Surprising Enzyme Uncovered in Iridoid Synthesis

Iridoids are a widespread and evolutionarily historic class of plant secondary metabolites belonging to the terpenes. They happen in hundreds of plant species and play an vital function in protection and different interactions between vegetation and their setting. Iridoids are additionally present in meals similar to olives and blueberries, and are believed to have anti-inflammatory properties. They are additionally important precursors for a lot of medically vital compounds, together with the most cancers drug vinblastine and the ipecacuanha alkaloids discovered within the medicinal vegetation, sage-leaved alangium and ipecac root. Despite their significance, the biosynthetic pathway had not but been absolutely elucidated. The essential step of cyclisation to nepetalactol — the essential construction of all iridoids — was nonetheless lacking.

Sarah O’Connor, head of the Natural Product Biosynthesis Department on the Max Planck Institute for Chemical Ecology in Jena, has been researching this biosynthetic pathway for over 15 years. ‘Enzymes that may kind the iridoid skeleton have been identified for a very long time. These iridoid synthases produce small quantities of nepetalactol and huge quantities of by-products concurrently. We due to this fact lengthy suspected that the essential cyclisation response might happen spontaneously, with out the assistance of one other enzyme. However, later experiments, together with these on catnip (see press launch How mint became catmint, May 14, 2020), supplied proof that cyclisation is catalyzed by an enzyme. Nevertheless, we had no thought what such an enzyme would possibly appear to be,’ says Sarah O’Connor, explaining the place to begin of the analysis. As it was not attainable to slender the search all the way down to particular enzyme courses, a whole lot of attainable candidates would usually have needed to be examined for exercise. However, due to a collaboration with Robin Buell from the University of Georgia (USA), a brand new dataset grew to become accessible that proved essential in narrowing down the variety of candidates.

Generated by Robin Buell’s laboratory utilizing state-of-the-art strategies, this dataset included gene expression in particular person ipecac cells, relatively than in numerous tissues as in a beforehand compiled dataset. Comparing the 2 datasets revealed that solely a really small variety of unknown genes correlated with the expression of the identified iridoid biosynthesis genes in each datasets. This small quantity enabled fast testing for exercise, which was carried out by grasp’s scholar Chloée Tymen. For one among these unknown genes, the researchers have been capable of reveal that the cyclisation response is catalyzed when it’s expressed in vegetation or micro organism. This confirmed that this gene encodes the long-sought cyclase. Comparing the amino acid sequence of the cyclase with sequences from hundreds of plant species in public databases revealed that the enzyme happens exactly in plant species that kind iridoids. ‘We have been capable of present that the response we investigated is certainly catalyzed by the enzyme and that the anticipated substance, nepetalactol, is fashioned.’ However, to our shock, the enzyme we discovered belongs to a totally surprising class of enzymes. This class of enzymes is thought for catalyzing a totally completely different response,” explains Maite Colinas, group chief in Sarah O’Connor’s division and first creator of the research.

The mechanistic means of cyclisation continues to be unclear. There are alternative ways during which a cyclization can happen chemically, and it isn’t but identified by means of which of the attainable chemical response mechanisms the found cyclisation proceeds. It can be unclear how the cyclisation perform evolutionary developed from a totally completely different enzyme response. These questions are the topic of additional investigation.

“Thanks to our discovery, we now know all the enzymes necessary for iridoid biosynthesis. This paves the way for the future biotechnological production of previously inaccessible forms of iridoids and other valuable medical compounds,” Maite Colinas.

The discovery of the cyclase vital for iridoid formation exhibits as soon as once more that enzymes can catalyze fully surprising reactions that can’t be predicted by bioinformatic strategies. This enzyme paves the best way for future biotechnological manufacturing of nepetalactol and its derivatives, such because the anti-cancer medication vinblastine and vincristine, in yeast, fungi, or different plant species.

Reference: Colinas M, Wood TC, David JC, et al. Discovery of iridoid cyclase completes the iridoid pathway in asterids. Nat Plants. 2025. doi: 10.1038/s41477-025-02122-6

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