Biological methylation of unactivated carbon and phosphorus atoms is an essential component of clinically useful natural product biosynthetic pathways, including those to potent antibiotics such as fosfomycin and carbapenem compounds. RS methylases (RSMTs) are a large class of enzymes (over 8,000 sequences identified to date) that facilitate these transformations, but their structures and mechanisms are largely unknown, hindering exploitation of these catalysts for technological applications. Class B RSMTs modify a wide array of substrates using an unprecedented combination of a methylcobalamin cofactor, a [4Fe-4S] cluster, and SAM for catalysis.

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