Comprehensive Understanding and Engineering of Fungal Xanthone Biosynthesis
DescriptionXanthone is a tricyclic organic compound with the molecular formula C13H8O2, and a great number of natural products with the xanthone scaffold have been isolated from microorganisms and plants. Naturally occurring xanthones comprise structurally diverse molecules with a wide range of biological activities and thus have provided promising leads for drug development. The wide occurrence and biological importance of xanthones have inspired researchers to investigate the biosynthesis of xanthones, but the biosynthesis of even a single xanthone natural product has yet to be fully elucidated, despite the intensive biosynthetic studies over the past few decades. Thus, biosynthetic studies on xanthones would facilitate our understanding of the xanthone biosynthesis and provide opportunities to exploit the biosynthetic knowledge to create novel xanthones with improved biological functions. Meanwhile, the applicant has recently identified the biosynthetic genes for the fungal xanthone heterodimer, neosartorin, inAspergillus novofumigatus,and partially elucidated the late-stage biosynthesis of the compound by a series of gene deletion experiments. Yet, there remain several ambiguities in the biosynthesis of neosartorin, which include how the xanthone skeleton is generated and the enzymes involved therein. This project aims to elucidate the molecular basis for the fungal xanthone biosynthesis in a comprehensive manner and to bioengineer the metabolic pathways to afford novel, useful xanthones. To achieve the abovementioned goals, the complete biosynthetic pathway of neosartorin will be initially elucidated to provide a first example in which a fungal xanthone pathway is fully described at a genetic/enzymatic level. As the applicant’s previous study has proposed a biosynthetic pathway leading to neosartorin, the proposed pathway will be examined by the heterologous reconstitution of the biosynthesis. Furthermore, selected enzymes will be purified forin vitroenzymatic reactions and biochemical characterizations to obtain in-depth insight into the neosartorin biosynthesis. Next, the biosynthesis of structurally related but somewhat different natural products will be investigated, which would identify the key enzymes that contribute to the structural diversification of fungal xanthones. Finally, attempts will be made to construct synthetic metabolic pathways to provide a series of new xanthones by combining biosynthetic genes from different fungal genomes. To this end, an efficient system to construct diverse pathways will also be developed. Collectively, this project will provide not only a comprehensive image of the fungal xanthone biosynthesis and enzymes responsible for chemically intriguing reactions but also a new methodology in which we can utilize accumulating genomic data to synthesize useful molecules.
|Effective start/end date||1/01/20 → …|