Novel Actinomycins Formed by Biosynthetic Incorporation of cis - and trans -4-Methylproline

Abstract

Streptomyces parvulus ( Streptomyces parvullus ) normally produces actinomycin D; in the presence of cis -4-methylproline, this species synthesizes two additional actinomycins, designated K 1c and K 2c , in which one and two proline sites, respectively, are occupied by cis -4-methylproline. Analogously, actinomycins K 1t and K 2t are formed in the presence of trans -4-methylproline. Both mixtures were separated chromatographically, and the four novel actinomycins were obtained in crystalline form. Their biological activities were compared with that of actinomycin D in respect to inhibition of ribonucleic acid, deoxyribonucleic acid, and protein synthesis and antimicrobial potency. In all cases examined, the order of activity D > K 1t > K 1c > K 2t > K 2c was observed, and the same sequence prevailed in a spectroscopic measure of their binding to deoxyribonucleic acid. In addition, proton nuclear magnetic resonance studies revealed that the replacement of proline by cis -4-methylproline alters the conformation of the antibiotic molecule.