Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis.
10.1016/j.apsb.2023.10.016
- Author:
Yucheng ZHAO
1
;
Yuedong HE
2
;
Liangliang HAN
3
;
Libo ZHANG
1
;
Yuanzheng XIA
3
;
Fucheng YIN
3
;
Xiaobing WANG
3
;
Deqing ZHAO
4
;
Sheng XU
5
;
Fei QIAO
4
;
Yibei XIAO
6
;
Lingyi KONG
3
Author Information
1. Department of Resources Science of Traditional Chinese Medicines, School of Traditional Chinese Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
2. College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
3. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
4. Key Laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China, Ministry of Agriculture, Tropical Crops Genetic Resources Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 517317, China.
5. Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China.
6. Department of Pharmacology, School of Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
Baldwin rules;
CYP450 cyclase;
Coumarins;
Tetrahydrofurans;
Tetrahydropyrans
- From:
Acta Pharmaceutica Sinica B
2024;14(2):869-880
- CountryChina
- Language:English
-
Abstract:
Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1-3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.
