Angew. Chem. Int. Ed., published online 12 September 2011, doi: 10.1002/anie.201104488

Fungi produce a diverse pool of secondary metabolites, but genome sequencing analysis has revealed that fungi have far more silent biosynthetic gene clusters than active ones. Recent studies have uncovered mechanisms that induce cryptic biosynthetic gene clusters and thus offer approaches for identifying new natural products. Scherlach et al. now identify the pheofungins, a new class of natural products from Aspergillus nidulans. The authors generated A. nidulans strains with mutations in protein N-acetyltransferases, which acetylate the N terminus of many eukaryotic proteins. A strain containing a mutation in the gene nidulans N-acetyltransferase B (nnaB) had a red-orange color in culture, unlike the typically yellow wild-type strains. Metabolic profiling of the ΔnnaB strain revealed that it produces a variety of phenolic carboxylic acids based on orsellinic acid and a series of red compounds. Characterization of this compound class, which the authors termed pheofungins, revealed that they contain a fused benzopyran-benzothiazinone scaffold that has not previously been seen in fungi but shares structural similarities to pheomelanins, a class of pigments found in red human hair and bird feathers. Profiling experiments revealed that pheofungin biosynthesis requires orsellinic acids and cysteine. Though its biological function remains unclear, pheofungin production is triggered by intracellular stress induced by defective N-terminal protein acetylation, suggesting that targeting other post-translational modifications is most likely a promising route for natural product discovery.