Mechanistic Studies of Ribonucleotide Reductase

核糖核苷酸还原酶的机理研究

基本信息

  • 批准号:
    1213550
  • 负责人:
  • 金额:
    $ 39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

In this award from the Chemistry of Life Processes Program in the Chemistry Division, Dr. Gary Gerfen, from the Albert Einstein College of Medicine of Yeshiva University, will investigate the mechanism of turnover by and inhibition of the enzyme ribonucleoside triphosphate reductase. Ribonucleotide reductases (RNRs) are present in all cellular non-parasitic organisms characterized to date, and are also encoded by many DNA viruses. These enzymes catalyze the reduction of nucleotides to the corresponding deoxyribonucleotides, the only known means of de novo generation of precursors for both DNA replication and repair. Despite significant progress being made in the study of all classes of RNR recently, questions remain regarding mechanisms of substrate turnover, inactivation by mechanistic inhibitors and allosteric regulation. The objective of this award is to focus on the simplest representative RNR, ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii. Gaining insight into the reaction mechanism and allosteric regulation of this simplest of the ribonucleotide reductases will contribute to basic understanding of this important class of enzymes. Dr. Gerfen will investigate the mechanism of substrate turnover using ribonucleotides and active site mutants, and the mechanism of inhibition and inactivation using mechanism-based inhibitors. Finally, the structure and dynamics of regions of RTPR thought to be important for allosteric regulation will be probed using room temperature continuous wave and low temperature pulsed site directed spin label electron paramagnetic resonance techniques.Ribonucleotide reductases are enzymes that provide the only known way to make the building blocks of DNA in almost all organisms. Because DNA is crucial to every aspect of cellular function, these enzymes play an essential role in the metabolism of organisms from bacteria to humans. Defects in the structure and function of these enzymes lead to many diseases, and antibacterial and anticancer drugs designed to inhibit the function ribonucleotide reductases are currently in clinical use. However, it is not understood how the drugs that inactivate these enzymes function. Dr. Gerfen's work will give us better understanding of the basic mechanisms by which ribonucleotide reductases function.
在化学部生命过程计划的化学奖中,来自叶史瓦大学阿尔伯特爱因斯坦医学院的加里格芬博士将研究核糖核苷三磷酸还原酶的周转机制和抑制机制。核糖核苷酸还原酶(RNR)存在于迄今为止表征的所有细胞非寄生生物体中,并且也由许多DNA病毒编码。这些酶催化核苷酸还原为相应的脱氧核糖核苷酸,这是唯一已知的从头产生DNA复制和修复前体的方法。尽管最近在所有类别的RNR的研究中取得了重大进展,但关于底物周转、机械抑制剂失活和变构调节的机制仍存在问题。该奖项的目的是专注于最简单的代表性RNR,来自莱氏乳杆菌的核糖核苷三磷酸还原酶(RTPR)。深入了解这种最简单的核糖核苷酸还原酶的反应机制和变构调节将有助于对这类重要酶的基本理解。Gerfen博士将研究使用核糖核苷酸和活性位点突变体的底物周转机制,以及使用基于机制的抑制剂的抑制和失活机制。最后,RTPR区域的结构和动力学被认为是重要的变构调节将使用室温连续波和低温脉冲位点定向自旋标记电子顺磁共振techniques.Ribonucleotide reductases是酶,提供了唯一已知的方式,使在几乎所有的生物体的DNA的积木。由于DNA对细胞功能的各个方面都至关重要,因此这些酶在从细菌到人类的生物体的代谢中发挥着重要作用。这些酶的结构和功能的缺陷导致许多疾病,并且设计用于抑制核糖核苷酸还原酶功能的抗菌和抗癌药物目前在临床上使用。然而,目前还不清楚抑制这些酶的药物是如何发挥作用的。Gerfen博士的工作将使我们更好地了解核糖核苷酸还原酶发挥作用的基本机制。

项目成果

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Gary Gerfen其他文献

Structural and Functional Characterization of cTnT in Familial Hypertrophic Cardiomyopathy
  • DOI:
    10.1016/j.bpj.2008.12.2576
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Rachel K. Moore;John Wilson;Pia Guinto;Michael Riegelhaupt;Gary Gerfen;Jil Tardiff
  • 通讯作者:
    Jil Tardiff
Structural and Functional Characterization of the TNT1 Domain of Cardiac Troponin T
  • DOI:
    10.1016/j.bpj.2009.12.1934
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Rachel K. Moore;Pia J. Guinto;John Wilson;Gary Gerfen;Jil C. Tardiff
  • 通讯作者:
    Jil C. Tardiff
P121 - Hemoglobin as a source of long-lived bioactive nitric oxide: Evaluating the nitrite anhydrase reaction
  • DOI:
    10.1016/j.niox.2014.09.068
  • 发表时间:
    2014-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Joel Friedman;Camille Roche;Mahantesh Navati;Gary Gerfen
  • 通讯作者:
    Gary Gerfen

Gary Gerfen的其他文献

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{{ truncateString('Gary Gerfen', 18)}}的其他基金

Supporting Highlighting and Advancing Recent Developments in Electron Paramagnetic Resonance (SHARED EPR)
支持突出和推进电子顺磁共振(SHARED EPR)的最新发展
  • 批准号:
    1412700
  • 财政年份:
    2014
  • 资助金额:
    $ 39万
  • 项目类别:
    Continuing Grant
Development of Rapid Freeze-Quench Sample Preparation Techniques for Use in High Frequency Electron Paramagnetic Resonance
用于高频电子顺磁共振的快速冷冻淬火样品制备技术的开发
  • 批准号:
    0096713
  • 财政年份:
    2001
  • 资助金额:
    $ 39万
  • 项目类别:
    Continuing grant

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Biochemical and Biophysical Studies of Human Ribonucleotide Reductase
人核糖核苷酸还原酶的生化和生物物理研究
  • 批准号:
    10463910
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:
Biochemical and Biophysical Studies of Human Ribonucleotide Reductase
人核糖核苷酸还原酶的生化和生物物理研究
  • 批准号:
    10613912
  • 财政年份:
    2022
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  • 项目类别:
Cellular response to modulation of iron levels: studies examining ASK1, thioredoxin and ribonucleotide reductase
细胞对铁水平调节的反应:检查 ASK1、硫氧还蛋白和核糖核苷酸还原酶的研究
  • 批准号:
    nhmrc : 1035762
  • 财政年份:
    2012
  • 资助金额:
    $ 39万
  • 项目类别:
    Early Career Fellowships
SOLUTION SAXS STUDIES OF SUBUNIT INTERACTIONS IN RIBONUCLEOTIDE REDUCTASE
核糖核苷酸还原酶中亚基相互作用的解决方案 SAXS 研究
  • 批准号:
    8363533
  • 财政年份:
    2011
  • 资助金额:
    $ 39万
  • 项目类别:
Structural Studies of Ribonucleotide Reductase Complexes
核糖核苷酸还原酶复合物的结构研究
  • 批准号:
    8013604
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
STRUCTURAL STUDIES OF EUKARYOTIC RIBONUCLEOTIDE REDUCTASE
真核核糖核苷酸还原酶的结构研究
  • 批准号:
    8171985
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Structural Studies of Ribonucleotide Reductase Complexes
核糖核苷酸还原酶复合物的结构研究
  • 批准号:
    7806713
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
STRUCTURAL STUDIES OF YEAST RIBONUCLEOTIDE REDUCTASE, AMYLOID-RECOGNIZING ANT
酵母核糖核苷酸还原酶、淀粉样蛋白识别蚂蚁的结构研究
  • 批准号:
    7956850
  • 财政年份:
    2009
  • 资助金额:
    $ 39万
  • 项目类别:
STRUCTURAL STUDIES OF YEAST RIBONUCLEOTIDE REDUCTASE, AMYLOID-RECOGNIZING ANT
酵母核糖核苷酸还原酶、淀粉样蛋白识别蚂蚁的结构研究
  • 批准号:
    7956842
  • 财政年份:
    2009
  • 资助金额:
    $ 39万
  • 项目类别:
STRUCTURAL STUDIES OF YEAST RIBONUCLEOTIDE REDUCTASE, AMYLOID-RECOGNIZING ANT
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  • 批准号:
    7726006
  • 财政年份:
    2008
  • 资助金额:
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