Effect of structural and stereochemical methylproline isomers on actinomycin biosynthesis.

The inhibitory effect of methylprolines on actinomycin biosynthesis by Streptomyces antibioticus was studied; the order of effectiveness was 3- >4- >5-methyl-dl-proline. Cis-3-methyl-dl-proline was 14 times more active than the trans isomer. It was also found that 4- and, possibly, 5-methylproline were incorporated into the actinomycin molecule. When 4-methylproline was present, three new actinomycins, representing 50 to 60% of the antibiotic mixture, were synthesized. Growth of the organism may be stimulated at concentrations (0.1 to 1.0 mug per ml) of 3-methylproline that inhibit antibiotic formation, thus providing additional evidence for a different mechanism of actinomycin synthesis from that of protein synthesis. Azetidine-2-carboxylic acid, piperdine-2-carboxylic acid, and hydroxyproline (but not sarcosine) reversed the inhibition due to 3-methylproline.