October 2026 TPJ Editor choice: Two roads to galanthamine turn out to be one

Two roads to galanthamine turn out to be one

by Charlay Wood

Research Highlight on: Lamichhane B., Niraula A., Merindol N., Gélinas S.-E., Lagüe P., Ricard S., Germain H. & Desgagné-Penix I. (2026) A Golgi-localized N-methyltransferase and reversible aldo–keto reductases coordinate dual terminal routes in galanthamine biosynthesis. The Plant Journal, 126(6), e70910.

Galanthamine is a plant-derived alkaloid licensed for the symptomatic treatment of Alzheimer’s disease and is produced naturally only by species within the Amaryllidoideae subfamily  Chemical synthesis is possible, but the drug is still extracted mainly from cultivated plants such as daffodils and summer snowflake (Leucojum aestivum), so an alternative route to production would be valuable. That prospect depends on knowing how the pathway ends, and its final steps have long been contested.

Two terminal routes were proposed (Figure 1A): reduction to norgalanthamine followed by N-methylation or N-methylation to narwedine followed by reduction. What remained missing was direct evidence that nornarwedine could be methylated in planta, leaving the field divided over which enzymes acted and in what order.

Lamichhane et al. (2026) set out to settle the matter. Mining the L. aestivum transcriptome, they compared three candidate methyltransferases: LaNMT, characterised previously, and two homologues of γ-tocopherol methyltransferases, LaTMT1 and LaTMT2. LaTMT2, the most active, methylated both nornarwedine and norgalanthamine, while three aldo–keto reductases (LaAKR1–3) interconverted the two redox pairs (Figure 1B). A single methyltransferase can therefore feed either route, and reversible reduction links the two branches. They found that L. aestivum leaf extracts could convert nornarwedine into narwedine, norgalanthamine and galanthamine.

Corresponding author Isabel Desgagné-Penix recalls the point at which the picture changed: “We began to realize that both routes might coexist when we saw that the AKRs could accept intermediates from both proposed pathways and that LaTMT2 could also N-methylate intermediates from both routes. At that point, it became difficult to argue that one pathway was right and the other wrong.” The decades-old either/or, it turned out, was the wrong question.

The most unexpected finding was where that methylation happens. Confocal imaging of EGFP fusions transiently expressed in Nicotiana benthamiana placed LaTMT2 in the Golgi apparatus, whereas LaNMT was cytosolic and partly associated with the endoplasmic reticulum, and LaTMT1 was targeted to plastids. Where within the Golgi LaTMT2 sits, and whether its products move on to the vacuole, remain open questions.

LaTMT2 turns over nornarwedine faster than norgalanthamine, favouring methylation before reduction without making it obligatory, while the reductases pull in opposite directions: LaAKR3 favours the reductive reactions and LaAKR1 the oxidative ones. The two routes therefore behave as one system, whose balance, the authors suggest, may depend on substrate supply and redox state. Desgagné-Penix sees metabolism less as a straight line than as “water finding its way to the ocean: there may be several routes, some preferred, some used only under particular conditions, but all providing possibilities.”

This complexity may also help explain why galanthamine remains difficult to produce efficiently on demand: N. benthamiana leaves co-expressing LaTMT2 with LaAKR3, when supplied with nornarwedine, produced only 0.078 ng of galanthamine per mg fresh weight. On raising production, Desgagné-Penix puts understanding first: “We should not only ask how to make plants produce more for us. We should first ask what the plant can teach us about how and why these molecules are made.” The study closes one long-standing gap while opening another: how to reproduce not only the necessary reactions, but also the spatial and biochemical organisation that makes them work in the plant.  In resolving the two roads to galanthamine, it offers a clearer view of how plants really build their chemistry.