Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Jia Tang; Yudai Matsuda

doi:10.1038/s41467-024-48771-7

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Jia Tang, Yudai Matsuda^*

^*Corresponding author for this work

Department of Chemistry

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

12 Citations (Scopus)

36 Downloads (CityUHK Scholars)

Abstract

Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in the field of genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped natural products from numerous available genome sequences. In this study, we developed a fungal genome mining tool that extracts BGCs encoding enzymes that lack a detectable protein domain (i.e., domainlessenzymes) and are not recognized as biosynthetic proteins by existing bioinformatic tools. We searched for BGCs encoding a homologue of Pyr4-family terpene cyclases, which are representative examples of apparently domainlessenzymes, in approximately 2000 fungal genomes and discovered several BGCs with unique features. The subsequent characterization of selected BGCs led to the discovery of fungal onoceroid triterpenoids and unprecedentedonoceroid synthases. Furthermore, in addition to the onoceroids, a previously unreported sesquiterpene hydroquinone, of which the biosynthesis involves aPyr4-family terpene cyclase, was obtained. Our genome mining tool has broad applicability in fungal genome mining and can serve as a beneficial platform for accessing diverse, unexploited natural products.

© The Author(s) 2024

Original language	English
Article number	4312
Journal	Nature Communications
Volume	15
Online published	21 May 2024
DOIs	https://doi.org/10.1038/s41467-024-48771-7
Publication status	Published - 2024

Funding

We thank Prof. Katsuya Gomi (Tohoku University) and Profs. Katsuhiko Kitamoto and Jun-ichi Maruyama (University of Tokyo) for the expression vectors and fungal strain. We are also grateful to Dr. Man Kit Tse and Dr. Kwok Chung Law (City University of Hong Kong) for the NMR spectra acquisition and Dr. Shek Man Yiu (City University of Hong Kong) for X-ray diffraction data collection and analysis. This work was supported by General Research Fund grants from the Research Grants Council of Hong Kong (Project Nos. 11301321 and 11309022 to Y.M.).

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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10.1038/s41467-024-48771-7

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GRF: Global Genome Mining for Unexploited Bioactive Natural Products in Filamentous Fungi
MATSUDA, Y. (Principal Investigator / Project Coordinator)
1/01/23 → …
Project: Research
GRF: Broadening the Chemical Space of Fungal Meroterpenoids and the Enzymatic Repertoire for Their Biosynthesis
MATSUDA, Y. (Principal Investigator / Project Coordinator)
1/01/22 → …
Project: Research

Cite this

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title = "Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining",

abstract = "Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in the field of genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped natural products from numerous available genome sequences. In this study, we developed a fungal genome mining tool that extracts BGCs encoding enzymes that lack a detectable protein domain (i.e., domainlessenzymes) and are not recognized as biosynthetic proteins by existing bioinformatic tools. We searched for BGCs encoding a homologue of Pyr4-family terpene cyclases, which are representative examples of apparently domainlessenzymes, in approximately 2000 fungal genomes and discovered several BGCs with unique features. The subsequent characterization of selected BGCs led to the discovery of fungal onoceroid triterpenoids and unprecedentedonoceroid synthases. Furthermore, in addition to the onoceroids, a previously unreported sesquiterpene hydroquinone, of which the biosynthesis involves aPyr4-family terpene cyclase, was obtained. Our genome mining tool has broad applicability in fungal genome mining and can serve as a beneficial platform for accessing diverse, unexploited natural products.{\textcopyright} The Author(s) 2024",

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AB - Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in the field of genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped natural products from numerous available genome sequences. In this study, we developed a fungal genome mining tool that extracts BGCs encoding enzymes that lack a detectable protein domain (i.e., domainlessenzymes) and are not recognized as biosynthetic proteins by existing bioinformatic tools. We searched for BGCs encoding a homologue of Pyr4-family terpene cyclases, which are representative examples of apparently domainlessenzymes, in approximately 2000 fungal genomes and discovered several BGCs with unique features. The subsequent characterization of selected BGCs led to the discovery of fungal onoceroid triterpenoids and unprecedentedonoceroid synthases. Furthermore, in addition to the onoceroids, a previously unreported sesquiterpene hydroquinone, of which the biosynthesis involves aPyr4-family terpene cyclase, was obtained. Our genome mining tool has broad applicability in fungal genome mining and can serve as a beneficial platform for accessing diverse, unexploited natural products.© The Author(s) 2024

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DO - 10.1038/s41467-024-48771-7

M3 - RGC 21 - Publication in refereed journal

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JO - Nature Communications

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Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Abstract

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Projects

GRF: Global Genome Mining for Unexploited Bioactive Natural Products in Filamentous Fungi

GRF: Broadening the Chemical Space of Fungal Meroterpenoids and the Enzymatic Repertoire for Their Biosynthesis

Cite this