Project
Biosynthesis and bioengineering of novel bacterial benzolactone enamide anti-cancer agents
The oximidines are unusual macrocyclic metabolites that were recently identified from Pseudomonas baetica bacteria and shown to have potent anti-cancer activity. They belong to the benzolactone enamide family of natural products, which inhibit tumor cell proliferation by selectively targeting mammalian vacuolar-type ATPases. Identification and analysis of the oximidine biosynthetic gene cluster has revealed a hybrid polyketide-nonribosomal peptide assembly line with a highly unusual architecture that catalyzes several unprecedented transformations, including O-methyloxime incorporation, diene isomerisation, hydroxybenzoic acid formation and a complex series of oxidative transformations. This project aims to investigate the fascinating oximidine biosynthetic pathway and elucidate the catalytic mechanisms of the enzymes responsible for the highly unusual transformations. It also aims to exploit this knowledge for biosynthetic pathway engineering aimed at generating novel benzolactone anti-cancer agents and constructing novel-to-nature hybrid assembly lines capable of producing pharmaceutically-important molecules.