Biochemistry, pharmacology, and in vivo function of arginases

The enzyme arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea. The 2 existing isoforms Arg1 and Arg2 exhibit 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 (NO) 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 are 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 l-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 arginases, 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: Further basic and translational research is needed to deepen our understanding of the regulation of Arg1 and Arg2 in different cell types in consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This will lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infectious diseases, and cancer.