TRIGEM · Unlocking Triterpenoid Structural Diversity and Bioactivity through Genome Mining

Unlocking Triterpenoid Structural Diversity and Bioactivity through Genome Mining

Plants produce myriads of bio-active small molecules/ natural products (NPs) (e.g. terpenoids), yet the diversity and bio-activity of plant NPs are still largely untapped and access to bio-active NPs remains challenging. The triterpenoids are one of the largest and most structurally complex plant natural products (NPs). They are widespread in the Plant Kingdom and have a huge array of structures and numerous associated biological activities. They have important roles in plant defence and signalling. They are also exploited by humans as food supplements, drugs and cosmetics across various sectors.2 In the past the discovery and production of triterpenoids has relied mainly on isolation from extracts of natural resources and subsequent structural elucidation and chemical synthesis. These methods suffer from low efficiency and high cost, and are not environmentally sustainable. We undertake a greener and more sustainable but as yet largely unexplored synthetic biology-based approach that involves genome mining and metabolic engineering to synthesise structural variants of triterpenoids, with a view to discovering novel structures with biological activities for various potential applications in a rapid manner. This project will lead to discovery of novel bioactive triterpenoids that can potentially be developed into commercial products to benefit the society. It will shed new light on the biosynthetic pathways of triterpenoids by uncovering new genes and enzymes, opening up opportunities for production of important triterpenoids via further metabolic manipulation in plant-based ‘green factories’ or in microbes. The overall objectives of TRIGEM are as follows: 1. To mine for triterpene genes encoding novel TCC, CYP and other tailoring enzymes. The 15 new TTC/CYP genes referred to above are already available for use in this project. We will also mine the sequenced genomes of other plants that produce bioactive triterpenoids to augment this resource, focusing on genes that are physically clustered and so likely to be functionally connected. 2. To functionally analyse the selected coding sequences with predicted functions in triterpene synthesis by expressing them in yeast and N. benthamiana. 3. To identify new compounds generated by heterologous expression of these selected genes by GC-MS or LC-MS as appropriate. Novel compounds will be isolated by chromatography and their structures determined by NMR. 4. To evaluate the bioactivities of isolated compounds using readily available assay models such as cytotoxicity and standard antifungal assays and other commercially available models.

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