Biosynthesis of Polysaccharides

多糖的生物合成

基本信息

  • 批准号:
    8337381
  • 负责人:
  • 金额:
    $ 29.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-08-03 至 2013-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Carbohydrates are ubiquitous in nature and play an essential role in a variety of important biological processes. In contrast to the in-depth understanding of the molecular mechanisms of nucleic acid and protein biosynthesis, polysaccharide biosynthesis is poorly understood. In spite of the remarkable structural diversity of polysaccharides, only three major elongation/polymerization mechanisms, namely wzy- dependent, ABC-transporter dependent and synthase-dependent, are utilized based on previous extensive genetic studies. Among them, the wzy-dependent pathway is the most widely used in nature. It has been implicated in the biosynthesis of a variety of hetero-polysaccharides such as O-polysaccharides, capsular polysaccharides, exo- polysaccharides, colonic acids and enterobacterial common antigens. The current working model for the wzy-dependent pathway is that the individual repeating oligosaccharide unit is synthesized in the cytoplasm by the sequential action of specific glycosyltransferases. The repeating unit is then transported to the periplasmic side of the membrane where it is polymerized into a polysaccharide by the polymerase Wzy. The chain length of the polymer is regulated by the Wzz protein. So far, with the exception of gene knockout experiments, this rough biosynthetic picture has never been experimentally tested in vitro. Most of the critical enzymes in the hypothesized pathway have never been biochemically characterized and their mechanisms of action (especially for the O-polysaccharide polymerization, regulation and transport) are rather speculative. In the past three years, using E. coli O86 O-polysaccharide as a model system, we have made significant progress towards understanding polysaccharide biosynthesis. In this proposed research period, we plan to focus on the following three specific aims: Aim 1. Chemo-enzymatic synthesis of O-unit-PP-lipid substrates/analogs. These chemically defined substrates will be used for probing Wzy polymerization reaction mechanism. Aim 2. Investigation of polymerase Wzy. This section includes development of in vitro assays to obtain reliable kinetics and investigation of lipid specificity and chain elongation direction. Aim 3. Investigation of Wzz and probing chain length regulation. This section includes the investigation of Wzy-Wzz interaction, Wzz-polysaccharide interaction and Wzz oligomeric states using a series of biochemical and biophysical approaches. In summary, this long-term research program will uncover the detailed biosynthetic mechanism of complex carbohydrate polymers. An in-depth understanding of biosynthesis of polysaccharides will have a considerable impact on research and development of novel antibiotics, vaccines, immuno-suppressors, and anti-inflammatory agents. PUBLIC HEALTH RELEVANCE: Many pathogenic bacteria species are surrounded by a capsular structure that is assembled from structurally diverse, high molecular weight polysaccharides. These cell surface polysaccharides play an essential role in mediating interactions between bacterial cells and their environment, and are recognized as an important pathogenic factor. Thus understanding how the polysaccharides are biosynthesized in the cell in molecular level is a fundamentally important biological question with significant medical implications. For example, it can provide new targets for the development of new antibiotics against emerging drug resistance problems; new methods to detect new pathogenic bacteria; new strategies to generate polysaccharide-based vaccines, immuno-suppressors and anti-inflammatory agents.
描述(由申请人提供):碳水化合物在自然界中普遍存在,并在各种重要的生物过程中发挥重要作用。与核酸和蛋白质生物合成的分子机制的深入理解相反,多糖生物合成的理解很少。尽管多糖具有显著的结构多样性,但基于先前广泛的遗传研究,仅利用了三种主要的延伸/聚合机制,即wzy依赖性、ABC转运蛋白依赖性和淀粉酶依赖性。其中,wzy依赖性途径是自然界中应用最广泛的途径。它与多种杂多糖如0-多糖、荚膜多糖、胞外多糖、结肠酸和肠细菌共同抗原的生物合成有关。目前wzy依赖性途径的工作模型是通过特异性糖基转移酶的顺序作用在细胞质中合成单个重复寡糖单元。然后将重复单元转运到膜的周质侧,在那里它通过聚合酶Wzy聚合成多糖。聚合物的链长由Wzz蛋白调节。到目前为止,除了基因敲除实验之外,这种粗略的生物合成图景从未在体外进行过实验测试。大多数的关键酶在假设的途径从来没有生化特性和他们的作用机制(特别是O-多糖聚合,调节和运输)是相当投机。在过去的三年里,利用E. coli O 86 O-多糖作为模型系统,我们在理解多糖生物合成方面取得了重大进展。在这一拟议的研究期间,我们计划重点关注以下三个具体目标:目标1。O-单元-PP-脂质底物/类似物的化学-酶促合成。这些化学定义的底物将用于探测Wzy聚合反应机理。目标2.聚合酶Wzy的研究。本节包括开发体外试验以获得可靠的动力学以及对脂质特异性和链延伸方向的研究。目标3.研究Wzz和探索链长调节。本节包括使用一系列生物化学和生物物理方法研究Wzy-Wzz相互作用、Wzz-多糖相互作用和Wzz寡聚状态。总之,这个长期的研究计划将揭示复杂碳水化合物聚合物的详细生物合成机制。对多糖生物合成的深入了解将对新型抗生素、疫苗、免疫抑制剂和抗炎剂的研究和开发产生相当大的影响。 公共卫生关系:许多致病菌被由结构多样的高分子量多糖组装而成的荚膜结构包围。这些细胞表面多糖在介导细菌细胞与其环境之间的相互作用中起重要作用,并且被认为是重要的致病因子。因此,从分子水平上了解多糖在细胞中的生物合成是一个具有重要医学意义的重要生物学问题。例如,它可以为开发针对新出现的耐药性问题的新抗生素提供新的目标;检测新病原菌的新方法;生产多糖疫苗,免疫抑制剂和抗炎剂的新策略。

项目成果

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Peng George Wang其他文献

"Armed and disarmed" theory in the addition of an azide radical to glucals
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Yunyan Zhao;Xiufang Xu;Wei Zhao;Peng George Wang;
  • 通讯作者:
Reply to Delanghe et al, Boudin et al, and Focosi et al
回复 Delanghe 等人、Boudin 等人和 Focosi 等人
  • DOI:
    10.1093/cid/ciaa1477
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    11.8
  • 作者:
    Jiao Zhao;Mingzhao Xing;Peng George Wang
  • 通讯作者:
    Peng George Wang
Characterization and application in recombinant emN/em-GlcNAc-protein production of a novel emendo/em-β-emN/em-acetylglucosaminidase from emListeria booriae/em
来自博氏李斯特菌的一种新型内切-β-N-乙酰氨基葡萄糖苷酶的特性及其在重组N-乙酰葡糖胺-蛋白质生产中的应用
  • DOI:
    10.1016/j.bioorg.2025.108290
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Weian Mao;Yongheng Rong;Hongmei Zhang;Fang Yuan;Yankang Wang;Mei Wang;Linhan Wang;Peng George Wang;Min Chen;Shengjun Wang;Yun Kong
  • 通讯作者:
    Yun Kong
Engineered yeast with PNGase F on cell surface for releasing of <em>N</em>-glycans from glycoproteins
  • DOI:
    10.1016/j.enzmictec.2006.10.029
  • 发表时间:
    2007-05-02
  • 期刊:
  • 影响因子:
  • 作者:
    Yishan Su;Houcheng Zhang;Li Gu;Min Chen;Min Xiao;Peng George Wang;Qingsheng Qi
  • 通讯作者:
    Qingsheng Qi
Bromocoumarinplatin, Targeting Simultaneous Mitochondrion and Cell Nucleus with p53 Apoptosis Pathway to Overcome Cisplatin Resistance.
  • DOI:
    org/10.1016/j.bioorg.2020.103768
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
  • 作者:
    Jing Ma;Linrong Li;Kexin Yue;Yingguang Li;Hanfang Liu;Peng George Wang;Chaojie Wang;Jiajia Wang;Wen Luo;Songqiang Xie
  • 通讯作者:
    Songqiang Xie

Peng George Wang的其他文献

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{{ truncateString('Peng George Wang', 18)}}的其他基金

Investigation on Oligosaccharides as Antimicrobial and Prebiotics
低聚糖作为抗菌剂和益生元的研究
  • 批准号:
    7741453
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Development of A Novel Strategy to Produce Antibacterial Glycoconjugate Vaccines
开发生产抗菌糖复合物疫苗的新策略
  • 批准号:
    7699611
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Investigation on Oligosaccharides as Antimicrobial and Prebiotics
低聚糖作为抗菌剂和益生元的研究
  • 批准号:
    8322023
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Research and Development of a Novel System to Produce Polysaccharide Conjugate Va
多糖复合物生产新系统的研究与开发
  • 批准号:
    8439987
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    8633090
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Research and Development of a Novel System to Produce Polysaccharide Conjugate Va
多糖复合物生产新系统的研究与开发
  • 批准号:
    7673238
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Development of A Novel Strategy to Produce Antibacterial Glycoconjugate Vaccines
开发生产抗菌糖复合物疫苗的新策略
  • 批准号:
    7932881
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    7906823
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Biosynthesis of Polysaccharides
多糖的生物合成
  • 批准号:
    8319742
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:
Hunting for Endogenous Ligands for Invariant Natural Killer T Cells
寻找恒定自然杀伤 T 细胞的内源配体
  • 批准号:
    7699675
  • 财政年份:
    2009
  • 资助金额:
    $ 29.74万
  • 项目类别:

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Lipid nanoparticle-mediated Inhalation delivery of anti-viral nucleic acids
脂质纳米颗粒介导的抗病毒核酸的吸入递送
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