Synthetic Biology-Based Discovery of Diterpenoid Pyrones from the Genome of Eupenicillium shearii

Abstract

Diterpenoid pyrones are a type of mainly fungal meroterpenoid metabolite consisting of a diterpene connected to a pyrone, some of which show potent bioactivity. Through genome mining and heterologous expression, nine new diterpenoid pyrones, shearones A−I (1−9), were discovered from the fungus Eupenicillium shearii IFM 42152, and their biosynthetic enzyme activities were revealed. Some of these heterologously biosynthesized diterpenoid pyrones exhibited moderate antiaggregative ability against amyloid β42 in vitro.

Lysine-targeting inhibition of amyloid β oligomerization by a green perilla-derived metastable chalcone in vitro and in vivo

“…Pyrone moieties as Michael acceptors expanded from catechol structures can contribute to the suppression of Ab42 aggregation. 20,21 Repositioning warfarin with 2-pyrone to delay the nucleation phase of Ab42 through Michael addition is a promising approach to identify anti-AD drugs because warfarin is widely used as coagulant drug. 11 However, there have been no validation studies regarding whether small ligands covalently bind to brain Ab in the pathological condition of AD.…”

Structure-based engineering of α-ketoglutarate dependent oxygenases in fungal meroterpenoid biosynthesis

“…Finally, the engineered enzymes can be utilized in combinatorial biosyntheses in heterologous expression hosts such as Aspergillus oryzae, to produce pharmaceutically useful molecules, as demonstrated by the recent successful productions of unnatural novel diterpene fungal meroterpenoids. [64][65][66] Therefore, the discovery, engineering, and reconstitution of fungal meroterpenoid oxidation pathway will continue to provide important insight into natural product chemistry and enzymology, and will lead to the production of benecial drugs.…”

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

“…Fungal genomes contain a number of biosynthetic genes that are attractive targets for genome mining of novel natural products and biosynthetic enzymes [16][17][18]. In our research group, genome-guided exploration of fungal natural products and biosynthetic machineries have been conducted, leading to the discovery of various new natural products and enzymes [19][20][21][22][23][24][25][26][27]. Although fungal LRDs are a biologically and pharmaceutically important class of natural products including DNA polymerase α inhibitor aphidicolin [28] and a ribosome-targeting antibiotic pleuromutilin [29] (Figure 1), they remained as underexplored targets in genome-mining approaches.…”