Playing Molecular detectives: making an Alzheimer's drug by discovering new metabolic pathways in daffodils

Explained version of pre-print paper by Niraj Mehta, Yifan Meng, Richard Zare, Rina Kamenetsky-Goldstein, and Elizabeth Sattely

Paper: A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes

Background

Analogous to contemporary technologies like cryopreservation of oocytes or our smartphone’s rest mode, plants and use dormancy as a survival strategy that responds to environmental cues. As their name implies, geophytes like Daffodils are a group of plants that can store their resources underground or under water—in organs such as bulbs, tubers, corms, or rhyzomes—before re-germinating.

These plants tend to produce chemical toxins to defend their food reserves from herbivores, one example being the organosulfur flavor compounds produced by onion and garlic. Such compounds that are not absolutely essential for growth, reproduction and development are termed secondary metabolites. In plants, they are classified by their structure into phenolics (the most abundant type, like Resveratrol), terpenoids (some of which are phytohormones), alkaloids (contain nitrogen), glucosinolates (contain sulfur and nitrogen, derived from glucose).

Snapshot of selected secondary metabolites from a particular plant shows the broad set of popular apps that plants synthesize.

Diversity-oriented biosynthesis tells us how chemical diversity can be generated through iteration of the same precursors. This paper focuses on the set of >150 Amaryllidaceae alkaloids (AmA) that derive from a common precursor, 4-O’-methylnorbelladine (4OMN) through either of 3 pathways (p-o’, o-p’, or p-p’).

Even though the enzyme CYP96T1 has previously been identified for the p-p’ pathway, the enzymes for other pathways were not known until now. In his outstanding PhD thesis work, Niraj set out to uncover the full AmA pathway by:

1. Identifying where the AmA are actively being synthesized

2. Finding the key coupling enzymes through expression of the known ones in N. Benthamiana (Benthy for us)

3. Working backwards from the previous ‘clues’ to uncover the whole pathway, thus enabling the production of that Alzheimer’s drug in simpler organisms through synthetic biology

   

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