Structural Investigation of Enzymes that Utilize Cobalamin and AdoMet Cofactors

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DESCRIPTION (provided by applicant): Over the past few decades, natural products, or chemical compounds derived from plants, animals, or microbes have greatly inspired drug discovery and development. As nature's compounds are more complex and architecturally unique than available man-made drugs, understanding nature's chemistry for engineering these molecules represents a significant milestone in natural product based drug discovery. Many medically important natural product biosynthetic pathways utilize the chemistry of enzymes that were once thought to be part of a tiny subgroup of the S-adenosylmethionine (AdoMet) radical superfamily. Today, this subgroup, the cobalamin-dependent class of AdoMet radical enzymes contains 2,685 unique members and can be found in the biosynthetic pathways of important compounds including fosfomycin, fortimicin A, and thiostrepton A antibiotics, and the anti-viral agent oxetanocin A. Despite the wealth of enzymes identified as belonging to this subgroup and the importance of the reactions they catalyze, there are few mechanistic details known about how they function. Mechanistic studies are currently impeded by a lack of structural information for this class of enzymes and lack of previously characterized enzymes that share a similar sequence and use the same combination of cofactors. Therefore, the objective of this proposal is to determine X-ray crystal structures for members of the cobalamin-dependent subgroup of the AdoMet radical superfamily. These results will aid in the design of future mechanistic studies and provide a framework for understanding the coordination and interplay of AdoMet and cobalamin cofactors in performing nature's chemistry.