nor-NOHA (acetate) (Synonyms: Nω-hydroxy-nor-Arginine)

nor-NOHA (acetate) (alpha-amino acid N(omega) -Hydroxy-Nor-L-arginine) is a potent and reversible selective arginase inhibitor, nor-NOHA (acetate) is about 40-fold more potent than NOHA to inhibit the hydrolysis of l-arginine to l-ornithine catalyzed by unstimulated murine macrophages (nor-NOHA IC(50) values 12 ±5µM^[4].

nor-NOHA (acetate) effectively induced apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Co-treatment with nor-NOHA (acetate) overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. its anti-leukemic activity was independent of ARG2 inhibition. nor-NOHA (acetate) has significant but off-target anti-leukemic activity among ARG2-expressing hypoxic cells^[3]. nor-NOHA (acetate) could inhibit the proliferation and induce the apoptosis of HepG2 cells. nor-NOHA (acetate) inhibited the invasion and migration of HepG2 cells. These data indicated that nor-NOHA (acetate) could induce cell apoptosis and inhibit the ability of invasion and migration of HepG2 cells by inhibiting Arg1^[1].Supplementation of nor-NOHA (acetate) in BMEC(bovine mammary epithelial cells) reduced cellular proliferation and casein synthesis. Addition of Arg to nor-NOHA (acetate) resulted in cellular proliferation and casein synthesis similar to that of nor-NOHA (acetate) alone. In contrast, addition of Orn to the medium with nor-NOHA (acetate) increased the synthesis of casein and cellular proliferation compared with nor-NOHA (acetate) ^[6].

nor-NOHA (acetate) treatment could fully restore the aortic response to Ach to that of healthy rats.Such beneficial effect was mediated by an increase in NOS activity and EDHF and reduced superoxide anion production, nor-NOHA (acetate) inhibited arginase activity in aorta with IC50 less than 1 µm ^[2].In Chinese Holstein cows .The activity of enzymes related to Arg metabolism, milk protein synthesis, and expression of AA transporters was determined. The infusion of nor-NOHA (acetate) decreased the activity of arginase. In addition, the infusion of nor-NOHA (acetate) also reduced protein and fat synthesis in milk but had no effect on milk yield^[5].Hyperthyroidism in rats is associated with the increased expression and activity of arginase in aorta, heart, and kidney. Chronic arginase inhibition with nor-NOHA (acetate) suppresses the characteristic hemodynamic manifestations of hyperthyroidism in association with a reduced oxidative stress^[7].

References:
[1]: Li X, Zhu F, et,al. [Arginase inhibitor nor-NOHA induces apoptosis and inhibits invasion and migration of HepG2 cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 Apr;33(4):477-482. Chinese. PMID: 28395717.
[2]: Prati C, Berthelot A, et,al. Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial function in rat adjuvant-induced arthritis. Arthritis Res Ther. 2012 May 30;14(3):R130. doi: 10.1186/ar3860. PMID: 22647483; PMCID: PMC3446511.
[3]: Ng KP, Manjeri A, et,al. The arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target. PLoS One. 2018 Oct 11;13(10):e0205254. doi: 10.1371/journal.pone.0205254. PMID: 30307989; PMCID: PMC6181325.
[4]: Tenu JP, Lepoivre M, et,al. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide. 1999 Dec;3(6):427-38. doi: 10.1006/niox.1999.0255. PMID: 10637120.
[5]: Ding LY, Chen LM, et,al.Inhibition of arginase via jugular infusion of Nω-hydroxy-nor-l-arginine inhibits casein synthesis in lactating dairy cows. J Dairy Sci. 2018 Apr;101(4):3514-3523. doi: 10.3168/jds.2017-13178. Epub 2018 Feb 4. PMID: 29397169.
[6]: Wang MZ, Ding LY, et,al. Short communication: Arginase inhibition reduces the synthesis of casein in bovine mammary epithelial cells. J Dairy Sci. 2017 May;100(5):4128-4133. doi: 10.3168/jds.2016-11823. Epub 2017 Feb 23. PMID: 28237582.
[7]: RodrÍguez-GÓmez I, Manuel Moreno J, et,al. Effects of Arginase Inhibition in Hypertensive Hyperthyroid Rats. Am J Hypertens. 2015 Dec;28(12):1464-72. doi: 10.1093/ajh/hpv049. Epub 2015 Apr 23. PMID: 25907224.