BIOSYNTHESIS OF SQUALENE

Abstract

Chemists at the University of Utah, Salt Lake City, have trapped a cationic intermediate in the biosynthesis of squalene, a key precursor of cholesterol. Their insights into the remarkable enzymatic reaction may offer important leads to the design of drugs that reduce cholesterol levels by blocking squalene biosynthesis. Squalene, a 30-carbon isoprenoid, is formed through a two-stage coupling of two C 15 farnesyl diphosphate molecules. The first step of the enzymatic dimerization leads to presqualene diphosphate, an unusual cyclopropyl compound. The same enzyme—squalene synthase—then catalyzes a reductive rearrangement of presqualene diphosphate to the straight-chain squalene molecule. Researchers have been struggling to understand the mechanisms of both parts of the reaction since presqualene diphosphate was discovered 25 years ago. Utah chemistry professor C. Dale Poulter—working with graduate students Michael B. Jarstfer and Brian S. J. Blagg and postdoctoral researcher Daniel H. Rogers—now has found t...