W0235

Conformational Energy in the HMG-CoA Cofactor Promotes Cleavage of the Thioester Bond in HMG-CoA Reductase. Calvin N. Steussy, John W. Burgner II, Jeff Watson, Timothy J. Schmidt, Cynthia V. Stauffacher, Biology, Purdue Univ., State St., West Lafayette, IN 47907 USA.

HMG-CoA reductase (HMGR) catalyzes the reduction of (S)-HMG-CoA to (R)-mevalonate stereospecifically, using NAD(P)H as the reductant in a series of two hydride transfers. Two classes of HMG-CoA reductases have been proposed from sequence comparisons. In this report, we examine a series of Class II HMGR structures with resolutions improved from the previously reported 3.0≈ to 1.7≈. These high resolution structures reveal details of the binding of the HMG-CoA and NAD co-factors, as well as the architecture of the catalytic pocket. A reaction intermediate is identified as the hemiacetal form of HMG-CoA as it cleaves to mevaldehyde and CoA-SH. A reaction mechanism involving steric tension in the co-factor conformation to facilitate cleavage of the thioester bond is proposed.