The mevalonate pathway, found in all kingdoms of life, is a biosynthetic pathway that converts the central metabolite acetyl-CoA into the building-block precursors of steroids, including cholesterol, and isoprenoids, the largest and most structurally diverse class of natural products. The committed step of the pathway is catalyzed by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), which reduces HMG-CoA to mevalonate utilizing two equivalents of the cofactor NAD(P)H. The mechanism of this enzyme is not fully understood; specifically, the role of a remarkably flexible C-terminal domain (CTD) and the structural basis of cofactor specificity observed among HMGR homologs remain unclear. Here we present crystal structures of the NADH-preferring HMGR from <i>Delftia acidovorans</i> (DaHMGR) bound to several ligands alongside complementary biochemical data, which reveal a novel location of the CTD and confirm the importance of a conserved helical motif in conferring cofactor specificity. In addition, this work may provide a rationale for altering cofactor specificity that can be used to expand and customize HMGR’s functionality. Collectively, these findings broaden the catalytic paradigm for HMGRs and provide insight into the mechanism of this important metabolic enzyme.

Conformational movements and cofactor specificity of bacterial HMG-CoA Reductase

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.