Protein phosphatases and kinases control multiple cellular events including proliferation, differentiation, and stress responses through regulating reversible protein phosphorylation, the most important post-translational modification. Members of metal-dependent protein phosphatase (PPM) family, also known as PP2C phosphatases, are Ser/Thr phosphatases that bind manganese/magnesium ions (Mn²⁺/Mg²⁺) in their active center and function as single subunit enzymes. In mammals, there are 20 isoforms of PPM phosphatases: PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, ILKAP, PDP1, PDP2, PHLPP1, PHLPP2, PP2D1, PPTC7, and TAB1, whereas there are only 8 in yeast. Phylogenetic analysis of the DNA sequences of vertebrate PPM isoforms revealed that they can be divided into 12 different classes: PPM1A/PPM1B/PPM1N, PPM1D, PPM1E/PPM1F, PPM1G, PPM1H/PPM1J/PPM1M, PPM1K, PPM1L, ILKAP, PDP1/PDP2, PP2D1/PHLPP1/PHLPP2, TAB1, and PPTC7. PPM-family members have a conserved catalytic core region, which contains the metal-chelating residues. The different isoforms also have isoform specific regions within their catalytic core domain and terminal domains, and these regions may be involved in substrate recognition and/or functional regulation of the phosphatases. The twenty mammalian PPM phosphatases are involved in regulating diverse cellular functions, such as cell cycle control, cell differentiation, immune responses, and cell metabolism. Mutation, overexpression, or deletion of the PPM phosphatase gene results in abnormal cellular responses, which lead to various human diseases. This review focuses on the structures and biological functions of the PPM-phosphatase family and their associated diseases. The development of specific inhibitors against the PPM phosphatase family as a therapeutic strategy will also be discussed.

蛋白磷酸酶和激酶通过调节可逆蛋白磷酸化（最重要的翻译后修饰）来控制多种细胞事件，包括增殖、分化和应激反应。金属依赖性蛋白磷酸酶 (PPM) 家族的成员，也称为 PP2C 磷酸酶，是结合锰/镁离子 (Mn ²⁺ /Mg ²⁺) 在它们的活性中心并作为单亚基酶发挥作用。在哺乳动物中，有 20 种 PPM 磷酸酶亚型：PPM1A、PPM1B、PPM1D、PPM1E、PPM1F、PPM1G、PPM1H、PPM1J、PPM1K、PPM1L、PPM1M、PPM1N、ILKAP、PDP1、PDP2、PPHLPP2、PPHLPP2、 TAB1，而酵母中只有 8 个。脊椎动物 PPM 异构体 DNA 序列的系统发育分析表明，它们可以分为 12 个不同的类别：PPM1A/PPM1B/PPM1N、PPM1D、PPM1E/PPM1F、PPM1G、PPM1H/PPM1J/PPM1M、PPM1K、PPM1L、ILKPDP2 、PP2D1/PHLPP1/PHLPP2、TAB1 和 PPTC7。PPM 家族成员具有保守的催化核心区域，其中包含金属螯合残基。不同的异构体在其催化核心域和末端域中也具有异构体特定区域，这些区域可能参与底物识别和/或磷酸酶的功能调节。二十种哺乳动物 PPM 磷酸酶参与调节多种细胞功能，例如细胞周期控制、细胞分化、免疫反应和细胞代谢。PPM 磷酸酶基因的突变、过度表达或缺失会导致异常的细胞反应，从而导致各种人类疾病。本综述重点介绍 PPM-磷酸酶家族及其相关疾病的结构和生物学功能。还将讨论作为治疗策略的针对 PPM 磷酸酶家族的特异性抑制剂的开发。免疫反应和细胞代谢。PPM 磷酸酶基因的突变、过度表达或缺失会导致异常的细胞反应，从而导致各种人类疾病。本综述重点介绍 PPM-磷酸酶家族及其相关疾病的结构和生物学功能。还将讨论作为治疗策略的针对 PPM 磷酸酶家族的特异性抑制剂的开发。免疫反应和细胞代谢。PPM 磷酸酶基因的突变、过度表达或缺失会导致异常的细胞反应，从而导致各种人类疾病。本综述重点介绍 PPM-磷酸酶家族及其相关疾病的结构和生物学功能。还将讨论作为治疗策略的针对 PPM 磷酸酶家族的特异性抑制剂的开发。