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首页> 外文学位 >Identification and mechanism of biosynthesis of the major Vibrio cholerae quorum-sensing autoinducer.
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Identification and mechanism of biosynthesis of the major Vibrio cholerae quorum-sensing autoinducer.

机译：主要霍乱弧菌群体感应自诱导物的生物合成鉴定及机理。

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摘要

Vibrio cholerae, the causative agent of the human disease cholera, uses cell-to-cell communication to control pathogenicity and biofilm formation. This process, known as quorum sensing, relies on the secretion and detection of signaling molecules called autoinducers. At low cell density V. cholerae activates the expression of virulence factors and forms biofilms. At high cell density the accumulation of two quorum-sensing autoinducers represses these traits. These two autoinducers, cholerae autoinducer-1 (CAI-1) and autoinducer-2 (AI-2), function synergistically to control gene regulation, although CAI-1 is the stronger of the two signals. V. cholerae AI-2 is the furanosyl borate diester (2S,4 S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran borate. This thesis describes the purification of CAI-1 and identification of the molecule as (S)-3-hydroxytridecan-4-one, a new type of bacterial autoinducer. The activities of both the R and S isomers of CAI-1 as well as simple homologues are evaluated. Synthetic (S )-3-hydroxytridecan-4-one functions as effectively as natural CAI-1 in repressing production of the canonical virulence factor TCP (toxin co-regulated pilus).;CAI-1 biosynthesis depends upon the CqsA enzyme. The mechanism of CqsA is investigated and its substrates are identified as (S)-2-aminobutyrate and decanoyl-coenzyme A. The product of CqsA activity is 3-aminotridecane-4-one (amino-CAI-1). Crystallographic analysis combined with spectral studies show that CqsA produces amino-CAI-1 by a pyridoxal phosphate (PLP)-dependent aminotransferase reaction. Though the mechanism is unknown, preliminary studies indicate that bacterial cultures are capable of converting amino-CAI-1 into CAI-1. Both molecules are detected in cell-free culture fluids, with amino-CAI-1 present at 1% of CAI-1 levels. The findings presented in this thesis suggest that CAI-1 or a CAI-1-analogue could be used as a therapy to prevent cholera infection and, furthermore, that strategies to manipulate bacterial quorum sensing hold promise in the clinical arena.
机译：霍乱弧菌是人类霍乱疾病的病原体，它利用细胞间通讯来控制致病性和生物膜形成。此过程称为定额感应，它依赖于称为自动诱导剂的信号分子的分泌和检测。在低细胞密度下，霍乱弧菌激活毒力因子的表达并形成生物膜。在高细胞密度下，两种群体感应自诱导物的积累抑制了这些特性。尽管CAI-1是这两个信号中最强的一种，但这两种自诱导物，霍乱自诱导物1（CAI-1）和自诱导物2（AI-2）具有协同作用，以控制基因调控。霍乱弧菌AI-2是呋喃糖基硼酸酯二酯（2S，4S）-2-甲基-2,3,3,4-四羟基四氢呋喃硼酸酯。本文介绍了一种新型的细菌自诱导剂CAI-1的纯化及其分子鉴定为（S）-3-hydroxytridecan-4-one。评估了CAI-1的R和S异构体以及简单同系物的活性。合成的（S）-3-羟基苯甲酰胺-4-酮在抑制典型毒力因子TCP（毒素共调节菌毛）产生方面与天然CAI-1一样有效。CAI-1的生物合成取决于CqsA酶。研究了CqsA的机理，并确定了其底物为（S）-2-氨基丁酸酯和癸酰基辅酶A。CqsA活性的产物为3-氨基十三烷-4-酮（氨基-CAI-1）。晶体学分析与光谱研究相结合表明，CqsA通过磷酸吡ido醛（PLP）依赖性氨基转移酶反应产生氨基-CAI-1。尽管机理尚不清楚，但初步研究表明细菌培养物能够将氨基CAI-1转化为CAI-1。两种分子均在无细胞培养液中检测到，氨基CAI-1的含量不到CAI-1水平的1％。本论文提出的发现表明，CAI-1或CAI-1类似物可以用作预防霍乱感染的疗法，此外，操纵细菌群体感应的策略在临床上也很有希望。

著录项

  • 作者

    Higgins, Douglas Alexander.;

  • 作者单位

    Princeton University.;

  • 授予单位 Princeton University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 125 p.
  • 总页数 125
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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