The long term goals of this research are to determine if any intracellular molecules function as global regulators of fungal secondary metabolism. Studies will directly determine the effects of regulators on production of sterigrnatocystin and penicillin in A. nidulans.
A complex and fascinating aspect of fungal development is the production of natural products, or secondary metabolites. These compounds - thought to provide fitness attributes to the producing organism - have tremendous importance to man in that they display a broad range of useful antibiotic and immunosuppressant activities as well as less desirable phyto- and mycotoxic activities. Many refined and informative studies have elucidated the unique biochemistry leading to natural product formation in fungi but, until recently, the molecular genetics of fungal secondary metabolism has lagged behind the biochemistry. In the last few years, however, significant progress has been made in cloning and characterizing the metabolic genes of several fungal natural products such as the mycotoxins sterigrnatocystin and ariatom and the antibiotic penicillin. Examination of the results of these studies have shown that secondary metabolism is regulated in a growth dependent manner. This latter characteristic is of extreme importance as it genetically validates the physiological and biochemical studies which have correlated morphological differentiation-typically sporulation - to alterations in secondary metabolism in the fungi. This validation was achieved by using Aspergillus nidulans to elucidate intmcellular signals that regulate several differentiation processes in the fungus. The signals, members of a heterotrimeric G protein signaling pathway, are required for sporulation and sterigrnatocystin biosynthesis in A. nidulans. Furthermore, the same heterotrimeric G protein signaling pathway is required for A. parasit~'cus sporulation and ariatoxin production.This provides evidence for the mainte/uance of conserved genetic mechanisms governing fungal differentiation processes. - The possibility of conserved regulatory signals for fungal development is a very exciting prospect that will be addressed in this project. Results from this study should help in controlling of production of both desired secondary metabolites (like penicillin) and undesired secondary metabolites (like sterigmatocystin and ariatoxin).