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Created by Dr. Luis Agulló (last update on 12-6-2007)



Arginase Inhibitors



Most of the cells that synthesizes NO also contain arginase. Arginases are a group of enzymes that catalyze the hydrolysis of L-arginine to yield L-ornithine and urea. Arginase I is constitutively expressed and arginase II is induced by endotoxin. The role of arginase in the regulation of NO/cGMP system is probably understimated. This enzyme is clearly crucial in the modulation of NO production under inflammatory conditions (NO synthesis by NOS2), but it might also play an important role in constitutive synthesis of NO. See references 1-8 for additional information:

1Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ. Arginase activity in endothelial cells: inhibition by NG-hydroxy-L-arginine during high-output NO production. Am J Physiol 1996;271:H1988.

2Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci 1999;55:1015 REVIEW .

3Tenu JP, Lepoivre M, Moali C, Brollo M, Mansuy D, Boucher JL. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide 1999;3:427.

4Colleluori DM, Ash DE. Classical and slow-binding inhibitors of human type II arginase. Biochemistry 2001;40:9356.

5Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L. Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J 2003;17:2328.

6Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003;108:2000.

7Masuda H, Yano M, Sakai Y, Kihara K, Yamauchi Y, Azuma H. Modulation of intrinsic cavernous tone and nitric oxide production by arginase in rabbit corpus cavernosum. J Urol 2004;171:490.

8Zhang C, Hein TW, Wang W, Miller MW, Fossum TW, McDonald MM, Humphrey JD, Kuo L. Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide-Mediated Dilation of Coronary Arterioles Hypertension 2004;44:935.



BEC

[(S)-(2-Boronoethyl)-L-cysteine]

Potency: Ki= 313 nM (for human recombinant type II) 1

Membrane permeability: Y / Solubility: H2O / MW: 229.5 (hydrochloride)

Comments: Boronic acid-based arginine analog. Competitive inhibitor. Slow-binding competitive transition state inhibitor of arginases I and II; it does not inhibit NOS1.

1Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003;108:2000.

CAUTION: -


ABH

[2(S)-amino-6-boronohexanoic acid]

Potency: IC50= 0.05-0.44 µM; Ki= 0.018-0.19 µM 1

Membrane permeability: Y / Solubility: H2O / MW: 229.5 (hydrochloride)

Comments: Boronic acid-based arginine analog. Competitive inhibitor1.

1Baggio R, Emig FA, Christianson DW, Ash DE, Chakder S, Rattan S. Biochemical and functional profile of a newly developed potent and isozyme-selective arginase inhibitor. J Pharmacol Exp Ther 1999;290:1409.

CAUTION: -


NG-Hydroxy-L-arginine

[NOHA; L-HO-Arg]

Potency: : Ki= 150 µM1.

Membrane permeability: Y / Solubility: H2O / MW: 250.3 (monoacetate salt)

Comments: Intermediate in the biosynthesis of NO1. See references 2-5 for additional information.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences.

2Boucher JL, Custot J, Vadon S, Delaforge M, Lepoivre M, Tenu JP, Yapo A, Mansuy D. N(omega)-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase. Biochem Biophys Res Commun 1994;203:1614.

3Daghigh F, Fukuto JM, Ash DE. Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun 1994;202:174.

4Hecker M, Nematollahi H, Hey C, Busse R, Racke K. Inhibition of arginase by NG-hydroxy-L-arginine in alveolar macrophages: implications for the utilization of L-arginine for nitric oxide synthesis. FEBS Lett 1995;359:251.

5Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ. Arginase activity in endothelial cells: inhibition by NG-hydroxy-L-arginine during high-output NO production. Am J Physiol 1996;271:H1988.

CAUTION: NOHA oxidation by cytochrome P450 results in NO.


Nomega-Hydroxy-nor-L-arginine

[nor-NOHA; L-2-Amino-(4-(2'-hydroxyguanidino)butyric acid]

Potency: IC50= 2-50 µM1.

Membrane permeability: - / Solubility: H2O / MW: 296.3 (diacetate salt)

Comments: It is not substrate or inhibitor of NOS1. See reference 2 for additional information.

1Alexis Biochemicals.

2Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003;108:2000.

CAUTION: -

1Tenu JP, Lepoivre M, Moali C, Brollo M, Mansuy D, Boucher JL. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide 1999;3:427.


DFMO

[DL-alfa-Difluoromethylornithine]

Potency: -

Membrane permeability: - / Solubility: - / MW: -

Comments: Commonly used as ornithine decarboxylase (ODC) inhibitor. ODC is the rate-limiting enzyme in polyamine biosynthesis1.

1Alexis Biochemicals.

CAUTION: -






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