Understanding Secondary Metabolite Biosynthesis as the Key to Unlock New Chemical Diversity in Fungi – from Viridicatumtoxin to the Immunosuppressive Neosartoricin
The advancement of DNA sequencing technology has unlocked an unprecedented amount of microbial genomic information. These genome sequences also revealed a large number of secondary metabolite (SM) genes in both bacteria and fungi. For filamentous fungi in particular, the number of SM gene clusters encoded in the genome are often beyond the number of compounds that are reported for individual species. This is likely attributed to the tight regulation of the SM genes by the eukaryotic fungi compared to their prokaryotic counterparts, where some SM genes are only expressed in the presence of appropriate environmental signals. Research is currently going on to uncover new methods to activate these "silent" gene clusters. However, at the same time, continuously expanding our understanding of the relationship between SM compounds, the biosynthetic genes and microbial ecology will assists us in navigating the exponentially expanding seas of genomic information in the search for new bioactive compounds. The past four years, I have been involved in the elucidation of the SM pathways for viridicatumtoxin, griseofulvin, tryptoquialanine, cytochalasins, lovastatins, echinocandin, fumagilin and azaphilones. A specific example is given here on how the investigation into the genes and enzymes involved in the biosynthesis of an interesting molecule, viridicatumtoxin, eventually leads to the discovery of a new immunosuppressive compound, neosartoricin, from the human pathogens Aspergillus fumigatus and Neosartorya fischeri.