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Elucidating its biosynthetic pathway is essential for strategies aimed at enhancing production through metabolic engineering. Galanthamine derives from the metabolic precursor 4\u2032\u2010\n                    <jats:italic>O<\/jats:italic>\n                    \u2010methylnorbelladine, which undergoes cytochrome P450\u2010mediated para\u2013ortho\u2032 C\u2010C phenol coupling to yield nornarwedine. Two competing terminal routes have been proposed: (i) reduction of nornarwedine to norgalanthamine, followed by\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylation, or (ii)\u00a0\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylation of nornarwedine to narwedine prior to reduction. Here, we identify three aldo\u2013keto reductase (AKR) candidates (\n                    <jats:italic>La<\/jats:italic>\n                    AKR1,\n                    <jats:italic>La<\/jats:italic>\n                    AKR2, and\n                    <jats:italic>La<\/jats:italic>\n                    AKR3) and three\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methyltransferase (NMT) candidates from\n                    <jats:italic>Leucojum aestivum<\/jats:italic>\n                    :\n                    <jats:italic>La<\/jats:italic>\n                    NMT, homologous to coclaurine N\u2010methyltransferase\u2010like (NMT\u2010like), and two \u03b3\u2010tocopherol methyltransferases (TMT) homologs,\n                    <jats:italic>La<\/jats:italic>\n                    TMT1 and\n                    <jats:italic>La<\/jats:italic>\n                    TMT2. Subcellular localization studies revealed distinct compartmentalization, with\n                    <jats:italic>La<\/jats:italic>\n                    NMT targeted to the ER\u2010cytosol,\n                    <jats:italic>La<\/jats:italic>\n                    TMT1 to plastids, and\n                    <jats:italic>La<\/jats:italic>\n                    TMT2 to the Golgi apparatus.\n                    <jats:italic>In vitro, La<\/jats:italic>\n                    TMT2 methylated both nornarwedine and norgalanthamine, with a kinetic preference for nornarwedine.\n                    <jats:italic>La<\/jats:italic>\n                    TMT1 methylated \u03b3\u2010tocopherol to \u03b1\u2010tocopherol (vitamin E). All three AKRs catalyzed reversible interconversions between nornarwedine and norgalanthamine, and between narwedine and galanthamine, with\n                    <jats:italic>La<\/jats:italic>\n                    AKR3 favoring the reduction reaction whereas\n                    <jats:italic>La<\/jats:italic>\n                    AKR1 the oxidation reaction. These findings identify\n                    <jats:italic>La<\/jats:italic>\n                    TMT2 and\n                    <jats:italic>La<\/jats:italic>\n                    AKRs as key branch\u2010enabling enzymes, reconcile long\u2010standing models of galanthamine biosynthesis, and provide a strategic target for metabolic engineering strategies to enhance galanthamine production.\n                  <\/jats:p>","DOI":"10.1111\/tpj.70910","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T22:14:44Z","timestamp":1782598484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Golgi\u2010localized N\u2010methyltransferase and reversible aldo\u2013keto reductases coordinate dual terminal routes in galanthamine biosynthesis"],"prefix":"10.1111","volume":"126","author":[{"given":"Basanta","family":"Lamichhane","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics and Forensic Science Universit\u00e9 du Qu\u00e9bec \u00e0 Trois\u2010Rivi\u00e8res  Trois\u2010Rivi\u00e8res Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Niraula","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics and Forensic Science Universit\u00e9 du Qu\u00e9bec \u00e0 Trois\u2010Rivi\u00e8res  Trois\u2010Rivi\u00e8res Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-6465","authenticated-orcid":false,"given":"Natacha","family":"Merindol","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics and Forensic Science Universit\u00e9 du Qu\u00e9bec \u00e0 Trois\u2010Rivi\u00e8res  Trois\u2010Rivi\u00e8res Qu\u00e9bec 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