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

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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 .