Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes
Copyright © 2020 American Chemical Society. All kingdoms of life use the transient 5′-deoxyadenosyl radical (5′-dAdoâ ) to initiate a wide range of difficult chemical reactions. Because of its high reactivity, the 5′-dAdo•must be generated in a controlled manner to abstract a specific H atom and avo...
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| Format: | Article |
| Language: | English |
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American Chemical Society (ACS)
2021
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| Online Access: | https://hdl.handle.net/1721.1/132589 |
| _version_ | 1826203797101215744 |
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| author | Brown, AC Suess, DLM |
| author_facet | Brown, AC Suess, DLM |
| author_sort | Brown, AC |
| collection | MIT |
| description | Copyright © 2020 American Chemical Society. All kingdoms of life use the transient 5′-deoxyadenosyl radical (5′-dAdoâ ) to initiate a wide range of difficult chemical reactions. Because of its high reactivity, the 5′-dAdo•must be generated in a controlled manner to abstract a specific H atom and avoid unproductive reactions. In radical S-Adenosylmethionine (SAM) enzymes, the 5′-dAdo•is formed upon reduction of SAM by an [Fe4S4] cluster. An organometallic precursor featuring an Fe-C bond between the [Fe4S4] cluster and the 5′-dAdo group was recently characterized and shown to be competent for substrate radical generation, presumably via Fe-C bond homolysis. Such reactivity is without precedent for Fe-S clusters. Here, we show that synthetic [Fe4S4]-Alkyl clusters undergo Fe-C bond homolysis when the alkylated Fe site has a suitable coordination number, thereby providing support for the intermediacy of organometallic species in radical SAM enzymes. Addition of pyridine donors to [(IMes)3Fe4S4-R]+ clusters (R = alkyl or benzyl; IMes = 1,3-dimesitylimidazol-2-ylidene) generates Râ , ultimately forming R-R coupled hydrocarbons. This process is facile at room temperature and allows for the generation of highly reactive radicals including primary carbon radicals. Mechanistic studies, including use of the 5-hexenyl radical clock, demonstrate that Fe-C bond homolysis occurs reversibly. Using these experimental insights and kinetic simulations, we evaluate the circumstances in which an organometallic intermediate can direct the 5′-dAdo•toward productive H-Atom abstraction. Our findings demonstrate that reversible homolysis of even weak M-C bonds is a feasible protective mechanism for the 5′-dAdo•that can allow selective X-H bond activation in both radical SAM and adenosylcobalamin enzymes. |
| first_indexed | 2024-09-23T12:43:11Z |
| format | Article |
| id | mit-1721.1/132589 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:43:11Z |
| publishDate | 2021 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1325892021-09-21T03:34:24Z Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes Brown, AC Suess, DLM Copyright © 2020 American Chemical Society. All kingdoms of life use the transient 5′-deoxyadenosyl radical (5′-dAdoâ ) to initiate a wide range of difficult chemical reactions. Because of its high reactivity, the 5′-dAdo•must be generated in a controlled manner to abstract a specific H atom and avoid unproductive reactions. In radical S-Adenosylmethionine (SAM) enzymes, the 5′-dAdo•is formed upon reduction of SAM by an [Fe4S4] cluster. An organometallic precursor featuring an Fe-C bond between the [Fe4S4] cluster and the 5′-dAdo group was recently characterized and shown to be competent for substrate radical generation, presumably via Fe-C bond homolysis. Such reactivity is without precedent for Fe-S clusters. Here, we show that synthetic [Fe4S4]-Alkyl clusters undergo Fe-C bond homolysis when the alkylated Fe site has a suitable coordination number, thereby providing support for the intermediacy of organometallic species in radical SAM enzymes. Addition of pyridine donors to [(IMes)3Fe4S4-R]+ clusters (R = alkyl or benzyl; IMes = 1,3-dimesitylimidazol-2-ylidene) generates Râ , ultimately forming R-R coupled hydrocarbons. This process is facile at room temperature and allows for the generation of highly reactive radicals including primary carbon radicals. Mechanistic studies, including use of the 5-hexenyl radical clock, demonstrate that Fe-C bond homolysis occurs reversibly. Using these experimental insights and kinetic simulations, we evaluate the circumstances in which an organometallic intermediate can direct the 5′-dAdo•toward productive H-Atom abstraction. Our findings demonstrate that reversible homolysis of even weak M-C bonds is a feasible protective mechanism for the 5′-dAdo•that can allow selective X-H bond activation in both radical SAM and adenosylcobalamin enzymes. 2021-09-20T18:23:13Z 2021-09-20T18:23:13Z 2020-11-12T19:01:30Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/132589 en 10.1021/jacs.0c05590 Journal of the American Chemical Society Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Brown, AC Suess, DLM Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title | Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title_full | Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title_fullStr | Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title_full_unstemmed | Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title_short | Reversible Formation of Alkyl Radicals at [Fe<inf>4</inf>S<inf>4</inf>] Clusters and Its Implications for Selectivity in Radical SAM Enzymes |
| title_sort | reversible formation of alkyl radicals at fe inf 4 inf s inf 4 inf clusters and its implications for selectivity in radical sam enzymes |
| url | https://hdl.handle.net/1721.1/132589 |
| work_keys_str_mv | AT brownac reversibleformationofalkylradicalsatfeinf4infsinf4infclustersanditsimplicationsforselectivityinradicalsamenzymes AT suessdlm reversibleformationofalkylradicalsatfeinf4infsinf4infclustersanditsimplicationsforselectivityinradicalsamenzymes |