News - December 22, 2018

Anticancer compound biosynthesis cracked

Roelof Kleis

Wageningen researchers have figured out the complete biosynthesis of kauniolide. This compound is used in drugs to fight cancer.

© Marc Willems

Kauniolide is one of the so-called sesquiterpenes, a large class of compounds (more than 4000 have been described) that are found in plants. Kauniolide belongs to a group of compounds that are effective against cancer, parasites and bacteria. But until now it was not known how kauniolide is formed in nature. Wageningen plant scientists and chemists have now jointly managed to figure out that path. The study is recently published in Nature Communications.

The search began with feverfew (Tanacetum parthenium), explains plant physiologist Sander van der Krol. Five years ago, PhD candidate Qing Liu managed to find the gene that plays a decisive role in the biosynthesis of kauniolide. Qing inserted the gene in a tobacco plant and demonstrated that it then produced kauniolide. Which was conclusive proof. But what does the protein involved, a P450 protein, actually do in chemical terms?

Twee reactiestappen verenigd in het zelfde enzym. Dat maakt het zo uniek
Maurice Franssen

To answer that question, organic chemist Maurice Franssen was brought on board. He is an expert on sesquiterpenes and how plants produce those compounds. Franssen was ‘amazed’ when he was presented with the case of the P450 protein, kauniolide synthase. ‘I immediately realized how special that protein was. Normally, P450 proteins add an oxygen atom to an organic compound. This one does that too, but then removes it again!’

‘Two reaction steps combined in the same enzyme,’ he continues enthusiastically. ‘There are hundreds of such enzymes but none that can do this. That makes it so unique.’ What is more, Qing’s study fits seamlessly with work done by previous PhD candidates of Franssen who tried to decipher the biosynthesis of compounds similar to kauniolide. The chemical steps for which the new enzyme is the catalyst were already predicted by one of those PhD candidates in 1996.

Franssen then figured out the chemical process. The protein operates in successive steps to eventually produce kauniolide’s typical ring structure. ‘A great example of One Wageningen research,’ says Franssen. The study has been published in Nature Communications. Van der Krol: ‘Once you have the basic skeleton, you can use other P450 enzymes to modify it to produce new variants of kauniolide that could be even more effective as medication.’