Exploiting the potential of meroterpenoid cyclases to expand the chemical space of fungal meroterpenoids
Files
Accepted manuscript
Date
2020-09-15
Authors
Abe, Ikuro
Mitsuhashi, Takaaki
Barra, Lena
Powers, Zachary
Kojasoy, Volga
Cheng, Andrea
Yang, Feng
Taniguchi, Yoshimasa
Kikuchi, Takashi
Fujita, Makoto
Version
Accepted manuscript
OA Version
Citation
Ikuro Abe, Takaaki Mitsuhashi, Lena Barra, Zachary Powers, Volga Kojasoy, Andrea Cheng, Feng Yang, Yoshimasa Taniguchi, Takashi Kikuchi, Makoto Fujita, Dean J Tantillo, John A Porco. 2020. "Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids.." Angew Chem Int Ed Engl, https://doi.org/10.1002/anie.202011171
Abstract
Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results, together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.