An atomic-resolution mechanism of 3-hydroxy-3-methylglutaryl–CoA synthase

Abstract

The quest to obtain details about enzyme mechanisms is a common goal among a wide range of scientific disciplines. Those goals range from characterizing a variety of chemistries catalyzed, to more applied goals, such as the development of potent inhibitors used to treat disease. In the study of enzymes, a continuum of scrutiny prevails in which the level of atomic detail aids understanding. Often the combination of a high-resolution structure of the enzyme along with detailed chemical and kinetic characterization leads to a working mechanism, or further strengthens an existing one. As the first committed step in cholesterol biosynthesis, the reaction catalyzed by 3-hydroxy-3-methylglutaryl–CoA (HMG-CoA) synthase is a recent success story. The structure of an abortive inhibited complex (1) gives a structural perspective to a wealth of mechanistic data (2–5) and offers a starting point for inhibitor design critical to cholesterol-lowering approaches (6). However, this level of understanding doesn't explain the intricacies of how the protein uses each and every interaction, as well as protein dynamics, in its catalytic role. In several cases, experiments that provide reliable structural models of the enzyme during its mechanism have started to provide the necessary data points to present a more complete and interesting picture, and ultimately may lead an atomic-resolution “movie” of what is going on. The work of Theisen et al. (7) in this issue of PNAS provides two revealing frames of the mechanistic movie catalyzed by HMG-CoA synthase. In the physiological direction, the mechanism of HMG-CoA synthase begins with acetyl-CoA binding, followed by the straightforward acetylation of …