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Moving beyond Methionine Synthase: New Insights into Cobalamin-Dependent Methyltransferase Reactions

Squire Booker (The Pennsylvania State University)
Monday, October 15, 2018
4:00-5:30 PM
Chem 1640 Chemistry Dow Lab Map
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 (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 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 agents. Fom3, which performs a key step in the biosynthesis of the broad-spectrum antibiotic fosfomycin, catalyzes the methylation of the sp3-hybridized C2’’ carbon of cytidylyl-2-hydroxyethylphosphonate to yield cytidylyl-2-hydroxypropylphosphonate. By contrast, TsrM catalyzes the first committed step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which is the methylation of the sp2-hybridized C2 carbon of the indole ring of L-tryptophan. As will be discussed, while both Fom3 and TsrM are cobalamin-dependent radical SAM methylases, they use two distinctly different strategies to catalyze their reactions.

Squire Booker (The Pennsylvania State University)
Building: Chemistry Dow Lab
Event Type: Other
Tags: Chemistry, Science
Source: Happening @ Michigan from Department of Chemistry