Authors
Chang Dai, Zi-Han Wang, Mei-Han Guo, Li-Wei Zou
Published in
Biochemical pharmacology. Pages 118533. Oct 11, 2026. Epub Oct 11, 2026.
Abstract
Arginase (ARG), a binuclear manganese metalloenzyme, hydrolyzes L-arginine to L-ornithine and urea, competitively regulating NO bioavailability with NOS. Mammals express two isoforms, ARG1 (cytosolic) and ARG2 (mitochondrial), that share a conserved catalytic core yet exert distinct physiological and pathological effects. ARG1 is essential for hepatic urea detoxification, as systemic Arg1 knockout mice develop hyperammonemia within 10-12 days after birth; in contrast, Arg2 knockout mice show only slightly elevated plasma arginine levels with no overt phenotypic abnormalities, this significant difference highlights the importance of a thorough analysis of the functional divergence between ARG1 and ARG2. Pathologically, ARG1 drives immunosuppression in the tumor microenvironment, promotes vascular dysfunction in hypertension and atherosclerosis, and contributes to fibrotic remodeling; ARG2 fuels M1 macrophage inflammatory responses, modulates mitochondrial metabolism, and participates in neurodegeneration. This review systematically examines isoform differences across four dimensions: structural-functional divergence, localization-driven functional segregation, differential pathological contributions, and the current landscape of isoform-selective inhibitors. We further discuss rational design strategies for specific ligands and highlight the translational prospects of isoform-targeted therapies. Exploiting ARG1/ARG2 differentiation represents a promising avenue for precision intervention in cancer, cardiovascular disease, inflammation, and neurodegenerative disorders.
PMID:
42860192
Bibliographic data and abstract were imported from PubMed on 12 Oct 2026.
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