Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis
Abstract The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecul...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62075-4 |
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| author | Hengyi Xu Xianyan Zhang Yawen Zhang Guowei Liu Yinghan Chen Xuewen Hou Xiaolin Liu Kaijin Zhang Chuanteng Ma Ruqian Feng Juan Shen Blaine A. Pfeifer Qian Che Tianjiao Zhu Guojian Zhang |
| author_facet | Hengyi Xu Xianyan Zhang Yawen Zhang Guowei Liu Yinghan Chen Xuewen Hou Xiaolin Liu Kaijin Zhang Chuanteng Ma Ruqian Feng Juan Shen Blaine A. Pfeifer Qian Che Tianjiao Zhu Guojian Zhang |
| author_sort | Hengyi Xu |
| collection | DOAJ |
| description | Abstract The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecular oxa/aza-nucleophilic addition in the biosynthesis of a family of eremophilane-like sesquiterpenoid derivatives, including farfugin A (1) and aza-janthinellin A (2a), a sesquiterpene-amino acid adduct. During this process, JanF, a flavoprotein functioning as a dehydrogenase, is demonstrated to be able to oxidize an allyl alcohol group of eremophilanes into an α,β-unsaturated aldehyde, thereby facilitating the binding of primary amines to the sesquiterpene skeleton. Furthermore, using JanF as a catalyst, we generate a series of aromatic aza-/thio-sesquiterpenoids (aza-janthinellins and thio-janthinellins), among which, thio-janthinellins exhibit potent cytotoxicity against human chronic myelogenous leukemia K562 cells. These findings advance our understanding of the biogenesis of aromatic compounds and enable the construction of diverse aza-/thio-terpenoids with enhanced biological activity. |
| format | Article |
| id | doaj-art-e496c2505ceb479c99252e8313cb1c14 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e496c2505ceb479c99252e8313cb1c142025-08-20T03:46:25ZengNature PortfolioNature Communications2041-17232025-08-0116111310.1038/s41467-025-62075-4Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesisHengyi Xu0Xianyan Zhang1Yawen Zhang2Guowei Liu3Yinghan Chen4Xuewen Hou5Xiaolin Liu6Kaijin Zhang7Chuanteng Ma8Ruqian Feng9Juan Shen10Blaine A. Pfeifer11Qian Che12Tianjiao Zhu13Guojian Zhang14Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical UniversityGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical UniversityDepartment of Chemical and Biological Engineering, University at Buffalo, The State University of New YorkKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of ChinaAbstract The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecular oxa/aza-nucleophilic addition in the biosynthesis of a family of eremophilane-like sesquiterpenoid derivatives, including farfugin A (1) and aza-janthinellin A (2a), a sesquiterpene-amino acid adduct. During this process, JanF, a flavoprotein functioning as a dehydrogenase, is demonstrated to be able to oxidize an allyl alcohol group of eremophilanes into an α,β-unsaturated aldehyde, thereby facilitating the binding of primary amines to the sesquiterpene skeleton. Furthermore, using JanF as a catalyst, we generate a series of aromatic aza-/thio-sesquiterpenoids (aza-janthinellins and thio-janthinellins), among which, thio-janthinellins exhibit potent cytotoxicity against human chronic myelogenous leukemia K562 cells. These findings advance our understanding of the biogenesis of aromatic compounds and enable the construction of diverse aza-/thio-terpenoids with enhanced biological activity.https://doi.org/10.1038/s41467-025-62075-4 |
| spellingShingle | Hengyi Xu Xianyan Zhang Yawen Zhang Guowei Liu Yinghan Chen Xuewen Hou Xiaolin Liu Kaijin Zhang Chuanteng Ma Ruqian Feng Juan Shen Blaine A. Pfeifer Qian Che Tianjiao Zhu Guojian Zhang Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis Nature Communications |
| title | Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis |
| title_full | Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis |
| title_fullStr | Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis |
| title_full_unstemmed | Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis |
| title_short | Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis |
| title_sort | nucleophilic addition promoted ring rearrangement aromatization in aza thio sesquiterpenoid biosynthesis |
| url | https://doi.org/10.1038/s41467-025-62075-4 |
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