Structural insight into key mevalonate pathway enzymes

Abstract

The mevalonate pathway produces the universal biosynthetic precursors of steroids and isoprenoids, the largest and most structurally diverse class of natural products. Two key enzymes control metabolic flux through the pathway: HMG‐CoA reductase (HMGR), which catalyzes the committed and rate‐determining step, and mevalonate kinase (MK), a target of feedback regulation in many organisms. Although HMGR inhibition by cholesterol‐lowering statin drugs is well studied, critical mechanistic and structural features are still unknown. With MK, large variations in the structures of MK homologs remain uncharacterized, even as greater structural insight may shed light on varying strategies of MK feedback inhibition. Using biochemical and X‐ray crystallographic methods, we have revealed large conformational movements in HMGR that control substrate and cofactor binding and release during the reaction, in addition to uncovering the structural basis for NAD(P)H cofactor specificity. We have also solved crystal structures of new MK homologs, suggesting novel structural strategies for MK inhibition. Overall, this work significantly advances our structural and mechanistic understanding of the two key enzymes of an important metabolic pathway.