Elucidation of the melitidin biosynthesis pathway in pummelo

ABSTRACT Specialized plant metabolism is a rich resource of compounds for drug discovery. The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene...

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Veröffentlicht in:Journal of integrative plant biology 2023-11, Vol.65 (11), p.2505-2518
Hauptverfasser: Shen, Shuangqian, Wang, Shouchuang, Yang, Chenkun, Wang, Chao, Zhou, Qianqian, Zhou, Shen, Zhang, Ran, Li, Yufei, Wang, Zixuan, Dai, Liupan, Peng, Wenjv, Hao, Yingchen, Guo, Hao, Cao, Guangping, Liu, Xianqing, Yao, Fan, Xu, Qiang, Fernie, Alisdair R., Luo, Jie
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container_end_page 2518
container_issue 11
container_start_page 2505
container_title Journal of integrative plant biology
container_volume 65
creator Shen, Shuangqian
Wang, Shouchuang
Yang, Chenkun
Wang, Chao
Zhou, Qianqian
Zhou, Shen
Zhang, Ran
Li, Yufei
Wang, Zixuan
Dai, Liupan
Peng, Wenjv
Hao, Yingchen
Guo, Hao
Cao, Guangping
Liu, Xianqing
Yao, Fan
Xu, Qiang
Fernie, Alisdair R.
Luo, Jie
description ABSTRACT Specialized plant metabolism is a rich resource of compounds for drug discovery. The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP‐glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti‐cholesterol statin drug candidate. Co‐expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites. Gene discovery, functional characterization, and metabolic engineering reveals a flavonoid gene cluster that is responsible for biosynthesis of melitidin, an effective candidate anti‐cholesterol statin in pummelo (Citrus grandis).
doi_str_mv 10.1111/jipb.13564
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The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP‐glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti‐cholesterol statin drug candidate. Co‐expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites. 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The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP‐glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti‐cholesterol statin drug candidate. Co‐expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites. Gene discovery, functional characterization, and metabolic engineering reveals a flavonoid gene cluster that is responsible for biosynthesis of melitidin, an effective candidate anti‐cholesterol statin in pummelo (Citrus grandis).</description><subject>bioactive metabolites</subject><subject>Biological activity</subject><subject>Biosynthesis</subject><subject>biosynthetic pathway</subject><subject>Cholesterol</subject><subject>Citrus grandis</subject><subject>Drug development</subject><subject>Flavone glycosides</subject><subject>Flavonoids</subject><subject>Gene expression</subject><subject>Genetic improvement</subject><subject>Genetic resources</subject><subject>melitidin</subject><subject>Metabolic engineering</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>natural variation</subject><subject>Plant metabolism</subject><subject>Reductases</subject><subject>Statins</subject><subject>Substrates</subject><issn>1672-9072</issn><issn>1744-7909</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kE9Lw0AQxRdRsFYvfoKACCKkzv5pdhe8aKlaKehBz8sm2dgtaTZmE2r89G6NePDgXGZ4_ObN8BA6xTDBoa7Wtk4nmE4TtodGmDMWcwlyP8wJJ7EETg7RkfdrACogISN0PS-7zOa6ta6KXBG1KxNtTGlbm9sqSq3zfRU0b31U63a11X0U9LrbBMgdo4NCl96c_PQxer2bv8we4uXT_WJ2s4wzBsBiJjNNsrRIGEjDeYGzQnOtOcOAqSThWW6ooEJAaoRhWCZJTnCe54xzTXJOx-h88N3qqtDVm1q7rqnCRfW5_UgJEIoxgAzcxcDVjXvvjG_VxvrMlKWujOu8IiIhWAo63Vme_UF_PYmQDIgQUxKoy4HKGud9YwpVN3ajm15hULvA1S5w9R14gPHPl7Y0_T-kelw83w47X8MUgOw</recordid><startdate>202311</startdate><enddate>202311</enddate><creator>Shen, Shuangqian</creator><creator>Wang, Shouchuang</creator><creator>Yang, Chenkun</creator><creator>Wang, Chao</creator><creator>Zhou, Qianqian</creator><creator>Zhou, Shen</creator><creator>Zhang, Ran</creator><creator>Li, Yufei</creator><creator>Wang, Zixuan</creator><creator>Dai, Liupan</creator><creator>Peng, Wenjv</creator><creator>Hao, Yingchen</creator><creator>Guo, Hao</creator><creator>Cao, Guangping</creator><creator>Liu, Xianqing</creator><creator>Yao, Fan</creator><creator>Xu, Qiang</creator><creator>Fernie, Alisdair R.</creator><creator>Luo, Jie</creator><general>Wiley Subscription Services, Inc</general><general>Yazhouwan National Laboratory,Sanya 572025,China</general><general>Centre of Plant Systems Biology and Biotechnology,Plovdiv 4000,Bulgaria%Sanya Nanfan Research Institute of Hainan University,Hainan University,Sanya 572025,China</general><general>Sanya Nanfan Research Institute of Hainan University,Hainan University,Sanya 572025,China%National Key Laboratory of Crop Genetic Improvement,National Center of Plant Gene Research(Wuhan),Huazhong Agricultural University,Wuhan 430070,China%Hubei Hongshan Laboratory,College of Life Science and Technology,College of Biomedicine and Health,Huazhong Agricultural University,Wuhan 430070,China%Key Laboratory of Horticultural Plant Biology of Ministry of Education,Huazhong Agricultural University,Wuhan 430070,China%Max Planck Institute of Molecular Plant Physiology,Potsdam-Golm 14476,Germany</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>2B.</scope><scope>4A8</scope><scope>92I</scope><scope>93N</scope><scope>PSX</scope><scope>TCJ</scope><orcidid>https://orcid.org/0000-0001-9026-1666</orcidid><orcidid>https://orcid.org/0000-0002-4393-7296</orcidid><orcidid>https://orcid.org/0000-0002-4931-7469</orcidid><orcidid>https://orcid.org/0000-0003-1590-8372</orcidid><orcidid>https://orcid.org/0000-0003-1101-6465</orcidid><orcidid>https://orcid.org/0000-0002-5568-816X</orcidid><orcidid>https://orcid.org/0000-0002-8459-0831</orcidid><orcidid>https://orcid.org/0000-0001-9000-335X</orcidid></search><sort><creationdate>202311</creationdate><title>Elucidation of the melitidin biosynthesis pathway in pummelo</title><author>Shen, Shuangqian ; 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The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP‐glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti‐cholesterol statin drug candidate. Co‐expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites. 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subjects bioactive metabolites
Biological activity
Biosynthesis
biosynthetic pathway
Cholesterol
Citrus grandis
Drug development
Flavone glycosides
Flavonoids
Gene expression
Genetic improvement
Genetic resources
melitidin
Metabolic engineering
Metabolism
Metabolites
natural variation
Plant metabolism
Reductases
Statins
Substrates
title Elucidation of the melitidin biosynthesis pathway in pummelo
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