Oxidative transformations are one of the most utilized classes of reactions, indispensible in the synthesis of pharmaceutical agents and small molecules used to study biological systems. While significant strides have been made in developing powerful methods for oxidative reactions, it remains challenging to carry out these transformations with high levels of chemo-, site- and stereoselectivity on complex molecules. In contrast to small molecule catalysts and reagents, enzymes from natural product biosynthetic pathways have evolved to carry out oxidation reactions with high levels of selectivity. The discovery of oxidative enzymatic reactions and development of the utility of these catalysts has the potential to enable to synthetic strategies and grant us access to new molecules with potent biological activity. This proposal describes several strategies for developing robust enzyme-mediated oxidation reactions and leveraging these tools for the streamlined synthesis of molecules with pharmaceutical potential. This work takes advantage of the powerful reactivity and selectivity that Nature has evolved within its synthetic routes to complex secondary metabolites. From this starting point provided by Nature, we (1) characterize the function of each enzyme and define the substrate flexibility of each enzyme, (2) use structure-guided protein engineering to alter the innate site- and stereoselectivity of a given catalysts, (3) develop chemomimetic biocatalytic reactions and (4) utilize strategies to expand the substrate scope of a given enzyme. Together, these approaches provide a suite of versatile catalysts that will be applied to the synthesis of biologically active target molecules. The biological properties of these molecules will be evaluated through direct collaborations with investigators at the University of Michigan Medical School as well as the Center for Chemical Genomics High Throughput Screening facility at the University of Michigan Life Sciences Institute. In summary, this proposal describes the development of chemo-, site- and stereoselective oxidative transformations mediated by biosynthetic enzymes. These methods will directly enable the synthesis of complex biologically active molecules relevant to human health.

Public Health Relevance

The proposed research is relevant to human health because the development of selective oxidative chemical reactions will enable the synthesis of new pharmaceutical agents and tools to study biological systems. Specifically, the proposed research will lead to the development of sustainable, environmentally enzyme- mediated reactions. Ultimately, this work will also lead to fundamental discoveries that will be applied to human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Bond, Michelle Rueffer
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Baker Dockrey, Summer A; Doyon, Tyler J; Perkins, Jonathan C et al. (2018) Whole-cell biocatalysis platform for gram-scale oxidative dearomatization of phenols. Chem Biol Drug Des :
Baker Dockrey, Summer A; Lukowski, April L; Becker, Marc R et al. (2018) Biocatalytic site- and enantioselective oxidative dearomatization of phenols. Nat Chem 10:119-125
Chun, Stephanie W; Hinze, Meagan E; Skiba, Meredith A et al. (2018) Chemistry of a Unique Polyketide-like Synthase. J Am Chem Soc 140:2430-2433