A study of biosynthesis of the polyketide polivione in Penicillium frequentans using 13C-, 2H-, and 18O-labelled precursors

Abstract

The biosynthesis of polivione (5), a metabolite of Penicillium frequentans, has been studied using ¹³C-, ²H-, and ¹⁸O-labelled precursors. Analysis of the labelled products by both n.m.r. and mass spectrometry suggests that polivione [and probably citromycetin (1) and fulvic acid (3)] is formed via a naphthalene intermediate having the same carbon skeleton as fusarubin (9). Incorporation of [1,2-¹³C₂]acetate resulted in compound (5) which contained seven intact acetate units arranged in a pattern consistent with that observed for citromycetin (1). Deuterium from CD₃CO₂Na was incorporated only in the starter methyl group and in the methine position of the aryl ring. The polivione produced after incorporation of [1-¹³C,1-¹⁸O₂]acetate showed isotopically shifted peaks in its ¹³C n.m.r. spectrum at C-7, C-9, and C-11, showing that ¹⁸O was retained at those sites. Significantly, there was no evidence that ¹⁸O was retained at the other two carboxy-derived sites, C-2 or C-4. The oxygens at C-4, C-12, and C-14 were shown to be derived from ¹⁸O₂ gas by the presence of isotopically shifted peaks in the ¹³C n.m.r. spectrum of polivione produced after incorporation of this precursor. Detailed pathways are proposed for the production of citromycetin (1), fulvic acid (3), and polivione (5) from a common polyketide precursor.