Viktoriia Savchenko, Miriam Jaegers, René Rasche, Eric Herrmann, Simone König, Daniel Kümmel, Thomas Böttcher, Susanne Fetzner, Simon Ernst
{"title":"揭示泰国伯克霍尔德氏菌抗菌甲基不饱和 2-烷基-4-喹啉酮生物合成的关键步骤","authors":"Viktoriia Savchenko, Miriam Jaegers, René Rasche, Eric Herrmann, Simone König, Daniel Kümmel, Thomas Böttcher, Susanne Fetzner, Simon Ernst","doi":"10.1016/j.xcrp.2024.102100","DOIUrl":null,"url":null,"abstract":"<p>The 2-alkyl-4(1<em>H</em>)-quinolone family of natural products comprises a diverse set of compounds acting as signals and antibiotics. The 2-alkyl-4(1<em>H</em>)-quinolone biosynthetic pathway of <em>Burkholderia thailandensis</em> exhibits a strong preference for the production of 3-methylated quinolones with <em>trans</em>-Δ<sup>2</sup>-unsaturated alkyl chains. Here, we complete the description of the pathway and decipher the biochemical rationale for this preference. Our data suggest that highly efficient methylation of the intermediate 2-aminobenzoylacetate to 2-(2′-aminobenzoyl)propionate (2-ABP), combined with substrate preference of the final condensing enzyme HmqBC for 2-ABP and a 3-alkenoyl donor, is the major factor determining the product pattern. Surprisingly, 2-ABP appears to largely decompose to 4-hydroxy-3-methyl-2(1<em>H</em>)-quinolone, indicating an enzymatic bottleneck created by HmqBC. While the diversity of quinolone products acting as a multitarget antibiotic cocktail may be advantageous, key enzymes of the pathway nevertheless have evolved toward promoting the production of congeners that are active especially toward gram-positive bacteria and fungi and, moreover, resist C3-targeted detoxification.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":null,"pages":null},"PeriodicalIF":7.9000,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Unraveling key steps in the biosynthesis of antimicrobial methylated unsaturated 2-alkyl-4-quinolones of Burkholderia thailandensis\",\"authors\":\"Viktoriia Savchenko, Miriam Jaegers, René Rasche, Eric Herrmann, Simone König, Daniel Kümmel, Thomas Böttcher, Susanne Fetzner, Simon Ernst\",\"doi\":\"10.1016/j.xcrp.2024.102100\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The 2-alkyl-4(1<em>H</em>)-quinolone family of natural products comprises a diverse set of compounds acting as signals and antibiotics. The 2-alkyl-4(1<em>H</em>)-quinolone biosynthetic pathway of <em>Burkholderia thailandensis</em> exhibits a strong preference for the production of 3-methylated quinolones with <em>trans</em>-Δ<sup>2</sup>-unsaturated alkyl chains. Here, we complete the description of the pathway and decipher the biochemical rationale for this preference. Our data suggest that highly efficient methylation of the intermediate 2-aminobenzoylacetate to 2-(2′-aminobenzoyl)propionate (2-ABP), combined with substrate preference of the final condensing enzyme HmqBC for 2-ABP and a 3-alkenoyl donor, is the major factor determining the product pattern. Surprisingly, 2-ABP appears to largely decompose to 4-hydroxy-3-methyl-2(1<em>H</em>)-quinolone, indicating an enzymatic bottleneck created by HmqBC. While the diversity of quinolone products acting as a multitarget antibiotic cocktail may be advantageous, key enzymes of the pathway nevertheless have evolved toward promoting the production of congeners that are active especially toward gram-positive bacteria and fungi and, moreover, resist C3-targeted detoxification.</p>\",\"PeriodicalId\":9703,\"journal\":{\"name\":\"Cell Reports Physical Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2024-07-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Reports Physical Science\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xcrp.2024.102100\",\"RegionNum\":2,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Physical Science","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.xcrp.2024.102100","RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Unraveling key steps in the biosynthesis of antimicrobial methylated unsaturated 2-alkyl-4-quinolones of Burkholderia thailandensis
The 2-alkyl-4(1H)-quinolone family of natural products comprises a diverse set of compounds acting as signals and antibiotics. The 2-alkyl-4(1H)-quinolone biosynthetic pathway of Burkholderia thailandensis exhibits a strong preference for the production of 3-methylated quinolones with trans-Δ2-unsaturated alkyl chains. Here, we complete the description of the pathway and decipher the biochemical rationale for this preference. Our data suggest that highly efficient methylation of the intermediate 2-aminobenzoylacetate to 2-(2′-aminobenzoyl)propionate (2-ABP), combined with substrate preference of the final condensing enzyme HmqBC for 2-ABP and a 3-alkenoyl donor, is the major factor determining the product pattern. Surprisingly, 2-ABP appears to largely decompose to 4-hydroxy-3-methyl-2(1H)-quinolone, indicating an enzymatic bottleneck created by HmqBC. While the diversity of quinolone products acting as a multitarget antibiotic cocktail may be advantageous, key enzymes of the pathway nevertheless have evolved toward promoting the production of congeners that are active especially toward gram-positive bacteria and fungi and, moreover, resist C3-targeted detoxification.
期刊介绍:
Cell Reports Physical Science, a premium open-access journal from Cell Press, features high-quality, cutting-edge research spanning the physical sciences. It serves as an open forum fostering collaboration among physical scientists while championing open science principles. Published works must signify significant advancements in fundamental insight or technological applications within fields such as chemistry, physics, materials science, energy science, engineering, and related interdisciplinary studies. In addition to longer articles, the journal considers impactful short-form reports and short reviews covering recent literature in emerging fields. Continually adapting to the evolving open science landscape, the journal reviews its policies to align with community consensus and best practices.