Microbial biosynthesis of benzodiazepines and nitrosugar containing natural products

Abstract

The biosyntheses of benzodiazepines and nitrosugar containing natural products in actinomycetes were investigated. The first biosynthetic gene cluster of a benzodiazepine natural product was identified in the genome of the anthramycin producer Streptomyces refuineus. The functional boundaries of this biosynthetic gene cluster were validated via a series of targeted gene disruptions and chemical complementation studies were utilized to elucidate aspects of the anthramycin biosynthetic pathway. In a separate study, heterologous expression of the anthramycin biosynthetic gene cluster demonstrated the completeness of the putative gene cluster and shed light on a potential temperature dependent regulation phenomenon. Lastly, the biosynthesis of nitrosugar natural products was investigated. A novel nitrososynthase was putatively identified in the previously sequenced biosynthetic gene cluster of everninomycin via comparative genomics and the biochemical function of this oxidase was demonstrated in the conversion a TDP-aminosugar to a TDP-nitrososugar via a hydroxylamine intermediate.