An Enzymatic Carbon-Carbon Bond Cleavage and Aldol Reaction Cascade Converts an Angular Scaffold into the Linear Tetracyclic Core of Ochraceopones

Yanqin Li; Mengjing Cong; Wengui Wang; Xiufeng Zhang; Yiguang Zhu; Yongxiang Song; Wenjun Zhang; Hua Xiao; Yonghong Liu; Changsheng Zhang; Junfeng Wang; Yan Yan

doi:10.1002/anie.202403365

An Enzymatic Carbon-Carbon Bond Cleavage and Aldol Reaction Cascade Converts an Angular Scaffold into the Linear Tetracyclic Core of Ochraceopones

Angew Chem Int Ed Engl. 2024 Mar 7:e202403365. doi: 10.1002/anie.202403365. Online ahead of print.

Authors

Yanqin Li^{1

2}, Mengjing Cong¹, Wengui Wang³, Xiufeng Zhang^{1

2}, Yiguang Zhu^{1

2

4}, Yongxiang Song^{1

2

4}, Wenjun Zhang^{1

2

4}, Hua Xiao^{1

2}, Yonghong Liu^{1

2

4}, Changsheng Zhang^{1

2

4}, Junfeng Wang^{1

2

4}, Yan Yan^{1

2

4}

Affiliations

¹ Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Innovation Academy of South China Sea Ecology and Environmental Engineering, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou, 510301, China.
² Sanya Institute of Oceanology Eco-Environmental Engineering, Yazhou Scientific Bay, Sanya, 572000, China.
³ School of Chemistry and Chemical Engineering, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan, 250022, China.
⁴ University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 100049, China.

PMID: 38454191
DOI: 10.1002/anie.202403365

Abstract

Meroterpenoids of the ochraceopones family featuring a linear tetracyclic scaffold exhibit exceptional antiviral and anti-inflammatory activities. The biosynthetic pathway and chemical logic to generate this linear tetracycle, however, remain unknown. In this study, we identified and characterized all biosynthetic enzymes to afford ochraceopones and elucidated the complete biosynthetic pathway. We demonstrated that the linear tetracyclic scaffold of ochraceopones was derived from an angular tetracyclic precursor. A multifunctional cytochrome P450 OchH was validated to catalyze the free-radical-initiated carbon-carbon bond cleavage of the angular tetracycle. Then, a new carbon-carbon bond was verified to be constructed using a new aldolase OchL, which catalyzes an intramolecular aldol reaction to form the linear tetracycle. This carbon-carbon bond fragmentation and aldol reaction cascade features an unprecedented strategy for converting a common angular tetracycle to a distinctive linear tetracyclic scaffold in meroterpenoid biosynthesis.

Keywords: aldolase; biosynthesis; meroterpenoids; ochraceopones.

Abstract

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