Targeting proteases in cardiovascular diseases by mass spectrometry-based proteomics.
Targeting proteases in cardiovascular diseases by mass spectrometry-based proteomics.
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通过基于质谱的蛋白质组学靶向心血管疾病中的蛋白酶。
DOI：
10.1161/circgenetics.110.957811
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Hardt,Markus
中科院分区：
文献类型：
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作者：
Klingler,Diana;Hardt,Markus
蛋白酶水解肽键，从而在翻译后水平上控制蛋白质和肽的功能。在心血管系统中，蛋白酶在血压、凝血和其他重要生理过程的调节中发挥着关键作用。因此，蛋白酶是治疗干预和诊断的主要靶标。蛋白酶是由酶、抑制剂、激活剂、底物和裂解产物组成的复杂蛋白水解网络的一部分。在系统范围内分析这些网络对于了解心血管功能以及失调如何导致病理状况至关重要。基于质谱的定量和动态蛋白质组学方法正在引领增强我们对蛋白水解网络（例如肾素-血管紧张素系统）的了解。在这里，我们批判性地回顾了蛋白酶生物学中使用的蛋白质组学工具，并概述了如何使用这些方法来表征和验证蛋白酶的功能。蛋白酶催化肽键的水解，从而导致蛋白质和肽链的裂解，从而导致蛋白质结构的不可逆改变。这一过程的基本性质使蛋白水解成为一种强大的翻译后修饰，可以控制蛋白质的功能和丰度。胃肠道中的消化蛋白酶相当不加区别地分解蛋白质，而参与细胞信号转导的肽酶则催化非常特异性的裂解反应以调节生物活性肽的丰度。不受控制的蛋白水解可能会带来灾难性的生理后果；因此，存在多种机制来严格调节蛋白水解过程。更基本的调节原则之一是底物特异性，其中蛋白酶的 3 维结构决定哪些底物可接近活性位点。其他调节机制包括从无活性前体（即酶原）激活蛋白酶以及将蛋白酶活性限制在特定的pH范围和区室（例如溶酶体蛋白酶）。另一个调节因素是蛋白水解网络成分的空间和时间相互作用。如果缺乏所有必需的因子（蛋白酶、底物及其各自的激活剂和抑制剂），反应可能不会发生（图 1）。肾素-血管紧张素系统可以作为蛋白水解网络如何调节生理过程的一个例子：1
Proteases hydrolyze peptide bonds, thereby controlling the function of proteins and peptides on the post-translational level. In the cardiovascular system, proteases play pivotal roles in the regulation of blood pressure, coagulation, and other essential physiological processes. Accordingly, proteases are prime targets for therapeutic interventions and diagnostics. Proteases are part of complex proteolytic networks comprised of enzymes, inhibitors, activators, substrates, and cleavage products. Analyzing these networks on a system-wide level is essential to understanding cardiovascular function and how disregulation can lead to pathological conditions. Mass spectrometry-based quantitative and dynamic proteomics approaches are leading the way to enhance our knowledge of proteolytic networks, such as the renin-angiotensin system. Here, we critically review proteomics tools used in protease biology and provide an overview on how these methods can be used to characterize and validate protease function.Proteases catalyze the hydrolysis of peptide bonds, which results in the cleavage of protein and peptide chains, and thereby lead to an irreversible change of protein structure. The fundamental nature of this process makes proteolysis a powerful post-translational modification that can control protein function and abundance. Digestive proteases in the gastrointestinal tract break down proteins fairly indiscriminately, while peptidases involved in cell signaling catalyze very specific cleavage reactions to regulate the abundances of bioactive peptides. Uncontrolled proteolysis could have disastrous physiological consequences; therefore, a multitude of mechanisms exist to tightly regulate proteolytic processing. One of the more basic regulatory principles is substrate specificity, in which the 3-dimensional structure of the protease determines which substrates are accessible to the active site. Other regulatory mechanisms include the activation of proteases from inactive precursors (ie, zymogens) and the limitation of protease activities to specific pH ranges and compartments (eg, lysosomal proteases). Another regulatory element is the spatial and temporal interplay of proteolytic network components; devoid of all required factors (proteases, substrates, and their respective activators and inhibitors) present, reactions may not occur (Figure 1). The renin-angiotensin system can serve as an example of how a proteolytic network regulates a physiological process: 1