Imitation is the sincerest form of flattery: reconstructing the biosynthesis of montbretin A

People have been using plant extracts as medicine for thousands of years. In the 19th century, plants entered the laboratory as a rich source of compounds for modern drug discovery and development. At present, a countless number of essential medicines, from aspirin to chemotherapy drugs, are synthetic versions of plant chemicals. A common first step in drug development is screening of natural compounds for the desired activity. But identifying the compound is just the beginning: often, it is necessary to uncover each step of the biochemical pathway that delivers the compound before recreating it in the laboratory. In this issue of The Plant Journal, Irmisch et al. (2019) report on the characterization of the biosynthesis pathway of a potential medicine for treating diabetes. Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin (a hormone that regulates blood sugar levels), or when the body cannot use insulin effectively. Due, in large part, to sugar-rich diets and lack of physical exercise, diabetes incidence is on the rise, and is rising more rapidly in middle- and low-income countries.. The World Health Organization estimates that diabetes was the 7th leading cause of death. Current drugs for treating diabetes reduce blood sugar levels by inhibiting the pancreatic alpha-amylase (HPA), which cleaves complex starches into smaller sugars, and alpha-glucosidases, which convert these sugars into glucose in the gut. However, the inhibition of alpha-glucosidases causes undigested sugars to end up in the lower bowel, leading to uncomfortable side effects. Hoping to find a better treatment alternative, Tarling et al. (2008) screened a repository of 30 000 biological extracts when searching for novel HPA inhibitors. They found a highly specific and potent inhibitor in the acylated flavonol glycoside montbretin A (MbA), extracted from the African ornamental Iris montbretia (Crocosmia × crocosmiiflora, see its beautiful flowers here). MbA’s anti-diabetes properties were tested with promising results in rats (Yuen et al., 2016). However, scientists soon discovered that scaling up MbA production in planta would be impossible: only the developing corms (underground bulb-like structures) of montbretia plants produce MbA, in small amounts, during a short window of time in early summer. In a chance meeting, Stephen Withers, the Chemistry professor who first discovered and characterized MbA, bumped into Joerg Bohlmann in the hallways of the University of British Columbia (Vancouver, Canada) and shared the exciting discovery and his predicament. Bohlmann is a professor in the Michael Smith Laboratories at the University of British Columbia and senior author in the study. From this chance encounter, the idea of investigating MbA biosynthesis was born. The project is funded by GlycoNet, a Canadian glycomics research network focused on human health. Sandra Irmisch, first author in the paper, is a post-doctoral Humboldt fellow in the Bohlmann laboratory. According to Irmisch, their biggest obstacle was figuring out when and where MbA is produced. This information was essential to create transcriptomic resources in which the genes of interest were expressed. At first, they assumed – as MbA is present in corms throughout the year – that biosynthesis is active all the time. It took the group about a year of closely monitoring the plants’ annual developmental cycle to realize that biosynthesis only occurs in a narrow window of time. With this information at hand, the authors are applying a combined approach that includes transcriptomics, cDNA cloning, enzyme characterization, and heterologous expression in tobacco to establish the steps in the biosynthesis of MbA, as well as the genes that encoded each enzyme. Last year, they described the first three steps (Irmisch et al., 2018), from the flavonol myricetin to the MbA precursor ‘mini-MbA’. Their new study describes the steps from mini-MbA to MbA, as well as the cloning and characterization of the gene encoding the enzyme responsible for the gluosylation of mini-MbA, the UDP-dependent glucosyltransferase CcUGT3 (see Figure 1). Heterologous expression of CcUGT3 alongside the genes for myricetin and mini-MbA biosynthesis in tobacco validated its function in planta. Now that they have discovered the sequence of MbA assembly, and four out of the six genes involved, the authors plan to resolve the two remaining uridine glucuronosyltransferases (UGTs). Once there is a complete enzymatic toolbox available, the next step will be to engineer MbA biosynthesis into a heterologous system such as yeast. This work will provide the foundation for engineering a system for large scale production of a potential anti-diabetes drug.

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