Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149

The rapid emergence of infectious diseases and multiresistant pathogens has increased the necessity for new bioactive compounds; thus, novel strategies have to be developed to find them. Actinomycetes isolated in symbiosis with insects have attracted attention in recent years as producers of metabolites with important bioactivities. Sipanmycins are glycosylated macrolactams produced byStreptomyces sp. CS149, isolated from leaf-cutting ants, and show potent cytotoxic activity. Here, we characterize thesip cluster and propose a biosynthetic pathway for sipanmycins. As far as we know, it is the first time that the cooperation between two different glycosyltransferases is demonstrated to be strictly necessary for the incorporation of the same sugar. Also, a third protein with homology to P450 monooxygenases, SipO2, is shown to be essential in the second glycosylation step, forming a complex with the glycosyltransferase pair SipS9-SipS14.