Fungal genomes carry many gene clusters seemingly capable of natural product biosynthesis, yet most clusters remain silent. This places a major constraint on the conventional approach of cloning and transferring these genes in more amenable heterologous host for the natural product biosynthesis. One way to overcome the difficulty is to develop a method to activate the silent gene clustres within the context of the target fungus.Here, we accomplished activationg a silent polyketide-nonribosomal peptice (PK-NRP) biosynthetic gene cluster in Chaetomium globosum by overexpressing a transcriptional regulator found within the cluster from a plasmid. Elucidation of the isolated product by NMR techniques revealed a complex sturcture 1 ?including polyene moiety and L-tyrosine biosynthesized by the polyketide-nonribosomal peptide synthetase (PKS-NRPS). This strateg allowed us to isolate a new PK-NRP hybrid molecule and efficiently decipher its metabolic pathway. Through this exercise, we also discovered unexpected activities of the domains found in the PKS-NRPS. These results indicate that our approach would be valuable in isolating novel natural products and engineering analogs possessing comparable, if not more potent, bioactivity.

Production of a novel secondary metabolite by using a slient biosynthetic gene from <i>Chaetomium globosum</i>

247th National Meeting (2014)

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Production of a novel secondary metabolite by using a slient biosynthetic gene from Chaetomium globosum