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首页> 外文学位 >Anaerobic Lipid A Palmitoylation in Pseudomonas aeruginosa is Regulated by Nitric Oxide Production.
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Anaerobic Lipid A Palmitoylation in Pseudomonas aeruginosa is Regulated by Nitric Oxide Production.

机译：铜绿假单胞菌中的厌氧脂质A棕榈酰化受一氧化氮产生的调节。

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摘要

Pseudomonas aeruginosa (PA) is a free-living Gram-negative opportunistic pathogen associated with long-term airway infections of patients with cystic fibrosis (CF). One early adaptation to the CF lung is production of a pro-inflammatory lipid A containing palmitate. Increasing inflammation leads to an increase in tissue destruction and lung function, ultimately resulting in premature death of the patient.;PagP, the biosynthetic enzyme responsible for this CF-specific modification of PA lipid A, had not yet been identified in PA. We identified PA1343 as a candidate gene with palmitoyltransferase activity. A deletion mutant was constructed and analyzed for changes in lipid A structure. The DeltaPA1343 mutant strain did not synthesize any palmitoylated lipid A species. Activity studies confirmed pro-inflammatory properties of palmitoylated lipid A as well as showed protection against specific cationic antimicrobial peptides.;Subsequent experiments focused on elucidating the mechanism by which PA PagP expression and activity through the two-component system, PhoP/Q were regulated. PA is known to replicate in the oxygen limited mucus plugs in patients' lungs. Growth of PA under oxygen limitation resulted in the synthesis of palmitoylated lipid A species. Further, deletion of phoP, phoQ, and pagP all resulted in a loss of palmitoylation under anaerobic growth conditions.;Anaerobic respiration in PA requires the involvement of the enzymes of the denitrification pathway. To determine if components of these pathways were stressors of PhoP/Q, palmitoyltransferase activity was determined after growth in media containing nitrate and nitrite. PA specifically lacking the nitrite reductase, NirS, was unable to synthesize palmitoylated lipid A structures.;The importance of the NirS component was believed to be due to enzyme activity and not merely structural interaction. Targeting of the active site of Nir, the heme d1 component confirmed the active enzyme was necessary. Growth of the nirS mutant, a NO deficient strain, was grown with the NO over-producing norC mutant. This restored the lipid A phenotype confirming the production of NO leads to anaerobic lipid A palmitoylation.;Collectively, this data indicates production of subinhibitory concentrations of NO within the CF lung contributes to disease progression by increasing signals leading to modification but not bacterial clearance.
机译：铜绿假单胞菌（PA）是一种与革兰氏阴性的机会性病原体，与囊性纤维化（CF）患者的长期气道感染有关。对CF肺的早期适应是产生含有棕榈酸酯的促炎脂质A。炎症的增加导致组织破坏和肺功能的增加，最终导致患者过早死亡。； PAgP是负责PA脂质A的CF特异性修饰的生物合成酶，尚未在PA中鉴定出来。我们确定PA1343为具有棕榈酰转移酶活性的候选基因。构建缺失突变体并分析脂质A结构的变化。 DeltaPA1343突变株未合成任何棕榈酰化的脂质A。活性研究证实了棕榈酰化脂质A的促炎特性，并显示了对特定阳离子抗菌肽的保护作用;随后的实验着眼于阐明通过两组分系统PhoP / Q调节PA PagP表达和活性的机制。已知PA在患者肺部的氧气受限的粘液栓塞中复制。在氧限制下PA的生长导致棕榈酰化脂质A物质的合成。此外，phoP，phoQ和pagP的缺失均导致厌氧生长条件下棕榈酰化的丧失。PA中的厌氧呼吸需要反硝化途径的酶参与。为了确定这些途径的成分是否是PhoP / Q的应激源，在含有硝酸盐和亚硝酸盐的培养基中生长后测定棕榈酰转移酶的活性。特别缺乏亚硝酸还原酶NirS的PA无法合成棕榈酰化的脂质A结构。NirS组分的重要性被认为是由于酶的活性，而不仅仅是结构的相互作用。血红素d1组分靶向Nir的活性位点，证实活性酶是必需的。 nirS突变体（NO缺乏菌株）的生长与NO过量产生的norC突变体一起生长。这恢复了脂质A的表型，证实了NO的产生导致了厌氧性脂质A的棕榈酰化。总体而言，该数据表明CF肺内亚抑制浓度的NO的产生通过增加导致修饰但不引起细菌清除的信号来促进疾病进展。

著录项

  • 作者

    Hittle, Lauren Elizabeth.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 198 p.
  • 总页数 198
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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