Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

Abstract

A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.

Branching and converging pathways in fungal natural product biosynthesis

“…12) [89, A methylated analogue of TAL (97), 5-methyl TAL (105), is often found in fungal meroterpenoid structures, and in recent years, the complete biosynthetic pathways of several 5-methyl TAL-derived meroterpenoids have been revealed (Fig. 13) [91][92][93]. In the biosynthesis of setosusin ( 106), 105 undergoes a series of reactions similar to those in TAL-derived meroterpenoid pathways to provide a precyclized intermediate 107, which is accepted by the terpene cyclase SetH to give 108 with a tricyclic terpenoid portion [93].…”

Heterologous production of cyanobacterial compounds

“…When developed, these heterologous hosts can be suitable platforms for structural diversification by precursor-directed biosynthesis, mutasynthesis and combinatorial biosynthesis (Cummings et al., 2019 ; Dhakal & Sohng, 2017 ; Yan et al., 2018 ), expanding the applications of discovered cyanobacterial NPs. Moreover, many synthetic biology approaches can facilitate the development of multivariate combinational setups to further expand structural diversity (Tsukada et al., 2020 ). We anticipate that the above approaches will lead to the discovery of significantly more new cyanobacterial NPs and analogs for broad applications in the coming years.…”

The Chemical Ecology Approach to Reveal Fungal Metabolites for Arthropod Pest Management

“…Heterologous expression of BGC of decalin-containing diterpene pyrones (DDPS) of several entomopathogenic and phytopathogenic fungi and genes responsible for their chemical modification in Aspergillus oryzae made it possible to obtain 22 DDPS, of which 15 were new. Some of them (subglutinol A and two new DDPS) showed insecticidal activity against the fruit fly D. melanogaster [ 258 ].…”