The biosynthetic origin of pyripyropene A (1) was studied by feeding sodium [1-13C]-, [2-13C]-, and [1,2-13C2]acetates, D,L-[2-13C]mevalonolactone, and [carboxy-14C]nicotinic acid to the producing organism Aspergillus fumigatus FO-1289-2501. 13C NMR and degradation experiments of 13C- and 14C-labeled 1 established that 1 is derived from three mevalonates, five acetates, and one nicotinic acid. The biosynthetic scheme for 1 proposes that (1) a pyridino-α-pyrone moiety is produced via condensation of a primer nicotinic acid with two acetates in a 'head-to-tail' fashion, (2) an all-trans farnesyl pyrophosphate is produced via the mevalonate pathway, (3) the two parts are linked and cyclized to form the core skeleton, and (4) then three acetyl residues from acetates are introduced into the skeleton to yield 1. This is the first demonstration that an intact nicotinic acid works as an acyl primer unit for oligoketide formation in fungal secondary metabolites.
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