Studies on the biosynthesis of cholesterol XIX. Steric course of hydrogen eliminations and of C—C bond formations in squalene biosynthesis

Abstract

1. Three molecules of isopentenyl pyrophosphate are used in the biosynthesis of one molecule of farnesyl pyrophosphate. In this process, one hydrogen atom is added and three are eliminated: these three were all originally attached to C-4 of an earlier precursor, mevalonate. It is demonstrated that these eliminations are stereospecific and that all three occur in the same stereochemical sense. The absolute configuration of the eliminated hydrogen is defined. 2. In the association of three isopentenyl pyrophosphate molecules to form farnesyl pyrophosphate, two new C-C bonds are formed with expulsion of two pyrophosphate ions. It is demonstrated that both these processes occur with inversion of configuration at the pyrophosphate-bearing carbon atom. 3. In the biosynthesis of squalene from two molecules of farnesyl pyrophosphate, one farnesyl residue suffers exchange of one hydrogen atom and one new C-C bond is formed. It is demonstrated that this bond is formed with inversion of configuration at that farnesyl residue which does not exchange hydrogen.