超分子多价值效应增强水性介质中的胺基形成,允许动态修改酶活性
Ferran Esteve1, Fidan Rahmatova1, Jean-Marie Lehn1
1Laboratoire de Chimie Supramoléculaire, Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg 8 allée Gaspard Monge 67000 Strasbourg France estevefranch@unistra.fr lehn@unistra.fr.
Chemical science
|September 29, 2023
概括
超分子多价性在生理条件下增强 imine 稳定性. 这一突破使可逆蛋白质生物结合和动态酶抑制成为可能,克服了化学生物学中的挑战.
科学领域:
- 超分子化学 超分子化学
- 有机合成 有机合成
- 化学生物学 化学生物学
背景情况:
- 伊胺形成在生物系统中至关重要,但由于在生理条件下胺的水解不稳定性而具有挑战性.
- 现有的方法通常需要恶劣的条件或缺乏特异性,限制它们在复杂的生物环境中的应用.
研究的目的:
- 研究超分子多价值对增强在生理条件下形成的 imines 的稳定性的影响.
- 为控制和可逆生物结合应用开发新型反应性化物.
- 探索使用超分子稳定酶的动态酶抑制和恢复的潜力.
主要方法:
- 新型反应性化物的合成,其中包含超分子活性位点 (例如,碳酸盐群).
- 与模型化物相比,对伊米因形成效率和稳定性的评估.
- 用氨基酸衍生物,和模型酶进行可逆结合的测试.
主要成果:
- 超分子多价性显著增加了胺基稳定性,在含有两个碳酸盐组的化物中观察到最佳性能.
- 超分子多价值性下降导致imine产量下降,这表明多价值性和稳定性之间存在直接的相关性.
- 用氨基酸衍生物和来实现Nα imine形成的高选择性,即使存在竞争性功能组.
- 一个模型酶通过伊胺形成被动性抑制,通过使用乙烯基化物效应剂将伊胺键位移而恢复活性.
结论:
- 超分子多价性是一种强大的策略,可以在生理条件下稳定 imines,克服固有的水解不稳定性.
- 开发的化物为可逆生物结合,改和蛋白质功能的动态控制提供了一个多功能平台.
- 这种方法对化学生物学,药物输送和诊断领域的应用具有前景,这些领域需要可控和可逆的分子相互作用.
相关概念视频
01:23Aldehydes and Ketones with Amines: Imine Formation Mechanism
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Imine formation involves the addition of carbonyl compounds to a primary amine. It begins with the generation of carbinolamine through a series of steps involving an initial nucleophilic attack and then several proton transfer reactions. The second part includes the elimination of water, as a leaving group, to give the imine.
Imines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the...
Imines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the...
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01:16Aldehydes and Ketones with Amines: Imine and Enamine Formation Overview
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Primary amines react with carbonyl compounds—aldehydes and ketones—to generate imines. Imines consist of a C=N double bond and are named Schiff bases after its discoverer—the German chemist Hugo Schiff. On the other hand, secondary amines react with carbonyl compounds to give enamines. In enamines, the presence of a C=C double bond adjacent to the nitrogen atom leads to the delocalization of the lone pair.
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01:14Aldehydes and Ketones with Amines: Enamine Formation Mechanism
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Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to...
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01:13Introduction to Mechanisms of Enzyme Catalysis
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For many years, scientists thought that enzyme-substrate binding took place in a simple "lock-and-key" fashion. This model stated that the enzyme and substrate fit together perfectly in one instantaneous step. However, current research supports a more refined view scientists call induced fit. The induced-fit model expands upon the lock-and-key model by describing a more dynamic interaction between enzyme and substrate. As the enzyme and substrate come together, their interaction causes...
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01:25Basicity of Heterocyclic Aromatic Amines
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Heterocyclic amines, where the N atom is a part of an alicyclic system, are similar in basicity to alkylamines. Interestingly, the heterocyclic amine having a nitrogen atom as part of an aromatic ring has much less basicity than its corresponding alicyclic counterpart. For this reason, as presented in Figure 1, piperidine (pKb = 2.8) is significantly more basic than pyridine (pKb = 8.8).
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