Burke T R, Zhang Z Y
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, MD 20892, USA.
Biopolymers. 1998;47(3):225-41. doi: 10.1002/(SICI)1097-0282(1998)47:3<225::AID-BIP3>3.0.CO;2-O.
Protein-tyrosine kinases (PTKs) and their associated signaling pathways are crucial for the regulation of numerous cell functions including growth, mitogenesis, motility, cell-cell interactions, metabolism, gene transcription, and the immune response. Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation states of proteins are governed by the opposing actions of PTKs and protein-tyrosine phosphatases (PTPs). In this light, both PTKs and PTPs play equally important roles in signal transduction in eukaryotic cells, and comprehension of mechanisms behind the reversible pTyr-dependent modulation of protein function and cell physiology must necessarily encompass the characterization of PTPs as well as PTKs. In spite of the large number of PTPs identified to date and the emerging role played by PTPs in disease, a detailed understanding of the role played by PTPs in signaling pathways has been hampered by the absence of PTP-specific agents. Such PTP-specific inhibitors could potentially serve as useful tools in determining the physiological significance of protein tyrosine phosphorylation in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. The goal of this review is therefore to summarize current understandings of PTP structure and mechanism of catalysis and the relationship of these to PTP inhibitor development. The review is organized such that enzyme structure is covered first, followed by mechanisms of catalysis then PTP inhibitor development. In discussing PTP inhibitor development, nonspecific inhibitors and those obtained by screening methods are initially presented with the focus then shifting to inhibitors that utilize a more structure-based rationale.
蛋白酪氨酸激酶（PTKs）及其相关信号通路对于调节众多细胞功能至关重要，这些功能包括生长、有丝分裂、运动、细胞间相互作用、代谢、基因转录和免疫反应。由于酪氨酸磷酸化在体内是可逆且动态的，蛋白质的磷酸化状态受PTKs和蛋白酪氨酸磷酸酶（PTPs）的相反作用支配。因此，PTKs和PTPs在真核细胞信号转导中发挥着同等重要的作用，要理解蛋白质功能和细胞生理学中依赖于酪氨酸磷酸化的可逆调节背后的机制，必然需要对PTPs以及PTKs进行表征。尽管迄今为止已鉴定出大量的PTPs，且PTPs在疾病中发挥着越来越重要的作用，但由于缺乏PTP特异性试剂，对PTPs在信号通路中所起作用的详细了解受到了阻碍。这种PTP特异性抑制剂可能会成为确定复杂细胞信号转导通路中蛋白质酪氨酸磷酸化生理意义的有用工具，并可能成为治疗多种人类疾病的有价值的治疗方法。因此，本综述的目的是总结目前对PTP结构、催化机制以及它们与PTP抑制剂开发之间关系的理解。综述的组织方式是首先介绍酶结构，接着是催化机制，然后是PTP抑制剂开发。在讨论PTP抑制剂开发时，首先介绍非特异性抑制剂和通过筛选方法获得的抑制剂，然后将重点转向基于更合理结构的抑制剂。
