Nocardamin Production by Streptomyces avermitilis

Abstract

Desferrioxamine B (desferal) is the only therapeutic agent for chronic iron overload and acute iron intoxication. Therefore, new drug candidates are required for more effective treatments. Recent genome analyses of microorganisms have enabled us to identify cryptic gene clusters of secondary metabolism. In a genomic analysis of Streptomyces avermitilis, we found the putative biosynthetic gene cluster for nocardamin and desferrioxamine derivatives, the production of which by S. avermitilis had been unknown. To determine the synthesis of nocardamin and discover new derivatives in S. avermitilis, we performed a comprehensive analysis and isolation of secondary metabolites of S. avermitilis. We obtained nocardamin and its related compounds, including a derivative that initially was isolated as a microbial product. The biosynthetic pathway of nocardamin and the substrate specificity of its biosynthesis enzymes were proposed based on the structures of the isolated nocardamin derivatives. The production of nocardamin by S. avermitilis was completely suppressed by the addition of more than 5M ferric ions. An iron-dependent regulatory protein (IdeR)-binding motif was located upstream of the sidABCD operon, using the profile hidden Markov model method. To determine the regulation of nocardamin synthesis by IdeR in S. avermitilis, we constructed ideR deletion mutants. The production of nocardamin by the deletion mutants was not suppressed by ferric ions (up to 100M).