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bioRxiv · 10.1101/2024.08.27.609176

Early steps of the biosynthesis of the anticancer antibiotic pleurotin

Weaver, J. A.·Alkhder, D.·Prasongpholchai, P.·Tadesse, M. D.·de los Santos, E. L. C.·Song, L.·Corre, C.·Alberti, F.
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Abstract

Pleurotin is a meroterpenoid specialised metabolite made by the fungus Hohenbuehelia grisea, and it is a lead anticancer molecule due to its irreversible inhibition of the thioredoxin-thioredoxin reductase system. Total synthesis of pleurotin has previously been achieved, including through a stereoselective route, however its biosynthesis has not been characterised. In this study, we used isotope-labelled precursor feeding to show that the non-terpenoid quinone ring of pleurotin and its congeners is derived from phenylalanine. We sequenced the genome of the pleurotin-producing fungus and used comparative transcriptomics to identify putative genes involved in pleurotin biosynthesis. Additionally, the heterologous expression of a UbiA-like prenyltransferase from H. grisea resulted in the isolation and characterisation of the first predicted pleurotin biosynthetic intermediate, 3-farnesyl-4-hydroxybenzoic acid. This work sets the foundation to fully elucidate the biosynthesis of pleurotin and its congeners, with long-term potential to optimise their production for therapeutic use and engineer the pathway towards the biosynthesis of valuable analogues.

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Weaver, J. A., Alkhder, D., Prasongpholchai, P., Tadesse, M. D., de los Santos, E. L. C., Song, L., Corre, C., Alberti, F.. 2024-08-27. Early steps of the biosynthesis of the anticancer antibiotic pleurotin. https://doi.org/10.1101/2024.08.27.609176

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