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Nonetheless, its exact mechanism of action still remains unclear. This work presents the first NOS model system where biologically proposed heme superoxo and peroxo intermediates are assessed as active oxidants against oxime substrates. Markedly, heme peroxo intermediates engaged in a bioinspired oxime oxidation reaction pathway, converting oximes to ketones and nitroxyl anions (NO<jats:sup>\u2212<\/jats:sup>). Detailed thermodynamic, kinetic, and mechanistic interrogations all evince a rate\u2010limiting step primarily driven by the nucleophilicity of the heme peroxo moiety. Coherent with other findings, <jats:sup>18<\/jats:sup>O and <jats:sup>15<\/jats:sup>N isotope substitution experiments herein suffice compelling evidence toward a detailed mechanism, which draw close parallels to one of the enzymatic proposals. Intriguingly, recent enzymatic studies also lend credence to these findings, and several relevant reaction intermediates have been observed during NOS turnover.<\/jats:p>","DOI":"10.1002\/anie.202211521","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T15:07:02Z","timestamp":1664377622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Role of Heme Peroxo Oxidants in the Rational Mechanistic Modeling of Nitric Oxide Synthase: Characterization of Key Intermediates and Elucidation of the Mechanism"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-1970","authenticated-orcid":false,"given":"Pritam","family":"Mondal","sequence":"first","affiliation":[{"name":"Department of Chemistry and O'Neal Comprehensive Cancer Center University of Alabama at Birmingham  Birmingham AL 35205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-1908","authenticated-orcid":false,"given":"Izumi","family":"Ishigami","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Albert Einstein College of Medicine  The Bronx NY 10461 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9858-386X","authenticated-orcid":false,"given":"Syun\u2010Ru","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Albert Einstein College of Medicine  The Bronx NY 10461 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7609-6406","authenticated-orcid":false,"given":"Gayan B.","family":"Wijeratne","sequence":"additional","affiliation":[{"name":"Department of Chemistry and O'Neal Comprehensive Cancer Center University of Alabama at Birmingham  Birmingham AL 35205 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9500500"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400415k"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00074"},{"key":"e_1_2_7_5_1","unstructured":"\u00a0"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2013.11.009"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep35169"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-016-1412-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14533"},{"key":"e_1_2_7_10_1","unstructured":"\u00a0"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.31727"},{"key":"e_1_2_7_12_2","first-page":"318087","volume":"21","author":"V\u00edte\u010dek J.","year":"2012","journal-title":"Mediators Inflamm."},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1039\/C3CS60467E"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b10498"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c11068"},{"key":"e_1_2_7_16_1","first-page":"6304851","volume":"2019","author":"Liao W.","year":"2019","journal-title":"BioMed Res. 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When the reaction between [(TPP)FeIII(O22\u2212)]\u2212and1\u2009ewas quenched at different time points product yields were evidenced to increase with respect to the reaction time before plateauing (Figure\u2005S30). This is in strong agreement with the measured reaction rates."},{"key":"e_1_2_7_89_1","unstructured":"In the absence of PPh3 there is some evidence for the formation of {FeTPP-NO}7as a minor product (see Figure\u2005S31). 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