Broadening the Chemical Space of Fungal Meroterpenoids and the Enzymatic Repertoire for Their Biosynthesis

Project: Research

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 Meroterpenoids are a class of naturally occurring, hybrid organic compounds (natural products), which are biosynthesized in part through terpenoid pathways. The hybrid nature of meroterpenoids contributes significantly to their structural diversity and broad biological activities. Although meroterpenoids are ubiquitously distributed in nature, those derived from fungi exhibit the greatest diversity. Therefore, the biosynthesis of fungal meroterpenoids has been intensively studied over the past few years. Despite this, there remain many structurally intriguing fungal meroterpenoids for which the biosynthetic pathways have not been characterized. Biosynthetic investigations into these unexplored molecules would broaden the repertoire of enzymes that can be harnessed for unusual chemical transformations. Additionally, the ever-increasing number of characterized biosynthetic genes and the rapid accumulation of genome sequences implies that new and useful molecules can be obtained efficiently by thoroughly exploiting the available genetic information. The proposed project aims to (i) discover novel enzymologies in fungal meroterpenoid pathways, (ii) obtain new meroterpenoids by activating cryptic gene clusters, and (iii) construct artificial biosynthetic pathways to synthesize “unnatural” natural products. To achieve the goals described above, the biosynthesis of two analogous fungal natural products, setosusin and brevione E, will be initially investigated by heterologously reconstituting the respective biosynthetic pathways, as both compounds display unique structural features. The enzymes responsible for constructing these intriguing molecular architectures will be biochemically characterized to outline the plausible reaction mechanisms. Next, attempts will be made to obtain new fungal meroterpenoids using genome mining and biosynthetic engineering approaches. To this end, a new methodology that allows for the rapid and efficient reconstitution of fungal natural product biosynthesis will be established. Using this methodology, uncharacterized gene clusters found in publicly available genome sequences will be heterologously expressed to enable the discovery of unreported fungal meroterpenoids. The methodology will also be used to create synthetic metabolic pathways involving biosynthetic genes from different sources, which could expand the chemical space of fungal meroterpenoids.  Collectively, the proposed project will uncover novel enzymatic mechanisms underlying the fungal meroterpenoid pathways and will generate several new molecules, some of which might have potent biological activities. The methodology that will be developed herein may be widely applicable in biosynthetic studies on fungal natural products, thus furthering our efforts to engineer the biosynthesis of such molecules.    


Project number9043185
Grant typeGRF
Effective start/end date1/01/22 → …