Biosynthesis of the fungal metabolite tenellin

Abstract

This thesis concerns the biosynthesis of tenellin, a bright yellow secondary metabolite of the fungus Beauveria bassiana. Several putative intermediates have been synthesised and feeding experiments performed in order to provide some insight into the biosynthetic pathway. Tenellin was originally thought to be formed from the condensation of phenylalanine and a polyketide moiety, however recent studies have now shown that tyrosine is the more direct amino acid precursor. The biosynthesis is proposed to occur by rearrangement of tyrosine to 3-amino-2-(4-hydroxy)-phenylpropionic acid, in a similar manner to the rearrangement observed in alkaloid biosynthesis. The synthesis of this β- amino acid is described and the subsequent incorporation study using labelled material discussed. The result argues against the intermediacy of this compound in the biosynthesis of tenellin. Consequently, it is proposed that the biosynthesis of tenellin does not include the rearrangement of tyrosine, but instead proceeds via a five membered teframic acid, which is considered to undergo rearrangement and ring expansion to generate the pyridone ring of tenellin. The putative acyl tetramic acid precursor is synthesised and administered to cultures of Beauveria bassiana. Preliminary (^2)H NMR spectra indicate a possible incorporation and that the tetramic acid has a role in tenellin biosynthesis. Further analysis by HPLC and LCMS is described. The biosynthetic origin of H-6 of tenellin has never been established. Several experiments, including the synthesis of [2-(^2)H]-tyrosine, are described, but the origin of this proton remains unclear.