Glucose 6-phosphate: the diversity of C-methylation in sugar moieties within natural product biosynthesis.

Covering: Up to 2026Methylation is one of the most frequent and functionally significant modifications in natural product biosynthesis. This transformation generally involves the cosubstrate S-adenosyl-L-methionine (SAM) and occurs with high regio-, chemo-, and stereo-selectivity. C-Methylation serves as an effective strategy for the incorporation of C₁ building blocks and plays a key role in both carbon skeleton extension and structural core decoration. A notable example is SAM-dependent C-methylation of nucleotide-activated sugar moieties catalyzed by C-methyltransferase (C-MT) during the biosynthesis of glycosylated natural products. A prerequisite in these pathways is the activation of the sugar by the attachment of a nucleotide diphosphate (NDP) tail. Sugar C-MTs exhibit remarkable substrate specificity and often act in concert with additional transformations, such as oxidation, decarboxylation, or reduction, to diversify sugar structures. Canonical SAM-dependent sugar C-MTs are capable of introducing methyl groups at C3, C4, or C5 positions of the sugar ring by an S_N2-like mechanism involving enolate intermediates. In contrast, C6 methylation has been attributed to radical SAM enzymes. These distinct strategies illustrate the enzymatic versatility and sophisticated control over sugar C-methylation in nature, contributing to the structural diversity of natural products.