Genome Mining and Comparative Biosynthesis of Meroterpenoids from Two Phylogenetically Distinct Fungi

Abstract

Two homologous meroterpenoid gene clusters consisting of contiguous genes encoding polyketide synthase (PKS), prenyltransferase (PT), terpenoid cyclase (TC) and other tailoring enzymes were identified from two phylogenetically distinct fungi through computational analysis. Media optimization guided by reverse‐transcription PCR (RT‐PCR) enabled two strains to produce eight new and two known meroterpenoids (1–10). Using gene inactivation, heterologous expression, and biochemical analyses, we revealed a new polyketide‐terpenoid assembly line that utilizes a pair of PKSs to synthesize 2,4‐dihydroxy‐6‐alkylbenzoic acid, followed by oxidative decarboxylation, farnesyl transfer, and terpene cyclization to construct the meroterpenoid scaffold. In addition, two of the isolated meroterpenoids (3 and 17 d) showed immunosuppressive bioactivity. Our work reveals a new strategy for meroterpenoid natural products discovery, and reveals the biosynthetic pathway for compounds 1–10.

Absolute Configuration of Bioactive Azaphilones from the Marine-Derived Fungus Pleosporales sp. CF09-1

“…In recent years, fungi inhabiting marine environments have attracted widespread attention for their ability to produce bioactive natural products with diverse structures . Additionally, it has been proven by genomic analyses that many secondary metabolite biosynthetic gene clusters in marine-derived fungi can be transcriptionally suppressed under certain cultivation conditions. − Using different conditions, including varying the period of cultivation, the composition of the culture medium, and temperature, is a popular approach to activate these gene clusters to generate new bioactive structures . In the course of our previous efforts to discover bioactive natural products from marine sources, an azaphilone derivative with an aromatic A-ring, was isolated from the marine-derived fungus Pleosporales sp.…”

Peculiarities of meroterpenoids and their bioproduction

“…Arthripenoid A (11), a 6/6/6/6-tetracyclic ring system from Arthrinium sp., has shown antimicrobial, cytotoxic, and immunosuppressive activities (Han et al 2020;Long et al 2019;Zhang et al 2018b). Atn cluster consisting of highly reducing polyketide synthase (HR-PKS), non-reducing polyketide synthase (NR-PKS), prenyltransferase, and terpenoid cyclase was found to be involved in the biosynthesis of arthripenoids.…”