Nature’s medicine cabinet: alkaloid biosynthesis breakthrough may plant seed for drug discovery

A step forward in our understanding of how plants produce alkaloids could herald new pharmaceuticals. 

Biologists from the University of York (UK) have discovered enzymes that catalyze the biosynthesis of alkaloids in a number of plant species. In doing so, they have identified a surprising similarity to bacteria and potentially opened the door to novel ways of making medicines.

Plant alkaloids are specialized, nitrogen-containing metabolites derived from amino acids, which can be incorporated in a symmetric or nonsymmetric manner. The compounds typically have strong pharmacologic activity, making up a key part of plants’ chemical arsenals, and as such, have great therapeutic potential. Common examples include nicotine, caffeine and morphine.

Casting light on the biosynthesis of alkaloids can boost the production of valuable pharmaceuticals; however, to date, no enzymes responsible for nonsymmetric alkaloid biosynthesis have been described.

This new research changes that. While investigating the biosynthesis of the alkaloid securinine in a plant called Flueggea suffruticosa, researchers discovered an enzyme capable of catalyzing an early step in this process: the nonsymmetric formation of piperideine from lysine.

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Transcriptomic analysis and enzyme characterization, including mutagenesis and isotope labeling, identified the enzyme encoded by F. suffruticosa gene 1864 (Fs1864). It’s part of the ornithine/lysine/arginine decarboxy-oxidase family, which is usually associated with prokaryotes.

The researchers demonstrated that enzymes in this family are widespread in plants, hinting that they repeatedly emerged through parallel evolution.

“Plants and bacteria are really different forms of life, and so it really was a surprise to see that this significant plant chemical was being driven from a bacterial-like gene,” commented Benjamin Lichman, an author on the study. “We think that this means plants ‘recycle’ biological tools that are more commonly found in microbes, when they can be useful to them. Even more interesting was that this gene makes securinine in a completely different way from other well-known plant chemicals.”

The team then used phylogenetics to investigate other plant species, identifying orthologs of Fs1864 in Nicotiana tabacum and Artemisia annua.

Their research introduces a new class of eukaryotic decarboxylase enzymes, capable of the nonsymmetric formation of alkaloids, which not only broadens our understanding of how plants grow and survive, but could inspire new therapeutic approaches.

“Alkaloids can be toxic, so when we use them in medicines they have to be highly controlled and often modified, so understanding the process that goes into making alkaloids can help us develop new methods for producing them in the lab or removing them to make some plants less toxic,” Lichman added.

“Now that we know how to look for this chemical production, and that we can find it in more plants than we originally thought, we have new avenues to explore for the production and discovery of safe drugs.”