CAREER: New Metalloenzyme-Catalyzed Transformations in Natural Product Biosynthesis

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With this award, the Chemistry of Life Processes Program in the Chemistry Division and the Cellular and Biochemical Engineering Program in the Division of Chemical, Bioengineering, Environmental and Transport Systems are funding Dr. Mohammad R. Seyedsayamdost from Princeton University to discover novel reactions carried out by metalloenzymes during natural product biosynthesis. Natural products are small molecules synthesized by diverse microorganisms and released into the environment where they have varied biological functions. The natural products are also a major source of therapeutics. Metalloenzymes are often implicated in the production of these molecules, but the reactions that they catalyze are in most cases unknown. The proposed experiments help define the transformations catalyzed by hundreds of metalloenzymes during natural product biosynthesis. In doing so, the research expands the chemical repertoire of metalloenzymes and delineate new biosynthetic strategies, which may be used in the industrial production of commodity molecules. At the same time, the experimental plan enables rigorous training for of graduate and undergraduate students who do research at the interface of chemistry and biology. The project is integrated into an outreach program designed to grow the scientific skills of teachers at local high schools.The recent explosion in microbial genome sequences has brought to light an abundance of new metalloenzymes. With the substrates of many of these enzymes unknown, mining this daunting and novel catalytic landscape is a big challenge. In this project, a bioinformatic approach is used to link substrates to yet uncharacterized metalloenzymes. The reactions carried out by these enzymes are then elucidated using biological experiments, NMR spectroscopy and mass spectrometry. Their detailed mechanisms is the subject of spectroscopic and kinetic studies. These investigations broaden the reaction scope of metalloenzymes and define new biosynthetic pathways. The results will shed light on the strategies that nature utilizes to catalyze difficult transformations during the synthesis of complex natural products.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.