Unveiling the Enigmatic Machinery of the Azinomycins

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The National Science Foundation, Chemistry of Life Processes Program in the Chemistry Division funds Dr. Coran M. H. Watanabe and his research group from Texas A&M University to study how a natural soil dwelling microbe makes a molecule known as azinomycin. This molecule is a member of an important class of molecules with cancer treatment potential. The research group is investigating the biosynthesis of the azinomycins, i.e. how nature constructs these molecules. These studies will not only shed light on how these molecules are constructed by nature but also pave the way for future engineering of the pathway genes for therapeutic purposes. These investigations enable graduate students, undergraduate students, and postdoctoral fellows to develop a broad skillset in chemical biology and biotechnology. Moreover, this research is integrated into the classroom where students learn that bioactive agents are often derived from the environment by carrying out their own field collection of soil samples, which are assayed for natural products with antibiotic activity. This project also includes an outreach component. High school students learn about natural products research through a lecture and lab on antibiotics and drug resistance. A tailored set of activities is carried out for elementary school students, which centers on "Man vs. Microbe."The azinomycins are densely functionalized and architecturally fascinating. The basic framework of the molecule is generated through a polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) skeleton while the aziridino[1,2-a]pyrollidine moiety is alkaloid derived. From an enzymological perspective the natural product represents a rich treasure trove of unusual biosynthetic transformations to be mined. The objective of this application is to functionally reconstitute and characterize enzymes of the azinomycin biosynthetic pathway and is being investigated through three primary project areas: [1] evaluation of the mechanism of polyketide ring expansion mediated by AziB and AziG, [2] evaluation of the catalytic role of AziA3, and [3] functional characterization of azabicycle biosynthetic enzymes.