Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships

丙二酰硫酯电子等排体测定酶的结构-功能关系

基本信息

  • 批准号:
    10263242
  • 负责人:
  • 金额:
    $ 30.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-20 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Malonyl-thioesters are one of the major reactive intermediates in the biosynthesis of fatty acids and polyketides. Because fatty acids are essential to cellular life, the inhibition of fatty acid synthases is a viable mechanism for the generation of antimicrobials, anticancer agents and control of metabolic disease. Polyketides on the other hand are widely used as antibiotics and anticancer agents, making polyketide synthases targets for enzyme engineering. While most intermediates in fatty acid and polyketide biosynthesis are used in reversible reactions, malonyl-thioesters are created in and used in essentially irreversible reactions. This makes studying the enzyme:malonyl-thioester interactions virtually impossible because the malonyl-thioesters are destroyed in the process. To overcome this problem analogs of malonyl-thioesters were generated by other researchers. These analogs replace the thioester ketone with a thioether or oxetane, both of which are stable to enzymatic activity. However, neither of these analogs bind in enzyme active sites in catalytically relevant orientations. Thus, there is a critical need to develop stable malonyl-thioester isosteres capable of binding in enzyme active sites to elucidate molecular interactions and conformational changes leading to efficient catalysis. The objective of this proposal is to overcome problems associated with the natural malonyl-thioesters and previously synthesized isosteres. We have a panel of malonyl-thioesters that preserve a key ketone lost in the previous isosteres. Our first aim is to solve crystal or cryo-EM structures of acyl-CoA carboxylase enzymes in complex with our best isosteres to elucidate the enzyme:substrate interactions and conformational changes. Our second aim is to solve crystal, cryo-EM or NMR structures of ȕ-ketoacyl synthase enzymes in complex with our best isosteres to elucidate enzyme:substrate interactions and conformational changes. Together these studies will validate the use of malonyl-thioester analogs with carboxylate isosteres to capture enzyme:substrate interactions. Our structures will reveal conformational changes during catalysis that can be targeted for drug design and that need to be accounted for during enzyme engineering.
项目摘要/摘要 丙二酰thioesters是脂肪酸和聚酮化合物生物合成的主要反应性中间体之一。 由于脂肪酸对于细胞寿命至关重要,因此脂肪酸合酶的抑制是可行的机制 抗菌药物,抗癌剂和代谢疾病的控制。另一个 手被广泛用作抗生素和抗癌剂,使聚酮化合物合成酶靶标成为酶的靶标 工程。虽然大多数脂肪酸和聚酮化合物生物合成中的中间体用于可逆反应,但 在基本不可逆的反应中创建并使用丙二酰thioesters。这使得研究 酶:Malonyl-Thioester相互作用几乎是不可能的,因为在 过程。为了克服这个问题的疟疾thioesters类似物,是由其他研究人员产生的。这些 类似物用硫乙烷或氧烷代替硫酯酮,两者都稳定在酶活性上。 但是,这些类似物在催化相关方向中均未结合酶的活性位点。那,那里 是开发能够在酶活性位点结合的稳定的丙二酰thioester Isosteres的迫切需要 阐明分子相互作用和会议变化,导致有效催化。这个目的 提案是要克服与自然丙二酰thioesters相关的问题,并以前合成 等值剂。我们有一个丙号型thioesters的小组,可以保留以前的ISOSTESTERS中损失的关键酮。我们的 第一个目的是解决与我们最好 阐明酶的等值剂:底物相互作用和构象变化。我们的第二个目标是解决 晶体,冷冻EM或NMR结构的ȕ-酮酰基合酶与我们最好的等值器中的复合物中的晶体结构 阐明酶:底物相互作用和构象变化。这些研究将共同​​验证 使用与羧酸盐等当等于捕获酶的丙二酰 - 硫酯类似物:底物相互作用。我们的 结构将揭示催化过程中的构象变化,可以针对药物设计,需要 在酶工程期间被解释。

项目成果

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Jeremy Ray Lohman其他文献

Jeremy Ray Lohman的其他文献

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{{ truncateString('Jeremy Ray Lohman', 18)}}的其他基金

Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10100290
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:
Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10891838
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:
Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10453633
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:
Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships - Undergrad Supplement
用丙二酰硫酯等排体确定酶的结构-功能关系 - 本科生补充材料
  • 批准号:
    10393793
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:

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Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10100290
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:
Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10891838
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
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Malonyl-thioester Isosteres to Determine Enzyme Structure-Function Relationships
丙二酰硫酯电子等排体测定酶的结构-功能关系
  • 批准号:
    10453633
  • 财政年份:
    2020
  • 资助金额:
    $ 30.38万
  • 项目类别:
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脂肪酸代谢酶的结构生物学
  • 批准号:
    7802861
  • 财政年份:
    2004
  • 资助金额:
    $ 30.38万
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Structural biology of enzymes in fatty acid metabolism
脂肪酸代谢酶的结构生物学
  • 批准号:
    8266394
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    2004
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