Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides

• Published in: Nature chemistry Vol. 7; no. 9; pp. 737 - 743
• Main Authors: Asai, Teigo, Tsukada, Kento, Ise, Satomi, Shirata, Naoki, Hashimoto, Makoto, Fujii, Isao, Gomi, Katsuya, Nakagawara, Kosuke, Kodama, Eiichi N., Oshima, Yoshiteru
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2015; Nature Publishing Group
• Subjects: 639/638/403/349; Analytical Chemistry; Aspergillus oryzae - enzymology; Benzopyrans - chemistry; Biochemistry; Biological Products - chemistry; Biological Products - metabolism; Biosynthesis; Chaetomium - metabolism; Chemistry; Chemistry/Food Science; Fungi - metabolism; Indolequinones - biosynthesis; Indolequinones - chemistry; Indoles - chemistry; Indoles - metabolism; Inorganic Chemistry; Metabolites; Organic Chemistry; Physical Chemistry; Pigments, Biological - chemistry; Polyketide Synthases - genetics; Polyketide Synthases - metabolism; Polyketides - chemistry; Polyketides - metabolism
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2308

The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho -quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates. The complexity and diversity of natural product structures make them an ideal starting point for the creation of chemical libraries. Now it is shown that a semi-synthetic process can combine heterologous expression of a multipotent biosynthetic intermediate with multiple non-enzymatic steps to produce libraries of pseudo-natural products.