Functionalization of unactivated sp2-hybridized carbon atoms

描述（由申请人提供）：大自然已经进化出多种策略来切割未活化的碳氢键，以使惰性碳中心功能化。这些反应总是使用金属辅助因子来产生强大的氧化剂，这些氧化剂可以从碳中心提取氢原子进行功能化，产生以碳为中心的自由基。在所有已建立的涉及H•提取的酶机制中，劈裂的C-H键是sp3杂化的，相关的均解键能（BDEs）小于（或等于）甲烷的104 kcal/mol特征。最近，越来越多的反应被发现暗示了sp2杂化碳中心的功能化和bde大于105 kcal/mol的键的裂解。这个项目的目的是表征三个这样的酶反应涉及甲基化，甲基硫化，和羟基化的sp2杂化碳中心。前两个反应是由属于自由基sam超家族的酶催化的，而第三个反应是由Fe(II)-和α-酮戊二酸依赖加氧酶家族中的酶催化的。这些研究的结果将极大地扩展我们对非活化sp2杂化碳中心功能化的自然策略的理解，并揭示反应机制的细节，这可能在设计这些过程的治疗性抑制剂方面被证明是实用的。

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 α-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.