{"title":"新型杀菌剂喹诺芬林对真菌二氢乙酸脱氢酶的选择性优于相应的人酶。","authors":"Norikazu Higashimura, Akira Hamada, Shinichi Banba","doi":"10.1584/jpestics.D22-035","DOIUrl":null,"url":null,"abstract":"<p><p>The species selectivity of class 2 dihydroorotate dehydrogenase (DHODH), a target enzyme for quinofumelin, was examined. The <i>Homo sapiens</i> DHODH (HsDHODH) assay system was developed to compare the selectivity of quinofumelin for fungi with that for mammals. The IC<sub>50</sub> values of quinofumelin for <i>Pyricularia oryzae</i> DHODH (PoDHODH) and HsDHODH were 2.8 nM and >100 µM, respectively. Quinofumelin was highly selective for fungal over human DHODH. Additionally, we constructed recombinant <i>P. oryzae</i> mutants where <i>PoDHODH</i> (<i>PoPYR4</i>) or <i>HsDHODH</i> was inserted into the <i>PoPYR4</i> disruption mutant. At quinofumelin concentration of 0.01-1 ppm, the <i>PoPYR4</i> insertion mutants could not grow, but the <i>HsDHODH</i> gene-insertion mutants thrived. This indicates that HsDHODH is a substitute for PoDHODH, and quinofumelin could not inhibit HsDHODH as in the HsDHODH enzyme assay. Comparing the amino acid sequences of human and fungal DHODHs indicates that the significant difference at the ubiquinone-binding site contributes to the species selectivity of quinofumelin.</p>","PeriodicalId":16712,"journal":{"name":"Journal of Pesticide Science","volume":"48 1","pages":"17-21"},"PeriodicalIF":1.5000,"publicationDate":"2023-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/2c/jps-48-1-D22-035.PMC9978249.pdf","citationCount":"0","resultStr":"{\"title\":\"Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme.\",\"authors\":\"Norikazu Higashimura, Akira Hamada, Shinichi Banba\",\"doi\":\"10.1584/jpestics.D22-035\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The species selectivity of class 2 dihydroorotate dehydrogenase (DHODH), a target enzyme for quinofumelin, was examined. The <i>Homo sapiens</i> DHODH (HsDHODH) assay system was developed to compare the selectivity of quinofumelin for fungi with that for mammals. The IC<sub>50</sub> values of quinofumelin for <i>Pyricularia oryzae</i> DHODH (PoDHODH) and HsDHODH were 2.8 nM and >100 µM, respectively. Quinofumelin was highly selective for fungal over human DHODH. Additionally, we constructed recombinant <i>P. oryzae</i> mutants where <i>PoDHODH</i> (<i>PoPYR4</i>) or <i>HsDHODH</i> was inserted into the <i>PoPYR4</i> disruption mutant. At quinofumelin concentration of 0.01-1 ppm, the <i>PoPYR4</i> insertion mutants could not grow, but the <i>HsDHODH</i> gene-insertion mutants thrived. This indicates that HsDHODH is a substitute for PoDHODH, and quinofumelin could not inhibit HsDHODH as in the HsDHODH enzyme assay. Comparing the amino acid sequences of human and fungal DHODHs indicates that the significant difference at the ubiquinone-binding site contributes to the species selectivity of quinofumelin.</p>\",\"PeriodicalId\":16712,\"journal\":{\"name\":\"Journal of Pesticide Science\",\"volume\":\"48 1\",\"pages\":\"17-21\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2023-02-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/2c/jps-48-1-D22-035.PMC9978249.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Pesticide Science\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://doi.org/10.1584/jpestics.D22-035\",\"RegionNum\":4,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENTOMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pesticide Science","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.1584/jpestics.D22-035","RegionNum":4,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENTOMOLOGY","Score":null,"Total":0}
Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme.
The species selectivity of class 2 dihydroorotate dehydrogenase (DHODH), a target enzyme for quinofumelin, was examined. The Homo sapiens DHODH (HsDHODH) assay system was developed to compare the selectivity of quinofumelin for fungi with that for mammals. The IC50 values of quinofumelin for Pyricularia oryzae DHODH (PoDHODH) and HsDHODH were 2.8 nM and >100 µM, respectively. Quinofumelin was highly selective for fungal over human DHODH. Additionally, we constructed recombinant P. oryzae mutants where PoDHODH (PoPYR4) or HsDHODH was inserted into the PoPYR4 disruption mutant. At quinofumelin concentration of 0.01-1 ppm, the PoPYR4 insertion mutants could not grow, but the HsDHODH gene-insertion mutants thrived. This indicates that HsDHODH is a substitute for PoDHODH, and quinofumelin could not inhibit HsDHODH as in the HsDHODH enzyme assay. Comparing the amino acid sequences of human and fungal DHODHs indicates that the significant difference at the ubiquinone-binding site contributes to the species selectivity of quinofumelin.
期刊介绍:
The Journal of Pesticide Science publishes the results of original research regarding the chemistry and biochemistry of pesticides including bio-based materials. It also covers their metabolism, toxicology, environmental fate and formulation.