Recent developments in the engineered biosynthesis of fungal meroterpenoids

Beilstein J Org Chem. 2024 Mar 13:20:578-588. doi: 10.3762/bjoc.20.50. eCollection 2024.


Meroterpenoids are hybrid compounds that are partially derived from terpenoids. This group of natural products displays large structural diversity, and many members exhibit beneficial biological activities. This mini-review highlights recent advances in the engineered biosynthesis of meroterpenoid compounds with C15 and C20 terpenoid moieties, with the reconstruction of fungal meroterpenoid biosynthetic pathways in heterologous expression hosts and the mutagenesis of key enzymes, including terpene cyclases and α-ketoglutarate (αKG)-dependent dioxygenases, that contribute to the structural diversity. Notable progress in genome sequencing has led to the discovery of many novel genes encoding these enzymes, while continued efforts in X-ray crystallographic analyses of these enzymes and the invention of AlphaFold2 have facilitated access to their structures. Structure-based mutagenesis combined with applications of unnatural substrates has further diversified the catalytic repertoire of these enzymes. The information in this review provides useful knowledge for the design of biosynthetic machineries to produce a variety of bioactive meroterpenoids.

Keywords: enzyme engineering; fungal meroterpenoids; synthetic biology; terpene cyclases; αKG-dependent dioxygenases.

Publication types

  • Review

Grants and funding

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grant Number JP21H02636 and JP22H05123), AMED (Grant Number JP21ak0101164) from Japan Science and Technology Agency, The Naito foundation, Nagase Science Technology Foundation, Yamada Science foundation, and The Mitsubishi Foundation.