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Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)\u2010peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)Fe\n                    <jats:sup>III<\/jats:sup>\n                    (O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \u22c5)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4\u2010nitroindole, the product analogous to that obtained with TxtE. Moreover,\n                    <jats:sup>15<\/jats:sup>\n                    N and\n                    <jats:sup>18<\/jats:sup>\n                    O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings.\n                  <\/jats:p>","DOI":"10.1002\/anie.202409430","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T13:14:33Z","timestamp":1722518073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-1970","authenticated-orcid":false,"given":"Pritam","family":"Mondal","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Alabama  Tuscaloosa AL 35487 United States"},{"name":"Current address: Department of Chemical Sciences Indian Institute of Science Education and Research, Mohali  Punjab 140306 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhilanka","family":"Udukalage","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Alabama  Tuscaloosa AL 35487 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abubaker A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN United Kingdom"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik P. H.","family":"Wong","sequence":"additional","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN United Kingdom"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2620-8788","authenticated-orcid":false,"given":"Sam P.","family":"de Visser","sequence":"additional","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  131 Princess Street Manchester M1 7DN United Kingdom"},{"name":"Department of Chemical Engineering The University of Manchester  Oxford Road Manchester M13 9PL United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7609-6406","authenticated-orcid":false,"given":"Gayan 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no spectral evidence for the formation of any reaction intermediates for example heme ferric peroxynitrite could be observed even at \u2212135\u2009\u00b0C in 2-methyl-THF solvent; see Figure\u2005S4."},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja904832j"},{"key":"e_1_2_7_67_1","unstructured":"Such a six-coordinate heme complex would encompass a low-spin FeIIIcenter which spin couples with \u22c5NO to result in an overall diamagnetic system."},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/ic902157z"},{"key":"e_1_2_7_69_1","unstructured":"\u00a0"},{"key":"e_1_2_7_70_2","unstructured":"Similar nitroindole yields were also observed when 1\u2005equiv of NO(g)was utilized by means of NO(g)solubilized in THF solvent;"},{"key":"e_1_2_7_71_2","unstructured":"We note here thatN-nitroindoles exhibit impaired stabilities and therefore their calculated yields could be less than actual reaction yields."},{"key":"e_1_2_7_72_1","unstructured":"Please see Supporting Information for characterization details on all the nitroindole products. Note that these results should be viewed within the caveat that NO(g)is present in excess under these conditions."},{"key":"e_1_2_7_73_1","unstructured":"Direct reactivity of peroxynitrite anions with indoles with and without the presence of ferric heme did not yield any nitroindole products."},{"key":"e_1_2_7_74_1","unstructured":"Our computational findings suggest that the formation of heme nitrate is highly favorable under these conditions."},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c00253"},{"key":"e_1_2_7_76_1","unstructured":"\u00a0"},{"key":"e_1_2_7_77_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00568"},{"key":"e_1_2_7_78_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0474620"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja9801036"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja980507y"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1039\/b607680g"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-079X.2000.290308.x"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c04542"},{"key":"e_1_2_7_84_1","unstructured":"In support when indole concentrations are increased up to ten-fold nitroindole yields are increased only by modest amounts (i.e. 2\u2009a: 10\u2009%;2\u2009a\u2032: 9\u2009%) and the total yields still remain below 50\u2009%."},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1142\/S108842461550025X"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.6064\/2012\/683729"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr0006627"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c11068"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.9b01273"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201600739"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202101878"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpca.5b12311"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP00794F"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.1c04029"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202409430","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202409430","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/anie.202409430","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202409430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T09:42:37Z","timestamp":1771148557000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202409430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,30]]},"references-count":94,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2024,12,2]]}},"alternative-id":["10.1002\/anie.202409430"],"URL":"https:\/\/doi.org\/10.1002\/anie.202409430","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,30]]},"assertion":[{"value":"2024-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202409430"}}