Evolution and function of cis-/trans elements of fungal secondary metabolism with emphasis on the penicillin biosynthesis
AXEL A. BRAKHAGE
Abteilung für Molekulare und Angewandte Mikrobiologie
Leibniz-Institut für
Naturstoff-Forschung und Infektionsbiologie
Hans-Knöll-Institut und Lehrstuhl für Mikrobiologie und Molekularbiologie
Friedrich-Schiller-Universität Jena
Beutenbergstraße 11a
D-07745 Jena
Axel.Brakhage@hki-jena.de
www.hki-jena.de
Up to now, the greatest progress in elucidation of the molecular regulation of the biosynthesis of a fungal secondary metabolite has been made in the penicillin-producer Aspergillus (Emericella) nidulans. We could identify several trans-acting factors: AnCF is a CCAAT-binding complex which is composed of three proteins designated HapB, HapC and HapE. AnBH1 is a transcription factor, whose binding site overlaps with the AnCF-binding site in the promoter of the penicillin biosynthesis gene aatA. During the ongoing project, an additional regulator, velvet A, involved in the penicillin biosynthesis was isolated. Velvet A is a light-dependent protein that acts as a repressor of the penicillin biosynthesis. This data indicates that also light is of importance for the biosynthesis of secondary metabolites. Besides external signals such as pH, light and carbon source transmitted via different transcription factors, internal signals regulate the penicillin biosynthesis. The influence of such signals on the transcription factors AnCF and AnBH1 has been analysed to understand the regulatory network in which the penicillin biosynthesis is integrated. We showed that protein kinase C (PkcA1) is involved in the regulation of AnBH1 and the penicillin biosynthesis. The physiological meaning of protein kinase C in filamentous fungi has not been understood yet, however, it is conceivable that this protein kinase senses cellular integrity. Furthermore, AnCF is regulated by both the redox status via thioredoxin and HapX, a protein involved in iron-regulation. The discovery of these two novel regulatory circuits predicts that penicillin is maximally produced under reducing conditions and when sufficient iron is available. Both oxidative conditions and iron limitation should lead to reduced secondary metabolism production. Taken together, these analyses will help to get a complete picture of the cis/trans elements involved in the regulation of the biosynthesis of a fungal secondary metabolite. Moreover, experiments are under way to proof the hypothesis of horizontal gene transfer of ß-lactam biosynthesis genes and the recruitment of regulators.
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