{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T11:02:53Z","timestamp":1761562973335,"version":"build-2065373602"},"reference-count":66,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"National Funds through FCT\/MCTES- Portuguese Foundation for Science and Technology","doi-asserted-by":"publisher","award":["UIDB\/50006\/2020","SFRH\/BD\/144205\/2019"],"award-info":[{"award-number":["UIDB\/50006\/2020","SFRH\/BD\/144205\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["UIDB\/50006\/2020","SFRH\/BD\/144205\/2019"],"award-info":[{"award-number":["UIDB\/50006\/2020","SFRH\/BD\/144205\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics\/Molecular Mechanics (QM\/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale.<\/jats:p>","DOI":"10.3390\/molecules28114265","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T07:00:02Z","timestamp":1684825202000},"page":"4265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Rational Engineering of (S)-Norcoclaurine Synthase for Efficient Benzylisoquinoline Alkaloids Biosynthesis"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4915-4946","authenticated-orcid":false,"given":"Jo\u00e3o P. M.","family":"De Sousa","sequence":"first","affiliation":[{"name":"LAQV\/REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto, Rua do Campo Alegre, s\/n, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-7844","authenticated-orcid":false,"given":"Nuno C. S. A.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto, Rua do Campo Alegre, s\/n, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-4722","authenticated-orcid":false,"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto, Rua do Campo Alegre, s\/n, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1007\/s11101-019-09644-w","article-title":"Benzylisoquinoline Alkaloid Biosynthesis in Opium Poppy: An Update","volume":"18","author":"Singh","year":"2019","journal-title":"Phytochem. 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