Utilization of the intact carbamoyl group of L-(NH2CO-13C,15N) citrulline in mitomycin biosynthesis by Streptomyces verticillatus.

Sir: It was shown previously that both L[guanidino-14C] arginine and L-[ureido-14C] citrulline are efficient mitomycin (I) precursors which specifically label the carbamoyl-group of these antibiotics1,3. Sodium-[14C] carbonates', [14C] urea1) and potassium-[14C] cyanate3' are inefficient precursors and this is presumably due to either inefficient uptake or loss of the label as carbon dioxide from the slightly acidic fermentation broth. Other precursors label the carbamoyl group probably after being metabolized to carbon dioxide4). The results of a competition feeding experiment between L-citrulline and L-arginine indicated, but did not prove, that the former was the more proximate precursor2) and they suggested that L-arginine is converted into L-citrulline prior to incorporation into the mitomycins. Thus the assumption can be made that the arginine dihydrolase pathways' is operative in S. verticillatus and that the carbamoylphosphate generated gives rise to the carbamoyl group of these antibiotics. However, a variety of factors, such as differences in uptake and different rates of metabolic conversions, may have influenced the outcome of the competition feeding experiment, which taken alone, was not completely self consistant, in that the suppression of labeled arginine incorporation in the presence of excess unlabeled citrulline