Chemistry and Biology of Bacterial Sulfonucleotide Reductases

细菌磺核苷酸还原酶的化学和生物学

基本信息

  • 批准号:
    8090538
  • 负责人:
  • 金额:
    $ 24.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-12-01 至 2013-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Sulfur metabolic pathways are essential for the virulence and survival of human pathogens. In microbial cysteine biosynthesis, sulfonucleotide reductases (SRs) catalyze the reduction of 5'-phosphosulfoadenosine (APS) or 3'-phospho-5'phosphosulfoadenosine (PAPS) to sulfite using reducing equivalents from a protein cofactor, thioredoxin (Trx). In later stages, sulfite is further reduced to sulfide, which is used for the production of essential sulfur-containing metabolites including cysteine, methionine, coenzymes, iron-sulfur clusters and antioxidants. SRs are excellent new targets for antibiotic development because of their critical role in bacterial survival and the lack of analogous enzymes in humans. This class of enzymes is particularly intriguing due to the nature of the chemical reaction they catalyze. In addition, our preliminary results suggest that a highly unusual iron-sulfur cluster in APS reductase may play an important catalytic role. However, many fundamental questions about their mechanism and structure remain unknown. Because the chemistry and biology of bacterial SRs is not well understood, scientists have not been able to explore the potential of these enzymes as anti-infective targets. To this end, the broad goal of this project is directed towards obtaining detailed mechanistic and structural information on bacterial SRs, and on identifying small molecule inhibitors of SRs. The proposed research has three Specific Aims: (1) To elucidate the function of the [4Fe-4S] cluster in APS reductase, (2) To investigate large-scale conformational dynamics in the SR catalytic cycle, and (3) To discover SR inhibitors using library screening and virtual docking approaches. This work may lead to the development of antibiotics that can be used to combat drug-resistant bacteria, which would have a major impact on human health. Furthermore, we anticipate that these experiments will lead to important new fundamental insights into the (bio)chemistry of protein-associated iron-sulfur clusters and bacterial sulfur metabolism. PUBLIC HEALTH RELEVANCE: Bacterial must assimilate sulfate from their environment in order to survive and initiate human infections. The discovery of methods to block this process could have a profound impact of public health. There is an urgent, global need for new antimicrobial therapies; the ability to interfere with bacterial virulence by intercepting sulfate metabolism represents a completely new therapeutic approach and is clinically timely.
描述(由申请人提供):硫代谢途径对人类病原体的毒力和存活至关重要。在微生物半胱氨酸生物合成中,磺核苷酸还原酶(SR)催化5 '-磷酸磺基腺苷(APS)或3'-磷酸-5 '-磷酸磺基腺苷(PAPS)使用来自蛋白质辅因子硫氧还蛋白(Trx)的还原当量还原成亚硫酸盐。在后期阶段,亚硫酸盐进一步还原为硫化物,其用于生产必需的含硫代谢物,包括半胱氨酸、甲硫氨酸、辅酶、铁硫簇和抗氧化剂。SR是抗生素开发的极好的新靶点,因为它们在细菌存活中起着关键作用,并且在人类中缺乏类似的酶。这类酶由于它们催化的化学反应的性质而特别有趣。此外,我们的初步结果表明,一个非常不寻常的铁硫簇在APS还原酶可能发挥重要的催化作用。然而,关于它们的机制和结构的许多基本问题仍然未知。由于细菌SR的化学和生物学尚未得到很好的理解,科学家们还无法探索这些酶作为抗感染靶点的潜力。为此,该项目的主要目标是获得有关细菌SR的详细机制和结构信息,并确定SR的小分子抑制剂。本论文的主要目的是:(1)阐明APS还原酶中[4Fe-4S]簇的功能;(2)研究SR催化循环中的大尺度构象动力学;(3)利用文库筛选和虚拟对接技术发现SR抑制剂。这项工作可能会导致抗生素的开发,可用于对抗耐药细菌,这将对人类健康产生重大影响。此外,我们预计,这些实验将导致重要的新的基本见解蛋白质相关的铁硫簇和细菌硫代谢的(生物)化学。公共卫生相关性:细菌必须从其环境中吸收硫酸盐才能生存并引发人类感染。发现阻止这一过程的方法可能会对公共卫生产生深远的影响。全球迫切需要新的抗微生物疗法;通过阻断硫酸盐代谢来干扰细菌毒力的能力代表了一种全新的治疗方法,在临床上是及时的。

项目成果

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Kate Suzanne Carroll其他文献

Kate Suzanne Carroll的其他文献

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{{ truncateString('Kate Suzanne Carroll', 18)}}的其他基金

Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
  • 批准号:
    10162539
  • 财政年份:
    2018
  • 资助金额:
    $ 24.31万
  • 项目类别:
Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
  • 批准号:
    10595875
  • 财政年份:
    2018
  • 资助金额:
    $ 24.31万
  • 项目类别:
Redox Modification and Targeting of Mutant KRas in Cancer
癌症中突变 KRa 的氧化还原修饰和靶向
  • 批准号:
    9912729
  • 财政年份:
    2018
  • 资助金额:
    $ 24.31万
  • 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
  • 批准号:
    9187426
  • 财政年份:
    2013
  • 资助金额:
    $ 24.31万
  • 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
  • 批准号:
    8969670
  • 财政年份:
    2013
  • 资助金额:
    $ 24.31万
  • 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
  • 批准号:
    8776280
  • 财政年份:
    2013
  • 资助金额:
    $ 24.31万
  • 项目类别:
Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases
用于靶向氧化还原敏感激酶的亲核抑制剂
  • 批准号:
    8631369
  • 财政年份:
    2013
  • 资助金额:
    $ 24.31万
  • 项目类别:
Probing the role of cysteine sulfenylation in cell signaling
探讨半胱氨酸磺酰化在细胞信号传导中的作用
  • 批准号:
    8653970
  • 财政年份:
    2012
  • 资助金额:
    $ 24.31万
  • 项目类别:
Probing the role of cysteine sulfenylation in cell signaling
探讨半胱氨酸磺酰化在细胞信号传导中的作用
  • 批准号:
    8342423
  • 财政年份:
    2012
  • 资助金额:
    $ 24.31万
  • 项目类别:
Chemical Tools for Probing Cysteine Sulfenation and Sulfination Redox Biology
用于探测半胱氨酸磺化和磺化氧化还原生物学的化学工具
  • 批准号:
    10658440
  • 财政年份:
    2012
  • 资助金额:
    $ 24.31万
  • 项目类别:

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