Studies on the biosynthesis of cholesterol. XVII. The asymmetric synthesis of a symmetrical molecule

Abstract

The differentiation between two identical chemical groups in the Ca'a"bd molecule in enzymic reactions is discussed first. It is then shown that squalene biosynthesized from two molecules of [1-D 2 ]farnesyl pyrophosphate is asymmetrically labelled at one of its central methylene carbon atoms, one of the deuterium atoms at C-l of one of the two farnesyl residues having been replaced stereospecifically by H B of reduced nicotinamide adenine dinucleotide phosphate. The trideuterio succinic acid obtained by ozonolysis from such squalene is shown to be dextrorotatory and to have the S absolute configuration. The steric position of H A and of H B at position 4 of the dihydronicotinamide ring in NADH and NADPH, transferred from substrates to coenzyme by ‘A’- and ‘B’-specific dehydrogenases respectively, is deduced. This was achieved by making a correlation between the laevorotatory 2 R -[2-D 1 ]succinic acid (made chemically from enzymically generated 2 S -3 R -[3-D 1 ]malic acid) and the [2-D 1 ]succinic acids derived by chemical degradation from positions 3, 4, 5 and 6 of the dihydronicotinamide ring of ‘A’-deuterio and ‘B’-deuterio NADH. The absolute configuration of C-4 of the dihydronicotinamide ring in ‘A’-deuterio NADH is R and in the ‘B’-deuterio NADH it is S .