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This enzyme has a promising biotechnological application in modified yeast strains to produce medicinal alkaloids, an alternative to the traditional opium poppy harvest. A generative machine learning software based on AlphaFold was used to build the structure of CYP76AD1 since there are no structural data for this specific enzyme. After model validation, l-Tyr was docked in the active site of CYP76AD1 to assemble the reactive complex, whose catalytic distances remained stable throughout the 100 ns of MD simulation. Subsequent QM\/MM calculations elucidated that l-Tyr hydroxylation occurs in two steps: hydrogen abstraction from l-Tyr by CpdI, forming an l-Tyr radical, and subsequent radical rebound, corresponding to a rate-limiting step of 16.0 kcal\u00b7mol\u20131. Our calculations suggest that the hydrogen abstraction step should occur in the doublet state, while the radical rebound should happen in the quartet state. The clarification of the reaction mechanism of CYP76AD1 provides insights into the rational optimization of the biosynthesis of alkaloids to eliminate the use of opium poppy.<\/jats:p>","DOI":"10.1021\/acs.jpcb.4c05209","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T07:35:56Z","timestamp":1724657756000},"page":"9447-9454","source":"Crossref","is-referenced-by-count":3,"title":["QM\/MM Study of\nthe Reaction Mechanism of\n                    <scp>L<\/scp>\n                    \u2011Tyrosine Hydroxylation\nCatalyzed by the Enzyme CYP76AD1"],"prefix":"10.1021","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4915-4946","authenticated-orcid":true,"given":"Joa\u0303o\nP. M.","family":"Sousa","sequence":"first","affiliation":[{"name":"Faculdade de Cie\u0302ncias Universidade do Porto , , Rua do Campo Alegre, s\/n , ,","place":["Porto, Portugal, 4169-007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7554-8324","authenticated-orcid":true,"given":"Maria J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Faculdade de Cie\u0302ncias Universidade do Porto , , Rua do Campo Alegre, s\/n , ,","place":["Porto, Portugal, 4169-007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-4722","authenticated-orcid":true,"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Faculdade de Cie\u0302ncias Universidade do Porto , , Rua do Campo Alegre, s\/n , ,","place":["Porto, Portugal, 4169-007"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"2026081805143797500_cit1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00425-014-2056-8","article-title":"Benzylisoquinoline alkaloid biosynthesis in opium poppy","volume":"240","author":"Beaudoin","year":"2014","journal-title":"Planta"},{"issue":"6","key":"2026081805143797500_cit2","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1007\/s11101-019-09644-w","article-title":"Benzylisoquinoline\nalkaloid biosynthesis in opium poppy: an update","volume":"18","author":"Singh","year":"2019","journal-title":"Phytochem. 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