Collaborative Research: Unveiling the Enigmatic Biosynthetic Machinery of the Azinomycins
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abstract
With this award, the Chemistry of Life Processes Program is funding Dr. Coran Watanabe from Texas A&M University and Dr. Stephen Ealick of Cornell University to collaboratively characterize enzymes of the azinomycin biosynthetic pathway both functionally and structurally. Specifically, this project is directed at the evaluation of thioesterase-domain interacting partners and structural characterization of the iterative polyketide synthase (PKS) AziB, as well as functional characterization of both AziA2, and the of azabicycle biosynthetic enzymes. This project also aims at a structural understanding of the bacterial Type I iterative polyketide synthase (PKS) involved in the construction of the azinomycin naphthoate. While it was long thought that all bacterial aromatic polyketides are derived from Type II PKSs, it is now clear that this is not the case and the azinomycin PKS serves as a specific example. The azinomycin PKS will thus serve as a model system for this bacterial Type I iterative PKS class. Experiments will elucidate the key role of an unusual non-ribosomal peptide synthetase (NRPS) module of unprecedented domain architecture (C-PCP-C). The azinomycins also contain an aziridine ring system, the biosynthesis of which is poorly understood. These studies should provide inroads into the route and mechanism of aziridine formation through the functional characterization of four enzymes of this pathway.Natural products or secondary metabolites are compounds that are produced by a given organism but are not essential to the survival of the host. Such compounds often possess potent bioactivities and serve as lead compounds for the development of therapeutic agents. The biosynthesis of the azinomycins is under investigation here. The azinomycins are a family of DNA crosslinking agents with demonstrated anti-tumor activity. Understanding how nature constructs these strained ring systems should shed light on a fundamental mechanistic question in biosynthesis and also pave the way for the engineering of the pathway genes for therapeutic purposes, in the longer term. This project also includes an outreach component where both undergraduate and high school students will be exposed to natural products research.
