A wealth of previously undescribed plant enzymes have been discovered by an international team of scientists led by the John Innes Centre, in which bioinformatics experts of Wageningen University took part. The team who uncovered the compounds hope that harnessing the power of these enzymes will unlock a rich new vein of natural products, including potential drug leads.
The research, published today in PNAS reveals new insights into the bio-production of sesterterpenoids, a rare and largely unexplored class of bio-chemicals. Prior to this work the majority of the approximately 1,000 known sesterterpenoids had been found in terrestrial fungi and marine sponges, with only 60-70 from plants.
Previously, very little was known about how these compounds were made. A handful of enzymes that make sesterterpenoids had been discovered in fungi, but the enzymes that make plant sesterterpenoids were largely unknown. The team led by Professor Anne Osbourn used genome mining technology to uncover a suite of enzymes, called sesterterpene synthases by searching the genomes of 55 different plant species.
The team of Marnix Medema, bioinformatics expert at Wageningen University & Research, was part of the international consortium and co-authored the article in PNAS. They drove the computational genome mining aspects of the work, through customization of an algorithm, ‘plantiSMASH’, which Medema’s team had recently developed. PlantiSMASH aims to facilitate automated identification of natural product biosynthetic pathways in genome sequences.
Medema: "This work shows that computational genome mining is a highly effective tool to uncover novel chemistry, even in model organisms like Arabidopsis. Moreover, the associated phylogenetic analysis helps us to understand how these molecules have evolved.”
Professor Osbourn adds: "What's fascinating is that the enzymes from plants are quite different to those from fungi, but in some cases they make similar molecules. It looks as though plants have independently arrived at their own way of making these molecules; they have 'worked it out for themselves'."
The next step is to widen the search for genes that encode plant sesterterpene synthases in order to get a fuller picture of the spectrum of chemical diversity of sesterterpenoids in other plant species, and to harness these enzymes to make compounds that can be evaluated for use as new drugs and medicines.
The project will continue to use transient plant expression technology developed by Professor George Lomonossoff at the John Innes Centre, in which plants can be used to produce a range of pharmacologically active proteins. Osbourn continues: "This is a flagship paper in terms of uncovering a swathe of new enzymes in plants to make chemicals that have never been accessed before."
This work, which is funded by the US-based National Institutes of Health (NIH) as part of the Genomes to Natural Products Network, was carried out in a collaboration of researchers of the John Innes Centre, the University of Cambridge in the UK, the University of California, Davis (US) and Wageningen University & Research in the Netherlands.