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The family of enzymes known as the radical S-adenosyl-L-methionine (SAM) enzymes, catalyze thousands of reactions across biology. Most radical SAM enzymes work via a mechanism in which cleavage of S-adenosyl-L-methionine forms a radical, hence their name. But an enzyme called TsrM, which catalyzes the addition of a methyl group to the indole of L-tryptophan during the synthesis of the antibiotic thiostrepton, isn’t your typical radical SAM enzyme. It uses SAM as a substrate but doesn’t form a radical.
Squire J. Booker and Hayley L. Knox of Pennsylvania State University, Catherine L. Drennan and Percival Yang-Ting Chen of the Massachusetts Institute of Technology, and coworkers report structures of TsrM from the bacterium Kitasatospora setae that may help explain the enzyme’s anomalous behavior (Nat. Chem. Biol. 2021, DOI: 10.1038/s41589-020-00717-y).
The team proposes that SAM plays a dual role in the reaction. It donates a methyl group to the enzyme’s cobalamin cofactor and then serves as a base when tryptophan removes that methyl group. That second part of the reaction is surprising, Booker says, because the carbon that gets methylated on tryptophan isn’t particularly nucleophilic and the cobalamin it has to displace, which is in the +1 oxidation state, is one of the strongest nucleophiles in nature.
The structures reveal why this is possible. An unexpected arginine residue in the cobalamin-binding region stabilizes a seemingly less-favorable oxidation state of the cobalt in cobalamin by blocking water. The enzyme also has a glutamate residue that coordinates to the 4Fe-4S cluster at the core of the enzyme, a hallmark of the radical SAM enzyme that is usually responsible for generating the eponymous radical. This glutamate blocks coordination of SAM with the cluster and is probably the reason the usual radical isn’t formed.
Olivier Berteau, an expert on radical SAM enzymes at the Micalis Institute, expects more catalysts without a radical mechanism to be uncovered among the 500,000 enzymes in the radical SAM superfamily. TsrM is known to bind many substrates; knowing its structure could help to exploit its synthetic potential, he adds.
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