Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.

中文翻译：

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精氨酸酶的生物化学、药理学和体内功能。


精氨酸酶催化 L-精氨酸水解成 L-鸟氨酸和尿素。两种现有的亚型 Arg1 和 Arg2 显示出不同的细胞定位和代谢功能。精氨酸酶活性对于尿素循环中的氮解毒、多胺的合成以及 l-精氨酸生物利用度和一氧化氮产生的控制至关重要。尽管在对精氨酸酶的生物化学和功能的理解方面取得了重大进展，但仍存在一些悬而未决的问题。最近的研究表明，Arg1 和 Arg2 的调节和功能在小鼠和人类中具有细胞类型特异性、物种特异性和显著差异。主要区别在于 Arg1 和 Arg2 在免疫细胞和红细胞中的分布和功能。与以前的看法相反，在血管壁稳态条件下，Arg1 活性似乎仅与血管 NO 信号传导部分相关，但其表达在疾病条件下增加，并且可能通过精氨酸酶抑制剂治疗来靶向。Arg2 似乎主要是一种分解代谢酶，参与 L-鸟氨酸、多胺和脯氨酸的合成，但可能在血压控制中发挥推定的作用，至少在小鼠中是这样。精氨酸酶介导的精氨酸耗竭的免疫抑制作用是癌症治疗的一个有前途的靶点。本综述批判性地修订和讨论了精氨酸酶的生物化学、药理学和体内功能，重点介绍了从分析细胞特异性 Arg1 和 Arg2 敲除小鼠以及使用精氨酸酶抑制剂或聚乙二醇化重组精氨酸酶的人体研究中获得的见解。 意义声明 该综述强调需要进一步研究，以加深我们对不同细胞类型中 Arg1 和 Arg 2 调节的理解，同时考虑它们的定位、物种特异性以及多种生化和生理作用。这可能会导致更好的药理学策略，以靶向肝脏、心血管、血液、免疫/感染疾病和癌症中的精氨酸酶活性。