A Global Regulator of Secondary Metabolism Gene Clusters

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

Filamentous fungi are unique organisms - rivaled only by Actinomycetes and plants - in producing a wide range of natural products called secondary metabolites. These compounds often have obscure or unknown functions in the producing organism but have tremendous importance to humankind in that they display a broad range of useful pharmaceutical activities as well as less desirable phyto- and mycotoxic activities. Insight into the molecular and cellular regulation of fungal secondary metabolism has come largely from studies of sterigmatocystin and penicillin in the genetic model Ascomycete Emericella nidulans (i.e. Aspergillus nidulans). Efforts on deciphering regulatory conduits of sterigmatocystin biosynthesis have been particularly insightful in revealing the complexity of secondary metabolite regulation. Like most fungal secondary biosynthetic genes, the biosynthetic genes of sterigmatocystin are clustered and their transcription requires activity of the sixth gene in the cluster, aflR encoding a sterigmatocystin-specific C2H6 transcription factor. aflR is both transcriptionally and post-transcriptionally regulated by members of a G protein/cAMP/protein kinase A signal transduction pathway. The focus of this project is a gene, laeA (for loss of aflR expression), that is regulated by protein kinase A and required for aflR transcription. LaeA appears be a novel protein methyltransferase that regulates not only expression of ST biosynthetic genes but also PN biosynthetic genes. This research will explore the hypothesis that LaeA is a global regulator of secondary metabolism gene clusters. Broader Impacts: This project will involve training of graduate students. The outcome of this research will be applicable to several fields of biology. These include diverse fields as food safety, agricultural and pharmaceutical sciences, ecology and pathology.