Effect of pipecolic acid isomers on the biogenesis of actinomycins

Streptomyces antibioticus produces a family of actinomycin components which differ solely at the "imino acid" site of the molecule; however, new congeners of actinomycin are synthesized when cultures are supplemented with pipecolic acid (PA). The quantitative and qualitative nature of the actinomycins produced differed when cultures were incubated in the presence of either l-, d-, or racemic PA. In the presence of d-PA, the quantitative and qualitative nature of those actinomycins produced were similar to those produced in the absence of supplementation. By contrast, in the presence of l-PA or dl-PA new actinomycin components containing PA were synthesized at the expense of normally produced components. Also, the total amount of antibiotic produced decreased in response to increasing concentrations of exogenously supplied l-PA. This effect occurred whether or not d-PA was also added to cultures. Concentrations of l-PA greater than 125 mug/ml of medium resulted in no additional decrease in the amount of antibiotic produced. Although PA-containing actinomycins were formed as early as 6 h after the addition of 250 mug of l-PA per ml, it was not until 24 h postaddition that the relative percentages of actinomycin components produced approached a constant value. Evidence presented here indicated that the l-isomer of PA replaces l-proline in the pentapeptide of actinomycin.