Proline Isomerization: From the Chemistry and Biology to Therapeutic Opportunities.
Proline Isomerization: From the Chemistry and Biology to Therapeutic Opportunities.
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作者：
脯氨酸异构化极大地影响蛋白质的折叠和功能，是一种独特的翻译后修饰，调节多种生物途径。尽管影响很大，但在生物系统中，作为一种调节机制的脯氨酸异构化的重要性和普遍性还没有得到充分的理解或认识。为了填补空白和带来新的认识，在这篇全面的综述中，我们试图将脯氨酸异构化的各个方面从其化学、历史发现、生物学功能以及相关疾病联系起来。这种独特的脯氨酸行为带来的治疗机会和未来与这一主题相关的迫切需求被清楚地传达出来。脯氨酸异构化是一种重要的、独特的翻译后修饰，它可以影响蛋白质的折叠和构象，最终调节蛋白质的功能和生物途径。尽管影响很大，但在生物系统中，作为一种调节机制的脯氨酸异构化的重要性和普遍性还没有得到充分的理解或认识。为了填补空白和带来新的认识，我们试图对Pro异构化进行全面的综述，首先介绍什么是Pro异构化及其背后的基本化学原理。在这一部分中，我们生动地展示了Pro具有显著丰度同时采用顺式和反式构象的独特能力的原因，源于这两种形式相似的空间位阻，而这两种形式不同于线性残基。然后我们讨论了历史上是如何发现Pro异构化的，然后介绍了所有三种类型的Pro异构酶，以及Pro异构化如何在细胞周期调节、DNA损伤修复、T细胞激活和离子通道门控等各种细胞反应中发挥作用。然后，我们探讨了与脯氨酸异构化失调有关的各种人类疾病。最后，我们总结了目前阶段开发的各种针对脯氨酸异构酶的抑制剂，作为治疗开发的一种策略。
Proline isomerization influences protein folding and function tremendously and serves as a unique type of post-translational modification that regulates multiple biological pathways. Although impactful, the importance and prevalence of proline isomerization as a regulation mechanism in biological systems has not been fully understood or recognized. Aiming to fill gaps and bring new awareness, in this wholistic review, we attempt to connect various aspects of proline isomerization from its chemistry, historic discovery, and biological function, to related diseases. Therapeutic opportunities opened up by this unique behavior of proline and future urgent needs pertinent to the topic are clearly communicated. Proline isomerization, the process of interconversion between the cis- and trans-forms of proline, is an important and unique post-translational modification that can affect protein folding and conformations, and ultimately regulate protein functions and biological pathways. Although impactful, the importance and prevalence of proline isomerization as a regulation mechanism in biological systems have not been fully understood or recognized. Aiming to fill gaps and bring new awareness, we attempt to provide a wholistic review on proline isomerization that firstly covers what proline isomerization is and the basic chemistry behind it. In this section, we vividly show that the cause of the unique ability of proline to adopt both cis- and trans-conformations in significant abundance is rooted from the steric hindrance of these two forms being similar, which is different from that in linear residues. We then discuss how proline isomerization was discovered historically followed by an introduction to all three types of proline isomerases and how proline isomerization plays a role in various cellular responses, such as cell cycle regulation, DNA damage repair, T-cell activation, and ion channel gating. We then explore various human diseases that have been linked to the dysregulation of proline isomerization. Finally, we wrap up with the current stage of various inhibitors developed to target proline isomerases as a strategy for therapeutic development.
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DOI：
10.3390/v15020457
发表时间：
2023-02-06
期刊：
Viruses
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Bjartmar, C;Trapp, BD
通讯作者：
Trapp, BD
影响因子：
6
作者：
Bao, L;Kimzey, A;Wang, DG
通讯作者：
Wang, DG
影响因子：
4
作者：
通讯作者：
--
影响因子：
14.9
作者：
Chao, SH;Greenleaf, AL;Price, DH
通讯作者：
Price, DH