Biological methylation underpins myriad cellular processes through the modification of proteins, lipids, nucleic acids, heavy metals, and a variety of small organic molecules. In the vast majority of these reactions, the appended methyl group derives from S-adenosylmethionine (SAM) and is attached most often to nitrogen and oxygen nucleophiles through a polar SN2 mechanism, although carbon, sulfur, and a variety of other nucleophilic atoms also receive SAM-derived methyl groups. Recently, it has become apparent that SAM is used to methylate non-reactive carbon and phosphorus atoms by mechanisms involving radical intermediates. To date, these reactions are catalyzed exclusively by radical SAM enzymes, a superfamily of enzymes that use an iron-sulfur (Fe-S) cluster to catalyze a reductive cleavage of SAM to methionine and the potent oxidant 5’-deoxyadenosin 5’-radical. There are at least five subclasses of radical SAM methylases. Class B methylases represent the largest subclass, and use cobalamin to methylate both sp2- and sp3-hybridized carbon centers or phosphinate phosphorus centers during the biosynthesis of numerous biomolecules, including natural products with antibiotic and anticancer activities. This lecture will focus on two Class B radical SAM methylases involved in the biosynthesis of antibacterial natural products that act by completely distinct mechanisms.

New Insights into Cobalamin-Dependent Methyltransferase Reactions

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

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