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Title: An Aspergillus flavus secondary metabolic gene cluster containing a hybrid PKS-NRPS is necessary for synthesis of the 2-pyridones, leporins

item Cary, Jeffrey
item UKA, VALDET - Ghent University
item HAN, ZHENG - Ghent University
item BUYST, DIETER - Ghent University
item Harris Coward, Pamela
item EHRLICH, KENNETH - Retired ARS Employee
item Wei, Qijian - Mei Mei
item Bhatnagar, Deepak
item Dowd, Patrick
item MARTENS, STACEY - Northern Illinois University
item CALVO, ANA - Northern Illinois University
item MARTINS, JOSE - Ghent University
item VANHAECKE, LYNN - Ghent University
item COENYE, TOM - Ghent University
item DE SAEGER, SARAH - Ghent University
item DIANA DI MAVUNGU, JOSE - Ghent University

Submitted to: Fungal Genetics and Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/25/2015
Publication Date: 6/4/2015
Citation: Cary, J.W., Uka, V., Han, Z., Buyst, D., Harris-Coward, P.Y., Ehrlich, K.C., Wei, Q., Bhatnagar, D., Dowd, P.F., Martens, S., Calvo, A.M., Martins, J.C., Vanhaecke, L., Coenye, T., De Saeger, S., Diana Di Mavungu, J. 2015. An Aspergillus flavus secondary metabolic gene cluster containing a hybrid PKS-NRPS is necessary for synthesis of the 2-pyridones, leporins. Fungal Genetics and Biology. 81:88-97.

Interpretive Summary: Filamentous fungi produce a number of secondary metabolic compounds that have been shown to be both of great value (i.e. antibiotics and anti-hypercholesterolemics) and great harm (i.e. aflatoxins and trichothecenes). The genes responsible for producing a particular secondary metabolite are often clustered together on the chromosome. We have identified a secondary metabolic cluster in the fungus Aspergillus flavus and shown it is responsible for the production of a class of compounds termed leporins. We showed that leporins regulate production of survival structures termed sclerotia and also provide the fungus with increased resistance to insect predation. Therefore, leporins play an important role in the ability of the fungus to survive in the field and propagate. Additionally, this represents the first report of the ability of leporins to form a dimer as well as a trimer that is capable of binding iron. This suggests that leporins may also function in acquisition of iron from the environment.

Technical Abstract: The genome of the filamentous fungus, Aspergillus flavus, has been shown to harbor as many as 55 putative secondary metabolic gene clusters including the one responsible for production of the toxic and carcinogenic, polyketide synthase (PKS)-derived family of secondary metabolites termed aflatoxins. Of these secondary metabolic gene clusters only 2 contain a hybrid PKS-nonribosomal peptide synthetase (NRPS). One of these clusters is known to produce the indole tetramic acid, cyclopiazonic acid (CPA) while the product of the other cluster (#23) is unknown. Inactivation of a cluster 23 gene encoding a putative Zn(2)-Cys(6) transcription factor (LepE) resulted in downregulation of nine of the fifteen predicted cluster 23 genes thus allowing delineation of the cluster. Overexpression of lepE (OElepE) resulted in transformants displaying orange-red pigmented hyphae compared to the light beige hyphae of the isogenic control. Mass spectral analysis of A. flavus OElepE extracts identified a number of related 2-pyridones not detected in the isogenic control. These included the N-methoxy-2-pyridone, leporin A, its N-hydroxy- derivative, leporin B, and the previously unreported N-demethoxy-derivative, leporin C. High resolution mass spectrometry (HRMS) showed that both leporin B and C could form homodimers while leporin B could also form a trimer capable of chelating iron indicating a possible role of this metabolite in iron acquisition or storage.