Third Faculty of Medicine, Charles University in Prague, Czech Republic.
Curr Med Chem. 2012;19(10):1530-66. doi: 10.2174/092986712799828274.
Protein tyrosine phosphatases (PTPs) are increasingly recognized as important effectors of host-pathogen interactions. Since Guan and Dixon reported in 1990 that phosphatase YopH serves as an essential virulence determinant of Yersinia, the field shifted significantly forward, and dozens of PTPs were identified in various microorganisms and even in viruses. The discovery of extensive tyrosine signaling networks in non-metazoan organisms refuted the moth-eaten paradigm claiming that these organisms rely exclusively on phosphoserine/phosphothreonine signaling. Similarly to humans, phosphotyrosine signaling is thought to comprise a small fraction of total protein phosphorylation, but plays a disproportionately important role in cell-cycle control, differentiation, and invasiveness. Here we summarize the state-of-art knowledge on PTPs of important non-metazoan pathogens (Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gingivalis, Caulobacter crescentus, Yersinia, Synechocystis, Leishmania, Plasmodium falciparum, Entamoeba histolytica, etc.), and focus also at the microbial proteins affecting directly or indirectly the PTPs of the host (Mycobacterium tuberculosis MTSA-10, Bacillus anthracis anthrax toxin, streptococcal β protein, Helicobacter pylori CagA and VacA, Leishmania GP63 and EF-1α, Plasmodium hemozoin, etc.). This is the first review summarizing the knowledge on biological activity and pharmacological inhibition of non-metazoan PTPs, with the emphasis of those important in host-pathogen interactions. Targeting of numerous non-metazoan PTPs is simplified by the fact that they act either as ectophosphatases or are secreted outside of the pathogen. Interfering with tyrosine phosphorylation represents a powerful pharmacologic approach, and even though the PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.
蛋白质酪氨酸磷酸酶（PTPs）越来越被认为是宿主-病原体相互作用的重要效应物。自 1990 年 Guan 和 Dixon 报道磷酸酶 YopH 是耶尔森氏菌的重要毒力决定因素以来，该领域取得了重大进展，数十种 PTPs 在各种微生物中甚至病毒中被鉴定出来。在非后生动物中发现广泛的酪氨酸信号网络，驳斥了仅依赖磷酸丝氨酸/磷酸苏氨酸信号的陈旧观点。与人类一样，磷酸酪氨酸信号被认为只占总蛋白磷酸化的一小部分，但在细胞周期控制、分化和侵袭性方面起着不成比例的重要作用。在这里，我们总结了重要非后生动物病原体（李斯特菌、金黄色葡萄球菌、牙龈卟啉单胞菌、新月柄杆菌、耶尔森氏菌、集胞藻、利什曼原虫、疟原虫、溶组织内阿米巴等）的 PTP 最新知识，并重点关注直接或间接影响宿主 PTP 的微生物蛋白（结核分枝杆菌 MTSA-10、炭疽杆菌炭疽毒素、链球菌β蛋白、幽门螺杆菌 CagA 和 VacA、利什曼原虫 GP63 和 EF-1α、疟原虫血影蛋白等）。这是第一篇总结非后生动物 PTP 的生物学活性和药理学抑制的综述，重点是那些在宿主-病原体相互作用中重要的 PTP。由于它们要么作为外磷酸酶起作用，要么被分泌到病原体之外，因此靶向许多非后生动物 PTP 变得简单。干扰酪氨酸磷酸化是一种强大的药理方法，尽管 PTP 抑制剂难以开发，但消除磷酸酶抑制的迷雾具有巨大的市场潜力和进一步的临床影响。
