Radical-Mediated Carbon Skeleton Formation in Cofactor and Natural Product Biosynthesis

Abstract

The past decade has experienced an emergence of radical SAM enzymes that catalyze C-C bond formation reactions in a variety of pathways, including natural product and cofactor biosynthesis and RNA modifications. The radical mediated C-C bond formation reactions, in general, proceed through three major steps; radical initiation, C-C bond formation, and radical quenching. The mechanisms of radical quenching step are particularly diverse and as yet significantly under-explored. Therefore, this review summarizes the reported radical SAM enzyme-catalyzed C-C bond formation reactions with particular focus on the radical quenching mechanism. MoaA, which is involved in the biosynthesis of the pterin backbone structure of molybdenum cofactor (Moco), is discussed as a specific case. The history of the studies of Moco biosynthesis and functional and mechanistic characterization of MoaA highlight the challenge in the characterization of Moco biosynthetic pathway and the presence of an elaborate mechanism to control the radical reactions in the MoaA active site. Overall, this review aims to provide a comprehensive view of the mechanism of radical-mediated C-C bond formations and specific insights into the mechanism of action of MoaA, a representative member of C-C bond forming radical SAM enzymes.