Sequence comparisons reveal two classes of 3-hydroxy-3-methylglutaryl coenzyme A reductase

Both in eukaryotes and in archaebacteria the enzyme 3-hydroxy-3-methylgluta ryl coenzyme A (HMG-CoA) reductase (E.C. 1.1.1.34) is known to catalyze an early reaction unique to isoprenoid biosynthesis. In humans, the HMG-CoA re ductase reaction is rate-limiting for the biosynthesis of cholesterol and t herefore constitutes a prime target of drugs that reduce serum cholesterol levels. Recent advances in genome sequencing that permitted comparison of 5 0 HMG-CoA reductase sequences has revealed two previously unsuspected class es of this enzyme. Based on sequence and phylogenetic considerations, we pr opose the catalytic domain of the human enzyme and the enzyme from Pseudomo nas mevalonii as the canonical sequences for Class I and Class II HMG-CoA r eductases, respectively, These sequence comparisons have revealed, in addit ion, that certain true bacteria, including several human pathogens, probabl y synthesize isoprenoids by reactions analogous to those of eukaryotes and that there therefore exist two distinct pathways for isoprenoid biogenesis in true bacteria. (C) 1999 Academic Press.