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Structural basis for non-radical catalysis by TsrM, a radical SAM methylase
Hayley L Knox1, Percival Yang-Ting Chen2,3, Anthony J Blaszczyk4,5
1Department of Chemistry, Pennsylvania State University, University Park, PA, USA.
Nature Chemical Biology
|January 19, 2021
Summary
Tryptophan 2C methyltransferase (TsrM) is a cobalamin-dependent enzyme. New structures reveal TsrM
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Tryptophan 2C methyltransferase (TsrM) is involved in thiostrepton biosynthesis.
- TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase.
- TsrM does not exhibit the canonical reductive cleavage of SAM characteristic of radical SAM enzymes.
Purpose of the Study:
- To determine the first structures of a cobalamin-dependent radical SAM methylase.
- To elucidate the structural basis for TsrM's unique catalytic mechanism.
Main Methods:
- X-ray crystallography of Kitasatospora setae TsrM.
- Structural analysis in the presence of substrates.
Main Results:
- First structures of a cobalamin-dependent radical SAM methylase (TsrM) were obtained.
- An essential arginine residue in the cobalamin coordination sphere was identified.
- A [4Fe-4S] cluster ligated by glutamate and cysteines in a canonical motif was observed.
- Substrate-assisted catalysis involving SAM's carboxylate group was proposed.
Conclusions:
- TsrM represents a novel class of cobalamin-dependent methyltransferases.
- The identified structural features suggest a unique catalytic mechanism distinct from canonical radical SAM enzymes.
- Understanding TsrM provides insights into diverse enzymatic methylation strategies.
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