New insights into cobalamin-dependent methyltransferase reactions Squire Booker Penn State University, USA 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 S N 2 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 (5’-dA•). There are at least five subclasses of radical SAM methylases. Class B methylases represent the largest subclass, and use cobalamin to methylate both sp 2 - and sp 3 -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.
K05
© The Author(s), 2022
Made with FlippingBook Learn more on our blog