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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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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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).</description><identifier>ISSN: 1672-9072</identifier><identifier>EISSN: 1744-7909</identifier><identifier>DOI: 10.1111/jipb.13564</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc</publisher><subject>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</subject><ispartof>Journal of integrative plant biology, 2023-11, Vol.65 (11), p.2505-2518</ispartof><rights>2023 Institute of Botany, Chinese Academy of Sciences.</rights><rights>Copyright © Wanfang Data Co. Ltd. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4004-49ca2cbf6409e77f1cfa7aa741013925647e383880be8e41966d21ddd477a2d73</citedby><cites>FETCH-LOGICAL-c4004-49ca2cbf6409e77f1cfa7aa741013925647e383880be8e41966d21ddd477a2d73</cites><orcidid>0000-0001-9026-1666 ; 0000-0002-4393-7296 ; 0000-0002-4931-7469 ; 0000-0003-1590-8372 ; 0000-0003-1101-6465 ; 0000-0002-5568-816X ; 0000-0002-8459-0831 ; 0000-0001-9000-335X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.wanfangdata.com.cn/images/PeriodicalImages/zwxb/zwxb.jpg</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjipb.13564$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjipb.13564$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Shen, Shuangqian</creatorcontrib><creatorcontrib>Wang, Shouchuang</creatorcontrib><creatorcontrib>Yang, Chenkun</creatorcontrib><creatorcontrib>Wang, Chao</creatorcontrib><creatorcontrib>Zhou, Qianqian</creatorcontrib><creatorcontrib>Zhou, Shen</creatorcontrib><creatorcontrib>Zhang, Ran</creatorcontrib><creatorcontrib>Li, Yufei</creatorcontrib><creatorcontrib>Wang, Zixuan</creatorcontrib><creatorcontrib>Dai, Liupan</creatorcontrib><creatorcontrib>Peng, Wenjv</creatorcontrib><creatorcontrib>Hao, Yingchen</creatorcontrib><creatorcontrib>Guo, Hao</creatorcontrib><creatorcontrib>Cao, Guangping</creatorcontrib><creatorcontrib>Liu, Xianqing</creatorcontrib><creatorcontrib>Yao, Fan</creatorcontrib><creatorcontrib>Xu, Qiang</creatorcontrib><creatorcontrib>Fernie, Alisdair R.</creatorcontrib><creatorcontrib>Luo, Jie</creatorcontrib><title>Elucidation of the melitidin biosynthesis pathway in pummelo</title><title>Journal of integrative plant biology</title><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).</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 ; 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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4004-49ca2cbf6409e77f1cfa7aa741013925647e383880be8e41966d21ddd477a2d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>bioactive metabolites</topic><topic>Biological activity</topic><topic>Biosynthesis</topic><topic>biosynthetic pathway</topic><topic>Cholesterol</topic><topic>Citrus grandis</topic><topic>Drug development</topic><topic>Flavone glycosides</topic><topic>Flavonoids</topic><topic>Gene expression</topic><topic>Genetic improvement</topic><topic>Genetic resources</topic><topic>melitidin</topic><topic>Metabolic engineering</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>natural variation</topic><topic>Plant metabolism</topic><topic>Reductases</topic><topic>Statins</topic><topic>Substrates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Shuangqian</creatorcontrib><creatorcontrib>Wang, Shouchuang</creatorcontrib><creatorcontrib>Yang, Chenkun</creatorcontrib><creatorcontrib>Wang, Chao</creatorcontrib><creatorcontrib>Zhou, Qianqian</creatorcontrib><creatorcontrib>Zhou, Shen</creatorcontrib><creatorcontrib>Zhang, Ran</creatorcontrib><creatorcontrib>Li, Yufei</creatorcontrib><creatorcontrib>Wang, Zixuan</creatorcontrib><creatorcontrib>Dai, Liupan</creatorcontrib><creatorcontrib>Peng, Wenjv</creatorcontrib><creatorcontrib>Hao, Yingchen</creatorcontrib><creatorcontrib>Guo, Hao</creatorcontrib><creatorcontrib>Cao, Guangping</creatorcontrib><creatorcontrib>Liu, Xianqing</creatorcontrib><creatorcontrib>Yao, Fan</creatorcontrib><creatorcontrib>Xu, Qiang</creatorcontrib><creatorcontrib>Fernie, Alisdair R.</creatorcontrib><creatorcontrib>Luo, Jie</creatorcontrib><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Wanfang Data Journals - Hong Kong</collection><collection>WANFANG Data Centre</collection><collection>Wanfang Data Journals</collection><collection>万方数据期刊 - 香港版</collection><collection>China Online Journals (COJ)</collection><collection>China Online Journals (COJ)</collection><jtitle>Journal of integrative plant biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Shuangqian</au><au>Wang, Shouchuang</au><au>Yang, Chenkun</au><au>Wang, Chao</au><au>Zhou, Qianqian</au><au>Zhou, Shen</au><au>Zhang, Ran</au><au>Li, Yufei</au><au>Wang, Zixuan</au><au>Dai, Liupan</au><au>Peng, Wenjv</au><au>Hao, Yingchen</au><au>Guo, Hao</au><au>Cao, Guangping</au><au>Liu, Xianqing</au><au>Yao, Fan</au><au>Xu, Qiang</au><au>Fernie, Alisdair R.</au><au>Luo, Jie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elucidation of the melitidin biosynthesis pathway in pummelo</atitle><jtitle>Journal of integrative plant biology</jtitle><date>2023-11</date><risdate>2023</risdate><volume>65</volume><issue>11</issue><spage>2505</spage><epage>2518</epage><pages>2505-2518</pages><issn>1672-9072</issn><eissn>1744-7909</eissn><abstract>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).</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1111/jipb.13564</doi><tpages>14</tpages><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><oa>free_for_read</oa></addata></record> |
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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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