Structural basis for non-radical catalysis by TsrM, a radical SAM methylase
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of l-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/133379.2 |
| _version_ | 1811073196086001664 |
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| author | Knox, Hayley L Chen, Percival Yang-Ting Blaszczyk, Anthony J Mukherjee, Arnab Grove, Tyler L Schwalm, Erica L Wang, Bo Drennan, Catherine L Booker, Squire J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Knox, Hayley L Chen, Percival Yang-Ting Blaszczyk, Anthony J Mukherjee, Arnab Grove, Tyler L Schwalm, Erica L Wang, Bo Drennan, Catherine L Booker, Squire J. |
| author_sort | Knox, Hayley L |
| collection | MIT |
| description | © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of l-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5ʹ-deoxyadenosyl 5ʹ-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe–4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion. [Figure not available: see fulltext.] |
| first_indexed | 2024-09-23T09:29:53Z |
| format | Article |
| id | mit-1721.1/133379.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:29:53Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/133379.22022-06-28T15:31:07Z Structural basis for non-radical catalysis by TsrM, a radical SAM methylase Knox, Hayley L Chen, Percival Yang-Ting Blaszczyk, Anthony J Mukherjee, Arnab Grove, Tyler L Schwalm, Erica L Wang, Bo Drennan, Catherine L Booker, Squire J. Massachusetts Institute of Technology. Department of Chemistry Howard Hughes Medical Institute Massachusetts Institute of Technology. Department of Biology © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of l-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5ʹ-deoxyadenosyl 5ʹ-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe–4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion. [Figure not available: see fulltext.] 2022-06-28T15:31:06Z 2021-10-27T19:52:26Z 2022-06-28T15:31:06Z 2021 2021-07-23T16:59:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133379.2 en 10.1038/s41589-020-00717-y Nature Chemical Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/octet-stream Springer Science and Business Media LLC PMC |
| spellingShingle | Knox, Hayley L Chen, Percival Yang-Ting Blaszczyk, Anthony J Mukherjee, Arnab Grove, Tyler L Schwalm, Erica L Wang, Bo Drennan, Catherine L Booker, Squire J. Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title | Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title_full | Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title_fullStr | Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title_full_unstemmed | Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title_short | Structural basis for non-radical catalysis by TsrM, a radical SAM methylase |
| title_sort | structural basis for non radical catalysis by tsrm a radical sam methylase |
| url | https://hdl.handle.net/1721.1/133379.2 |
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