The biosynthesis of penicillin. 7. Further experiments on the utilization of l- and d-valine and the effect of cystine and valine analogues on penicillin synthesis

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Abstract
The effect of amino acids related to cystine and valine on penicillin biosynthesis was studied with washed mycelium of 2 strains of Penicillium chrysogenum. Penicillin formation was markedly stimulated by L- or DL-cystine and by DL-cysteic acid. L-Methionine, S-benzyl-L-cysteine, S-methyl-L-cysteine, N-methyl-L-cystine and the erythro- and threo-isomers of ft-methyl-DL-cystine (thiothreonine A and B disulfides) had no effect on penicillin biosynthesis by washed mycelium. When C14-labeled [beta]-methylcystine was added to fermentations producing penicillin, no conversion of this cystine analog into a C(5)-substituted penicillin could be detected. Inhibition of penicillin biosynthesis was observed with [alpha]-methyl-DL-cystine and [beta][beta]-dimethyl-L- and D-cystine (L- and D-penicillamine disulfide). DL-isoleucine, o-methyl-DL-valine and DL-valine inhibited penicillin biosynthesis, but N-methyl-DL-valine had no effect. Both isoleucine and a-methylvaline inhibited the conversion of C14-labeled D-valine into penicillin to a greater extent than that of L-valine. A different strain of P. chrysogenum (WIS 51/10 F3) from that used in previous work utilized L-valine for penicillin, biosynthesis much better than D-valine. It is concluded from the better conversion of L-valine into penicillin by strain WIS 51/20 F 3 and from the preferential inhibition of the utilization of D-valine by [alpha]-methylvaline or isoleucine that D-valine is not a penicillin precursor, but that either L-valine or, less likely, the keto acid, [alpha]-oxoisovaleric acid, is the precursor of the penicillamine moiety of penicillin.