Until 2023

Bioprospecting of natural products in fungi

  • Synthetic biology
  • Molecular and functional genetics
  • Identification and expression of cryptic secondary metabolite gene clusters
  • Regulation of secondary metabolites

Natural products are an inestimable source of active compounds. Fungi have the capacity to produce very diverse spectra of chemicals that can be potentially used as therapeutics, or for biological control of plant pests. With the beginning of the genomic era, secondary metabolite biosynthetic pathways can be predicted by genome mining. These pathways can be isolated and heterologously expressed in amenable organisms to identify new metabolites. Such an approach is more powerful than stochastically trying to activate chemical biosynthesis in lab conditions.

The isolation and structure elucidation of new chemicals can be theoretically used to assign a function to these molecules and to understand their ecological meaning. This approach is not only suitable to increase knowledge about chemical diversity, but can be exploited to uncover the natural role of concealed secondary metabolites.

Head

Vito Valiante
Head

Microreactors

In cooperation with partners from the Leibniz Research Cluster we are building cell free biosynthetic systems. Enzymes responsible for specific reactions are isolated and purified, and subsequently immobilized on synthetic polymers. This cell free approach will be optimized in order to obtain complex active molecules starting from simple chemical units.

Cryptic gene clusters

Learning from Picornaviruses, we exploited 2A peptides to express entire biosynthetic pathways as single polycistronic genes. Assembling plasmids and read out systems were developed in order to efficiently screen transformed recipient organisms.

Cryptic gene clusters

Signalling pathways

Environmental changes are sensed by fungi and transduced via signal transduction pathways. Comparative studies highlighted that MAPKs, calmodulin/calcineurin, TOR and Ras/cAMP signalling pathways are well conserved in eukaryotic organisms. Our goal is to elucidate the meaning of signal transduction pathways for gene regulation.

Publications

Fischer J, Müller SY, Netzker T, Jäger N, Gacek-Matthews A, Scherlach K, Stroe MC, García-Altares M, Pezzini F, Schoeler H, Reichelt M, Gershenzon, Krespach MK, Shelest E, Schroeckh V, Valiante V, Heinzel T, Hertweck C, Strauss J, Brakhage AA (2018) Chromatin mapping identifies BasR, a key regulator of bacteria-triggered production of fungal secondary metabolites. eLife 7, e40969.
Hoefgen S, Lin J, Fricke J, Stroe MC, Mattern DJ, Kufs JE, Hortschansky P, Brakhage AA, Hoffmeister D, Valiante V (2018) Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi. Metab Eng 48, 44-51.
Manfiolli AO, de Castro PA, Dos Reis TF, Dolan S, Doyle S, Jones G, Riaño Pachón DM, Ulaş M, Noble LM, Mattern DJ, Brakhage AA, Valiante V, Silva-Rocha R, Bayram O, Goldman GH (2017) Aspergillus fumigatus protein phosphatase PpzA is involved in iron assimilation, secondary metabolite production, and virulence. Cell Microbiol 19(12),
Mattern DJ, Valiante V, Horn F, Petzke L, Brakhage AA (2017) Rewiring of the Austinoid Biosynthetic Pathway in Filamentous Fungi. ACS Chem Biol 12(12), 2927-2933.
Valiante V (2017) The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production. J Fungi 3(4), 68. (Review)
Valiante V, Mattern DJ, Schüffler A, Horn F, Walther G, Scherlach K, Petzke L, Dickhaut J, Guthke R, Hertweck C, Nett M, Thines E, Brakhage AA (2017) Discovery of an Extended Austinoid Biosynthetic Pathway in Aspergillus calidoustus. ACS Chem Biol 12(5), 1227-1234.
Weber J, Valiante V, Nødvig CS, Mattern DJ, Slotkowski RA, Mortensen UH, Brakhage AA (2017) Functional Reconstitution of a Fungal Natural Product Gene Cluster by Advanced Genome Editing. ACS Synth Biol 6(1), 62-68.
Bruder Nascimento AC, Dos Reis TF, de Castro PA, Hori JI, Bom VL, de Assis LJ, Ramalho LN, Rocha MC, Malavazi I, Brown NA, Valiante V, Brakhage AA, Hagiwara D, Goldman GH (2016) Mitogen activated protein kinases SakA (HOG1) and MpkC collaborate for Aspergillus fumigatus virulence. Mol Microbiol 100(5), 841-859.
Horn F, Linde J, Mattern DJ, Walther G, Guthke R, Scherlach K, Martin K, Brakhage AA, Petzke L, Valiante V (2016) Draft genome sequences of fungus Aspergillus calidoustus. Genome Announc 4(2), e00102-16.
Macheleidt J, Mattern DJ, Fischer J, Netzker T, Weber J, Schroeckh V, Valiante V, Brakhage AA (2016) Regulation and Role of Fungal Secondary Metabolites. Annu Rev Genet 50, 371-392. (Review)