MECHANISMS FOR ENZYME CATALYSIS OF HETEROLYTIC REACTIONS

酶催化杂解反应的机制

基本信息

  • 批准号:
    3306773
  • 负责人:
  • 金额:
    $ 14.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1992
  • 资助国家:
    美国
  • 起止时间:
    1992-05-01 至 1996-04-30
  • 项目状态:
    已结题

项目摘要

Several problems are presented that are directly related to the mechanism for enzymatic catalysis of aldose-ketose isomerization reactions, glycosyl transfer reactions and aldol condensation reactions. The solutions to these problems have eluded investigations employing some of the most sophisticated experimental methods of mechanistic enzymology. This proposal describes how these problems may be resolved by an application of the tools and principles of physical organic chemistry. Three different projects are described. (1) It is not known whether the nonenzymatic or enzyme-catalyzed isomerization reactions of sugars proceed by a hydride or a proton transfer mechanism, or if general acids and metal ions are effective catalysts of these reactions. Questions about the nonenzymatic reactions will be resolved by a study of the isomerization of glyceraldehyde and a related substrate. Proton and hydride transfer reactions win be distinguished by use of deuterium or tritium-labelled compounds. Catalysis by general acids and metal ions will also be studied. (2) It is not known whether the glycosyl transfer reactions catalyzed by beta-galactosidase proceed by a mechanism with discrete chemical steps for every change in bonding, or by a concerted mechanism where two or more changes in bonding occur in a single step. These distinctions are necessary for the definition of the roles of the catalytically essential amino acid residues Glu-461 and Tyr-503. Stepwise and concerted mechanisms for the addition of nucleophiles to the galactosyl-enzyme intermediate (E-Gal) will be distinguished in a study of the reactions of nucleophilic anions. Stepwise and concerted mechanisms for general base-catalyzed cleavage of the acylal linkage will be distinguished by a determination of the effect of changing the basicity of the nucleophile on the reactivity of E-Gal toward alkyl alcohols and phenols, and the solvent deuterium isotope effects on these reactions. The transition state for the general base-catalyzed reaction will be characterized on a two-dimensional reaction coordinate profile. (3) The barrier for the addition reaction of an enolate ion to a carbonyl group in water will be determined, in order to assess whether it is advantageous for enzyme catalysts (e.g., aldolases) to stabilize the transition state for this reaction. The effectiveness of buffer acids as catalysts of addition of enolates to the carbonyl group will also be determined. It has been demonstrated on numerous occasions that studies on enzyme mechanisms may provide information critical for drug design (enzyme inhibitors), to the understanding metabolic diseases, and to the resolution of other health-related problems.
提出了几个与该机制直接相关的问题 对于醛糖-酮糖异构化反应的酶催化, 糖基转移反应和羟醛缩合反应。这个 这些问题的解决方案没有得到调查,这些调查使用了一些 机械酶学最复杂的实验方法。 该提案描述了如何通过 物理有机化学工具和原理的应用。 描述了三个不同的项目。 (1)目前尚不清楚是非酶还是酶催化的 由氢化物或质子进行的糖的异构化反应 转移机制,或一般酸和金属离子是否有效 这些反应的催化剂。关于非酶反应的几个问题 将通过研究甘油醛的异构化和一种 相关底物。质子和氢化物转移反应Win Be 以使用氚或氚标记的化合物来区分。 还将研究一般酸和金属离子的催化作用。(2)它是 尚不清楚由其催化的糖基转移反应是否 β-半乳糖苷酶通过离散化学步骤的机制进行 对于键的每一次变化,或通过协调机制,其中两个或 只需一步,就会发生更多的结合变化。这些区别是 对于定义催化本质的作用来说是必要的 氨基酸残基Glu-461和Tyr-503。循序渐进,步调一致 半乳糖基酶加成亲核试剂的机理 中间体(E-Gal)将在反应研究中加以区分 亲核阴离子。循序渐进的协调机制 碱基催化的酰基键的裂解将通过 改变亲核试剂碱性的效果测定 E-Gal对烷醇和苯酚的反应性 溶剂氚同位素对这些反应的影响。过渡时期 一般碱催化反应的状态将在 二维反应坐标分布。(3)设置障碍 烯醇离子与水中的羰基的加成反应将是 测定,以评估它是否对酶有利 催化剂(例如,醛缩酶)以稳定这一过渡态 反应。缓冲酸作为加成催化剂的有效性 还将测定羰基的烯醇化产物。 已经在许多场合证明,对酶的研究 机制可提供对药物设计(酶)至关重要的信息 抑制剂),了解代谢性疾病,以及 解决其他与健康有关的问题。

项目成果

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John P Richard其他文献

John P Richard的其他文献

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{{ truncateString('John P Richard', 18)}}的其他基金

Studies on Enzyme Activation and Novel Modes of Inhibition
酶激活和新抑制模式的研究
  • 批准号:
    10317064
  • 财政年份:
    2020
  • 资助金额:
    $ 14.06万
  • 项目类别:
Studies on Enzyme Activation and Novel Modes of Inhibition
酶激活和新抑制模式的研究
  • 批准号:
    10543563
  • 财政年份:
    2020
  • 资助金额:
    $ 14.06万
  • 项目类别:
Activation of Enzymes for Catalysis: The Role of Substrate-Induced Structural Changes
催化酶的激活:底物诱导的结构变化的作用
  • 批准号:
    9198549
  • 财政年份:
    2016
  • 资助金额:
    $ 14.06万
  • 项目类别:
Ribozymes for new genetic coding systems
用于新遗传编码系统的核酶
  • 批准号:
    7188027
  • 财政年份:
    2000
  • 资助金额:
    $ 14.06万
  • 项目类别:
Ribozymes for new genetic coding systems
用于新遗传编码系统的核酶
  • 批准号:
    7012204
  • 财政年份:
    2000
  • 资助金额:
    $ 14.06万
  • 项目类别:
Ribozymes for new genetic coding systems
用于新遗传编码系统的核酶
  • 批准号:
    6844940
  • 财政年份:
    2000
  • 资助金额:
    $ 14.06万
  • 项目类别:
MECHANISMS FOR ENZYME CATALYSIS OF HETEROLYTIC REACTION
酶催化杂解反应的机理
  • 批准号:
    2184725
  • 财政年份:
    1992
  • 资助金额:
    $ 14.06万
  • 项目类别:
MECHANISMS FOR ENZYME CATALYSIS OF HETEROLYTIC REACTION
酶催化杂解反应的机理
  • 批准号:
    2184726
  • 财政年份:
    1992
  • 资助金额:
    $ 14.06万
  • 项目类别:
MECHANISMS FOR ENZYME CATALYSIS OF HETEROLYTIC REACTIONS
酶催化杂解反应的机制
  • 批准号:
    3306774
  • 财政年份:
    1992
  • 资助金额:
    $ 14.06万
  • 项目类别:
MECHANISMS FOR ENZYME CATALYSIS OF HETEROLYTIC REACTION
酶催化杂解反应的机理
  • 批准号:
    3306775
  • 财政年份:
    1992
  • 资助金额:
    $ 14.06万
  • 项目类别:

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创伤性脑损伤后衰老相关β-半乳糖苷酶染色
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  • 财政年份:
    2004
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  • 批准号:
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  • 财政年份:
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  • 批准号:
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  • 财政年份:
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β-半乳糖苷酶缺陷型基因敲除小鼠的发病机制和治疗
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