Aspergillus nidulans: a Model for Elucidation ofAspergillus fumigatusSecondary Metabolism

This chapter reviews the contributions made by Aspergillus nidulans to the understanding of fungal secondary metabolism and the ways in which advances in our understanding of this species have spurred parallel studies of Aspergillus fumigatus. The most thorough insight into fungal secondary metabolite regulation has arisen from studies of the mycotoxin sterigmatocystin (ST) and the antibiotic penicillin in A. nidulans. With possibly the exception of the penicillin metabolic cluster, the most thoroughly examined fungal secondary-metabolite gene clusters are those involved in mycotoxin biosynthesis, particularly the aflatoxin (AF) and ST biosynthetic clusters found in several Aspergillus spp. Coordinate regulation is largely explained by transcriptional control by pathway-specific regulatory factors (e.g., aflR) and global regulatory proteins including transcription factors mediating environmental signals (pH, carbon, and nitrogen) and the cluster-specific methylase, LaeA. Specific oxylipins, e.g., various prostaglandins, are ligands to G-protein-coupled receptors (GPCR), which are important in inflammatory and immune responses in mammals. Interestingly, recent studies have identified three A. nidulans GPCR that impact asexual and sexual spore production, and efforts are under way to determine if Ppo products may be potential ligands for these receptors. PGs, along with leukotrienes, comprise a class of oxylipins called eicosanoids formed from C20 fatty acids (dihomo-γ-linolenic acid, arachidonic acid, and eicosanopentaenoic acid). Initial studies of laeA and ppo function in A. fumigatus indicate a potent role for these secondarymetabolite genes in pathogenesis. A thorough understanding of the function of these and other secondary metabolism genes may assist in the development of future therapeutics.