Analysis of reveromycin A biosynthetic gene cluster in Streptomyces reveromyceticus

Shunji Takahashi
Unit Leader
Shunji Takahashi

Streptomyces reveromyceticus Streptomyces produce wide variety of natural products which are used for medicinal drug and bioprobes for the elucidation of biological functions. Recently, Streptomyces genome analyses revealed 20-30 gene clusters which are speculated to be involved in the biosynthesis of secondary metabolites. In post-genome era, the functional identification of unknown genes in the cluster is an important subject to expand our knowledge of the chemical diversity in nature. Reveromycin A, which is a polyketide compound produced by Streptomyces reveromyceticus, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. The understanding of the polyketide biosynthesis and post PKS modification system enables us to design new reveromycin derivatives which have a strong biological activity for drug development. Reveromycin A To address the biosynthetic mechanisms, we have cloned and identified reveromycin A biosynthetic gene cluster (about 90 kb). We are now investigating the unknown gene function by gene disruption, metabolite analysis, biochemical characterization of purified protein and co-crystal structure analysis. The utilization of new enzymes identified from reveromycin biosynthetic gene cluster will contribute to expand polyketide compounds which can be applicable for the development of new drug seeds and bioprobes.

Identification and engineering of fungal metabolite biosynthetic gene clusters

Naoki Kato
Research Scientist

fumitremorgin A highly complex structure is one of the characteristics of natural products and is often related to their potent and specific biological activities. An understanding of biosynthetic machinery that decorates the structures of natural products is important to expand structural diversity of natural products and improve their biological activities. We have been working on the biosynthesis of fungal bioactive metabolites possessing unique polycyclic ring systems, such as fumitremorgins, okaramines, and fusarisetin. Genetic and biochemical dissection of the biosynthetic gene clusters for the metabolites revealed key enzymes for structural features in the biosynthetic pathways. Our research provides a strategy to exploit the biosynthetic potential for structural diversity and biological activities.