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Peer-reviewedCC BY-NC-ND 4.0ACS Omega

Enzyme-Guided Classification of Fungal Eremophilane Biosynthetic Gene Clusters Provides a Predictive Framework for Structural Diversity

  • Xinge Shi1
  • Ying Ye2
  • Shusuke Sato3
  • Xueting Liu4
  • Masaru Hashimoto5
  • Chengwei Liu1
  • Hideaki Oikawa6
  • Atsushi Minami3
6 affiliations
  1. 1Northeast Forestry University , , ,
  2. 2Huazhong University of Science and Technology , , ,
  3. 3Institute of Science Tokyo , , ,
  4. 4East China University of Science and Technology , , ,
  5. 5Hirosaki University , , 3-Bunkyo-Cho , ,
  6. 6Hokkaido University , , ,
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Abstract

Elucidating how oxidative tailoring enzymes generate structural diversity in natural products remains a major challenge, because their functions are difficult to predict directly from sequence information. Fungal eremophilanes (EMPs), which share a conserved bicyclic core yet exhibit extensive oxidative diversification, provide an ideal model system to address this problem. Here, we establish a systematic framework linking biosynthetic gene cluster (BGC) to EMP chemical diversity by integrating bioinformatics and chemoinformatics analyses. Analysis of 371 BGCs identified six groups defined by combination of key modification enzymes, which rationalize the major structural features of 195 reported EMPs. This framework enables prediction of core scaffolds and major oxidative modifications, thereby constraining the accessible chemical space of EMPs. It also facilitates structure-guided identification of candidate BGCs, including atypical or divergent clusters that are not readily identified by sequence similarity alone. Experimental validation of a predicted peribysin biosynthetic gene cluster further supported the predictive capability of this framework. Together, these results demonstrate that oxidative diversification in EMP biosynthesis follows a limited and interpretable set of transformation patterns and establish a generalizable strategy for constraining terpenoid chemical space from genomic information.

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Cite

BibTeXRIS
BibTeX
@article{shi2026enzymeguided,
  title = {{Enzyme-Guided Classification of Fungal Eremophilane Biosynthetic Gene Clusters Provides a Predictive Framework for Structural Diversity}},
  author = {Xinge Shi and Ying Ye and Shusuke Sato and Xueting Liu and Masaru Hashimoto and Chengwei Liu and Hideaki Oikawa and Atsushi Minami},
  journal = {ACS Omega},
  year = {2026},
  month = oct,
  doi = {10.1021/acsomega.6c05589},
  url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c05589/5456448/Enzyme-Guided-Classification-of-Fungal},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Enzyme-Guided Classification of Fungal Eremophilane Biosynthetic Gene Clusters Provides a Predictive Framework for Structural Diversity
AU  - Xinge Shi
AU  - Ying Ye
AU  - Shusuke Sato
AU  - Xueting Liu
AU  - Masaru Hashimoto
AU  - Chengwei Liu
AU  - Hideaki Oikawa
AU  - Atsushi Minami
PY  - 2026
DA  - 2026/10/22
JO  - ACS Omega
DO  - 10.1021/acsomega.6c05589
UR  - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c05589/5456448/Enzyme-Guided-Classification-of-Fungal
AB  - Elucidating how oxidative tailoring enzymes generate structural diversity in natural products remains a major challenge, because their functions are difficult to predict directly from sequence information. Fungal eremophilanes (EMPs), which share a conserved bicyclic core yet exhibit extensive oxidative diversification, provide an ideal model system to address this problem. Here, we establish a systematic framework linking biosynthetic gene cluster (BGC) to EMP chemical diversity by integrating bioinformatics and chemoinformatics analyses. Analysis of 371 BGCs identified six groups defined by combination of key modification enzymes, which rationalize the major structural features of 195 reported EMPs. This framework enables prediction of core scaffolds and major oxidative modifications, thereby constraining the accessible chemical space of EMPs. It also facilitates structure-guided identification of candidate BGCs, including atypical or divergent clusters that are not readily identified by sequence similarity alone. Experimental validation of a predicted peribysin biosynthetic gene cluster further supported the predictive capability of this framework. Together, these results demonstrate that oxidative diversification in EMP biosynthesis follows a limited and interpretable set of transformation patterns and establish a generalizable strategy for constraining terpenoid chemical space from genomic information.
SN  - 2470-1343
ER  -