Signals that effectively communicate environmental information are required for development in bacteria and fungi. Different {dollar}gamma{dollar}-butyrolactone compounds have been demonstrated to act as microbial signaling factors in bacterial Streptomyces species, regulating the developmental conversion from primary to secondary metabolism and inducing both morphological and physiological changes in the host organism. Butyrolactone I ({dollar}alpha{dollar}-oxo-{dollar}beta{dollar}-(p-hydroxyphenyl)-{dollar}gamma{dollar}-(p-hydroxy-m-3,3-dimethylallyl-benzyl)-{dollar}gamma{dollar}-methoxycarbonyl-{dollar} gamma{dollar} butyrolactone) is produced as a secondary metabolite by Aspergillus terreus and has been shown to be a potent inhibitor of the eukaryotic cyclin-dependent kinases. In this present work, the effects of butyrolactone I on the producing organism were examined, particularly with respect to changes in morphology, sporulation and secondary metabolism. Increases in hyphal branching with a decrease in average hyphal growth unit were evident after butyrolactone I treatment. Submerged sporulation increased up to three-fold upon addition of butyrolactone I. Effects on secondary metabolism were also observed, as the addition of butyrolactone I to growing A. terreus cultures advanced the timing of secondary metabolism by approximately ten hours. Addition after growth had slowed and secondary metabolism had started resulted in a two to three-fold increase in secondary metabolite production. During the transition to secondary metabolism, differential protein phosphorylations occur in A. terreus. The addition of PP1/PP2A serine/threonine phosphatase inhibitors to both wildtype reisolate and lovastatin-overproducing cultures resulted in a dose-dependent increase in secondary metabolite production. The addition of a serine/threonine kinase inhibitor, staurosporine, to the same cultures resulted in a decrease in secondary metabolite production. Taken together, these findings indicate that butyrolactone I induces differentiation in A. terreus and enhances secondary metabolite production. In addition, these findings suggest that a serine/threonine kinase(s) plays a positive role in regulating secondary metabolite production.
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