Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids

• Published in: Angewandte Chemie International Edition Vol. 59; no. 52; pp. 23772 - 23781
• Main Authors: Mitsuhashi, Takaaki, Barra, Lena, Powers, Zachary, Kojasoy, Volga, Cheng, Andrea, Yang, Feng, Taniguchi, Yoshimasa, Kikuchi, Takashi, Fujita, Makoto, Tantillo, Dean J., Porco, John A., Abe, Ikuro
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 21.12.2020; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Biosynthetic Pathways - genetics; Catalytic activity; Chemistry; Chemistry, Multidisciplinary; chemoenzymatic synthesis; Combinatorial analysis; combinatorial biosynthesis; Complexity; crystalline-sponge x-ray diffraction; Drug development; Fungi; Fungi - chemistry; meroterpenoid cyclase; meroterpenoids; Natural products; NMR; Nuclear magnetic resonance; Physical Sciences; Quantum chemistry; Science & Technology; Substrates; Terpenes - chemistry; PATHWAYS; chemoenzymatic synthesis; TERRETONIN BIOSYNTHESIS; meroterpenoid cyclase; PENICILLIUM SP FO-3929; ACYL-COA; IDENTIFICATION; combinatorial biosynthesis; GENE-CLUSTER; DIPHOSPHATE SYNTHASE; A-D; INHIBITORS; crystalline-sponge x-ray diffraction; meroterpenoids; CYCLIZATION
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202011171

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 which 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. Fungal meroterpenoid cyclases, a recently discovered family of membrane‐integrated terpene cyclases, have been exploited as tools for the synthesis of second generation meroterpenoid natural products. The results demonstrate a broad substrate tolerance leading to several new meroterpenoid scaffolds. DFT calculations provided insights into the mechanism of enzyme‐mediated polyene cyclizations.