Mechanistic insight into radical S-adenosylmethionine enzymes in lipid modification

Covering: up to 2025Lipids are structurally diverse biomolecules that play a critical role in the homeostasis of organisms across all domains of life. While biogenesis of lipids varies by organism, the strategies employed to modify or functionalize inert lipid hydrocarbon chains often require the power of radical-based chemistry. Recently, an increasing number of lipid-modifying radical S-adenosylmethionine (RS) enzymes have been identified. RS enzymes are well known to mediate >100 reactions. In the context of lipids, these radical-mediated reactions proceed through Csp² and Csp³ centers, affording C-C bond formations, methylations, cyclizations, and/or ring contractions. This review highlights our understanding of the function and mechanism of lipid-modifying RS enzymes. Mechanistic considerations of lipid modification by RS enzymes reveal the significance of cofactors (particularly B12) and auxiliary metal centers in substrate activation and intermediate stabilization. Understanding the function and mechanism strategies of these enzymes is crucial not only to advancing our understanding of RS enzymes but also to inform paleoenvironmental reconstructions and the emerging field of lipid-based drug delivery.