Functionalization of unactivated sp2-hybridized carbon atoms

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Nature has evolved a variety of strategies to cleave unactivated carbon-hydrogen bonds in order to functionalize inert carbon centers. These reactions invariably employ metallocofactors to create powerful oxidants that can abstract hydrogen atoms from the carbon centers to be functionalized, generating carbon-centered radicals. In all well-established enzyme mechanisms involving H abstraction, the cleaved C-H bonds are sp3-hybridized, and the associated homolytic bond-dissociation energies (BDEs) are less than (or equal to) the 104 kcal/mol characteristic of methane. Recently, a growing number of reactions have been identified that imply functionalization of carbon centers that are sp2-hybridized with cleavage of bonds that have BDEs of greater than 105 kcal/mol. This project aims to characterize three such enzymatic reactions involving methylation, methylthiolation, and hydroxylation of sp2-hybridized carbon centers. The first two reactions are catalyzed by enzymes belonging to the radical-SAM superfamily, while the third is catalyzed by an enzyme in the Fe(II)- and ?-ketoglutarate-dependent oxygenase family. The results of these studies should significantly expand our understanding of Nature's strategies for functionalization of unactivated sp2-hybridized carbon centers and reveal details of reaction mechanisms that may prove practically useful in design of therapeutic inhibitors of these processes. ) PUBLIC HEALTH RELEVANCE: Reactions in which sp2-hybridized carbon centers are functionalized constitute key steps in the biosynthesis of numerous antibiotic natural products and the maturation of certain tRNAs. The inability to functionalize an sp2-hybridized carbon center in a tRNA that specifies lysine incorporation into proteins is a major risk factor for type I diabetes across all ethnic groups. An understanding of these reactions could suggest strategies for design of new antibiotics and other drugs.
Effective start/end date7/2/126/30/13


  • National Institute of General Medical Sciences: $265,938.00

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