivity targets for future studies.