University of Southern California
Natural products (secondary metabolites) are an abundant source of bioactive compounds. These small molecules play substantial roles in modern drug development. Aspergillus, a member of filamentous fungi, can produce a range of natural products. This genus has been known for a long time for its medical and commercial importance. In recent years, the genomes of several species of the genus Aspergillus have been fully sequenced. Surprisingly, the genome sequence data reveal that the number of putative secondary metabolite pathways largely overtake the number of natural products that have been isolated and identified from Aspergillus. This discrepancy is a result of the fact that most biosynthetic genes remain silent under standard laboratory culture conditions. The sequence data of A. nidulans along with the development of efficient gene targeting approaches in this specie greatly facilitate the investigation of secondary metabolite biosynthesis. The work presented herein demonstrates the power of a combination of bioinformatics, molecular gene targeting and natural product chemistry approaches in secondary metabolite biosynthesis research. The study subjects include the biosynthesis of emericellamides and austionl/dehydroaustionl in A. nidulans. In addition, epigenetic regulation in activating silent secondary metabolites was also described herein, as deletion of cclA which encodes a crucial component of the COMPASS protein complex, a chromatin modifier, in A. nidulans, led to the discovery of several secondary metabolites.