C-Methylated natural products: biosynthetic stage and significance of C-methylation.

Covering: up to 2026C-Methylation is a fundamental transformation in natural product biosynthesis. Although methyl groups are often regarded as simple functional groups that modulate physicochemical properties, they frequently play decisive roles in directing enzymatic reactivity and controlling biosynthetic pathway progression. Cobalamin (Cbl)-dependent radical S-adenosyl-L-methionine (SAM) C-methyltransferases catalyze the installation of C-methyl groups at sp3-hybridized carbon centers in biosynthetic intermediates. Recent studies have uncovered their remarkable catalytic capabilities, including precise control over regio- and stereoselectivity. Moreover, the installed methyl groups often influence downstream transformations and are essential for late-stage biosynthetic events. This highlight focuses on the functional roles of C-methylation mediated by Cbl-dependent radical SAM enzymes, emphasizing how these seemingly small modifications shape the biosynthesis of complex natural products.