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Various enzymes in nature are involved in the biosynthesis of an isonitrile group in biomolecules. Thus, the\n                    <jats:italic>mycobacterial<\/jats:italic>\n                    Rv0097 isonitrilase reacts the terminal Gly residue in a protein chain through successive oxidative desaturation and decarboxylation steps to form an isonitrile substituent. To find antibacterial treatments against\n                    <jats:italic>Mycobacteria<\/jats:italic>\n                    it is important to understand the unique biosynthesis processes in the organism and hence a computational study was performed. To gain insight into the details of the mechanism and the order of the reaction steps, we performed a comprehensive computational study that included molecular dynamics and quantum chemical calculations. The MD simulation shows tight binding of the substrate inside the active site and a highly rigid protein fold that keeps the product from the first cycle bound. Subsequent large QM cluster calculations explored various possible pathways and mechanisms. The work shows that the reaction steps happen in a specific order with an initial desaturation prior to decarboxylation to prevent side reactions such as substrate hydroxylation. The substrate binding pocket holds and positions the substrate tightly to trigger a regioselective N\u2500H hydrogen transfer to guide the reaction to desaturation. In a second cycle with another molecule of dioxygen and \u03b1\u2010ketoglutarate a hydrogen atom abstraction followed by decarboxylation leads to the isonitrile\u2010containing product.\n                  <\/jats:p>","DOI":"10.1002\/chem.71694","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:05:59Z","timestamp":1789394759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of Isonitrilase, a Nonheme Iron Decarboxylase Involved in the Biosynthesis of the Isonitrile Group in Peptides: A Computational Study"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6658-3331","authenticated-orcid":false,"given":"Chengxu","family":"Zhu","sequence":"first","affiliation":[{"name":"Manchester Institute of Biotechnology The University of Manchester  Manchester UK"},{"name":"Department of Chemical Engineering The University of Manchester  Manchester 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