Citation: Wentao Sun, Lin Xiang, Runming Wang, Meilan Huang, Bo Lv, Youcai Hu, Chun Li. Microenvironment accessibility enables rare oxidation type of triterpenoids by plant P450[J]. Chinese Chemical Letters, ;2026, 37(2): 110965. doi: 10.1016/j.cclet.2025.110965 shu

Microenvironment accessibility enables rare oxidation type of triterpenoids by plant P450

Wentao Sun ^{a, b} ,
Lin Xiang ^c ,
Runming Wang ^d ,
Meilan Huang ^e ,
Bo Lv ^{c, *,} ,
Youcai Hu ^b ,
Chun Li ^{a, c, f, g, *,}

a.
Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
b.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
c.
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
d.
Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
e.
School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast BT9 5AG, Northern Ireland, United Kingdom
f.
Key Lab for Industrial Biocatalysis, Ministry of Education, Tsinghua University, Beijing 100084, China
g.
Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China

lv-b@bit.edu.cn

lichun@tsinghua.edu.cn

Received Date: 22 December 2024
Revised Date: 14 February 2025
Accepted Date: 17 February 2025
Available Online: 19 February 2025

Figures(5)

Triterpenoids are valuable medicinal scaffolds, characterized by excellent pharmacological properties and the presence of hydroxyl and carboxyl groups that allow for further structural modifications. Expanding the scope of oxidative modifications on these molecules is crucial for increasing their synthetic structural diversity and unlocking new potential pharmacological activities. However, the progress has been limited by the scarcity of suitable tailoring enzymes. Here, we reported a break-through in achieving targeted and remote dual-site oxidation of licorice triterpenoids using a single P450 mutant. This approach successfully enabled the selective synthesis of the rare triterpenoid, liquiritic acid and 24-OH-liquiritic acid. Our findings demonstrate that microenvironmental accessibility engineering of triterpenoid substrates within the P450 enzyme is essential for continuous and regioselective oxidation. This study not only sheds light on the mechanistic aspects of P450 catalysis but also expands the enzymatic toolkit for selective oxidative modifications in triterpenoid biosynthesis.
- Microenvironment accessibility,
- P450,
- Triterpenoid,
- Enzyme engineering,
- Remote oxidation
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