Unveiling the Enigmatic Biosynthetic Machinery of the Azinomycins

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Azinomycins are natural products from microbes that target DNA (the genetic basis of all life) and have demonstrated anti-tumor and anti-bacterial activities. The National Science Foundation, Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Coran M. H. Watanabe from Texas A&M University to determine how nature constructs the azinomycins. These studies characterize the functions and structures of the proteins that catalyze the unique biochemical steps involved in generating the chemical features of the azinomycins that are important for their biological activity. The knowledge gained from this research paves the way for future engineering of genes to synthesize azinomycins within a tumor cell to treat cancer. This project enables graduate and undergraduate students, and postdoctoral trainees to develop broad skills in chemical biology and biotechnology. Moreover, this research is integrated into a class that teaches how bioactive agents are derived from the environment. Students in this class collect soil samples, which are then assayed for natural products that show antibiotic activity. In addition, local elementary, middle, and high school students learn about natural products and microbes in their lives through tailored lectures, demonstrations, and laboratory experiences. Finally, as opportunities arise, Dr. Watanabe participates in events such as the American Cancer Society Relay for Life Events to inform the general public about cancer research and the daily work-related activities of a research active faculty member. The azinomycins are architecturally fascinating natural products. The natural product is densely functionalized with a naphtoate, epoxide, enol, and azabicyclic ring system. The basic skeletal framework of the molecule is generated through a polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) pathway, while the aziridino[1,2-a]pyrollidine moiety is alkaloid derived. From an enzymological perspective, this natural product represents a treasure trove of unusual biosynthetic transformations to be mined and paves the way for chemoenzymatic/synthetic biology efforts. The goals of this project are to functionally reconstitute and characterize enzymes of the azinomycin biosynthetic pathway, and begin to develop ways to manipulate the pathway. The objectives towards these goals include 1) characterizing the enzymatic mechanism for biosynthesis of the naphthoate moiety of the azinomycins and analyze the structure-activity relationships of structurally and functionally related analogs of this mioety, 2) exploring the chemistry of the epoxide unit, and 3) functionally characterizing the enzymes for the biosynthesis of the azabicycle moiety.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.