Studies on the biosynthesis of cholesterol XVIII. The stereospecificity of mevaldate reductase and the biosynthesis of asymmetrically labelled farnesyl pyrophosphate

Abstract

It is demonstrated that mevaldate reductase transfers hydrogen stereospecifically from the 'A'-side of NADH or NADPH to substrate. When 4R-[$^{3}$H$_{1}$]NADH, or NADPH, is used for the reduction of mevaldate the resulting [5-$^{3}$H$_{1}$]mevalonate is stereospecifically labelled at C-5 with an absolute configuration of R. Mevaldate reductase shows no stereospecificity for the asymmetric carbon atom, C-3, in mevaldate: the product of the reduction of 3RS-mevaldate is 3RS-mevalonate. 5R-[5-$^{3}$H$_{1}$]- and 5R-[5-D$_{1}$]mevalonate have been prepared and used for the synthesis of 1R-[1,5,9-$^{3}$H$_{3}$]- and 1R-[1,5,9-D$_{3}$]farnesyl pyrophosphate and squalene. It is shown that when squalene is synthesized from such farnesyl pyrophosphate all the isotopic label appears in the squalene without loss. The implications of the last observations are discussed in the light of previous results.