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

Abstract

Both in eukaryotes and in archaebacteria the enzyme 3-hydroxy-3-methylglutaryl 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 reductase reaction is rate-limiting for the biosynthesis of cholesterol and therefore constitutes a prime target of drugs that reduce serum cholesterol levels. Recent advances in genome sequencing that permitted comparison of 50 HMG-CoA reductase sequences has revealed two previously unsuspected classes of this enzyme. Based on sequence and phylogenetic considerations, we propose the catalytic domain of the human enzyme and the enzyme from Pseudomonas mevalonii as the canonical sequences for Class I and Class II HMG-CoA reductases, respectively. These sequence comparisons have revealed, in addition, that certain true bacteria, including several human pathogens, probably synthesize isoprenoids by reactions analogous to those of eukaryotes and that there therefore exist two distinct pathways for isoprenoid biogenesis in true bacteria.