Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases.

The biosynthesis of isopentenyl diphosphate (isopentenyl pyrophosphate), the precursor of isoprenoids in all forms of life, occurs by two distinct metabolic pathways, the mevalonate pathway (Fig. 1) and the glyceraldehyde 3-phosphate/pyruvate pathway, often termed the nonmevalonate pathway (17). Whereas many gram-negative bacteria employ the nonmevalonate pathway (26), humans, other eukaryotes, archaea, grampositive cocci, and the spirochete Borrelia burgdorferi utilize the enzymes and intermediates of the mevalonate pathway (15, 16, 20, 21, 26). This review addresses 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the catalyst for the ratelimiting reaction of the mevalonate pathway for isopentenyl diphosphate biosynthesis. HMG-CoA reductase catalyzes the reductive deacylation of (S)-HMG-CoA to (R)-mevalonate: The reaction proceeds in three stages, the first and third of which are reductive, and it involves successive formation of enzyme-bound mevaldyl-CoA and mevaldehyde. While mevaldehyde is not released during the course of the reaction,