© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Biological significance of endogenous methylarginines that inhibit nitric oxide synthases
Centre for Clinical Pharmacology & Therapeutics, University College London, London, UK
* Corresponding author. Tel.: +44-171-504-4088; fax. +44-171-837-1347 james.leiper{at}ucl.ac.uk
The guanidino-methylated arginine analogue NG monomethyl-L-arginine (L-NMMA) has been the standard nitric oxide synthase inhibitor used to evaluate the role of the L-arginine:nitric oxide pathway. However, L-NMMA and other methylated arginine residues are also synthesised in vivo by the action of a family of enzymes known as protein arginine methyltransferases. Proteolysis of proteins containing methylated arginine residues releases free methylarginine residues into the cytosol from where they may pass out of the cell into plasma. Of the three known methylarginine residues produced in mammals only asymmetrically methylated forms (L-NMMA and asymmetric dimethylarginine (ADMA)) but not symmetrically methylated arginine (symmetric dimethylarginine (SDMA)) inhibit nitric oxide synthase (NOS). We and others have proposed that endogenously produced asymmetrically methylated arginines may modulate NO production and that the accumulation of these residues in disease states may contribute to pathology. The activity of the enzyme dimethylarginine dimethylaminohydrolase that metabolises asymmetric methylarginines may be of critical importance in affecting NO pathways in health or disease.
KEYWORDS Dimethylarginine dimethylaminohydrolase; Methylarginine; Nitric oxide synthase
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Sharma, Z. Zhou, H. Miura, A. Papapetropoulos, E. T. McCarthy, R. Sharma, V. J. Savin, and E. A. Lianos ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1386 - F1395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Richir, R. H. Bouwman, T. Teerlink, M. P.C. Siroen, T. P.G.M. de Vries, and P. A.M. van Leeuwen The Prominent Role of the Liver in the Elimination of Asymmetric Dimethylarginine (ADMA) and the Consequences of Impaired Hepatic Function JPEN J Parenter Enteral Nutr, November 1, 2008; 32(6): 613 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Baylis Nitric oxide deficiency in chronic kidney disease Am J Physiol Renal Physiol, January 1, 2008; 294(1): F1 - F9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Malecki, A. Undas, K. Cyganek, B. Mirkiewicz-Sieradzka, P. Wolkow, G. Osmenda, M. Walus-Miarka, T. J. Guzik, and J. Sieradzki Plasma Asymmetric Dimethylarginine (ADMA) Is Associated With Retinopathy in Type 2 Diabetes Diabetes Care, November 1, 2007; 30(11): 2899 - 2901. [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Pope, L. Druhan, J. E. Guzman, S. P. Forbes, V. Murugesan, D. Lu, Y. Xia, L. G. Chicoine, N. L. Parinandi, and A. J. Cardounel Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1679 - C1686. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. C. Luiking and N. E. P. Deutz Biomarkers of Arginine and Lysine Excess J. Nutr., June 1, 2007; 137(6): 1662S - 1668S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Vassilakopoulos, K. Govindaraju, D. Parthenis, D. H. Eidelman, Y. Watanabe, and S. N. A. Hussain Nitric oxide production in the ventilatory muscles in response to acute resistive loading Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L1013 - L1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Gillard, C. G. Coburn, A. de Leon, E. P. Snissarenko, L. G. Bauce, Q. J. Pittman, B. Hou, and M. C. Curras-Collazo Vasopressin Autoreceptors and Nitric Oxide-Dependent Glutamate Release Are Required for Somatodendritic Vasopressin Release from Rat Magnocellular Neuroendocrine Cells Responding to Osmotic Stimuli Endocrinology, February 1, 2007; 148(2): 479 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Cardounel, H. Cui, A. Samouilov, W. Johnson, P. Kearns, A.-L. Tsai, V. Berka, and J. L. Zweier Evidence for the Pathophysiological Role of Endogenous Methylarginines in Regulation of Endothelial NO Production and Vascular Function J. Biol. Chem., January 12, 2007; 282(2): 879 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hu, M. Chouinard, A. L. Cox, P. Sipes, M. Marcelo, J. Ficorilli, S. Li, H. Gao, T. P. Ryan, M. D. Michael, et al. Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation J. Biol. Chem., December 29, 2006; 281(52): 39831 - 39838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. O. Yildirim, P. Bulau, D. Zakrzewicz, K. E. Kitowska, N. Weissmann, F. Grimminger, R. E. Morty, and O. Eickelberg Increased Protein Arginine Methylation in Chronic Hypoxia: Role of Protein Arginine Methyltransferases Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 436 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matsuguma, S. Ueda, S.-i. Yamagishi, Y. Matsumoto, U. Kaneyuki, R. Shibata, T. Fujimura, H. Matsuoka, M. Kimoto, S. Kato, et al. Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2176 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Leiper and P. Vallance New tricks from an old dog: nitric oxide-independent effects of dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1419 - 1420. [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Carello, S. E. Whitesall, M. C. Lloyd, S. S. Billecke, and L. G. D'Alecy Asymmetrical dimethylarginine plasma clearance persists after acute total nephrectomy in rats Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H209 - H216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fenning, G. Harrison, R. Rose'meyer, A. Hoey, and L. Brown L-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1408 - H1416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Baek and J. P. Shapleigh Expression of Nitrite and Nitric Oxide Reductases in Free-Living and Plant-Associated Agrobacterium tumefaciens C58 Cells Appl. Envir. Microbiol., August 1, 2005; 71(8): 4427 - 4436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ziegler, F. Mittermayer, C. Plank, E. Minar, M. Wolzt, and G.-H. Schernthaner Homocyst(e)ine-Lowering Therapy Does Not Affect Plasma Asymmetrical Dimethylarginine Concentrations in Patients with Peripheral Artery Disease J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2175 - 2178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Cardounel, Y. Xia, and J. L. Zweier Endogenous Methylarginines Modulate Superoxide as Well as Nitric Oxide Generation from Neuronal Nitric-oxide Synthase: DIFFERENCES IN THE EFFECTS OF MONOMETHYL- AND DIMETHYLARGININES IN THE PRESENCE AND ABSENCE OF TETRAHYDROBIOPTERIN J. Biol. Chem., March 4, 2005; 280(9): 7540 - 7549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cakir, O. Ozcan, H. Yaman, E. O. Akgul, C. Bilgi, M. K. Erbil, and Z. Yesilova Elevated Plasma Concentration of Asymmetric Dimethylarginine That Is Reduced by Single Dose Testosterone Administration in Idiopathic Hypogonadotropic Hypogonadism Patients J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1651 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Krzyzanowska, F. Mittermayer, H.-P. Kopp, M. Wolzt, and G. Schernthaner Weight Loss Reduces Circulating Asymmetrical Dimethylarginine Concentrations in Morbidly Obese Women J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6277 - 6281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Stuehr Enzymes of the L-Arginine to Nitric Oxide Pathway J. Nutr., October 1, 2004; 134(10): 2748S - 2751S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-D. Lajoix, M. Pugniere, F. Roquet, J.-C. Mani, S. Dietz, N. Linck, F. Faurie, G. Ribes, P. Petit, and R. Gross Changes in the Dimeric State of Neuronal Nitric Oxide Synthase Affect the Kinetics of Secretagogue-Induced Insulin Response Diabetes, June 1, 2004; 53(6): 1467 - 1474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vallance and J. Leiper Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1023 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Miranda, M. Miranda, A. Frankel, and S. Clarke PRMT7 Is a Member of the Protein Arginine Methyltransferase Family with a Distinct Substrate Specificity J. Biol. Chem., May 28, 2004; 279(22): 22902 - 22907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]
|
|
|
|
|
|
R. Kohli, C. J. Meininger, T. E. Haynes, W. Yan, J. T. Self, and G. Wu Dietary L-Arginine Supplementation Enhances Endothelial Nitric Oxide Synthesis in Streptozotocin-Induced Diabetic Rats J. Nutr., March 1, 2004; 134(3): 600 - 608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-M. Lu, Y.-A. Ding, S.-J. Lin, W.-S. Lee, and H.-C. Tai Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention Eur. Heart J., November 1, 2003; 24(21): 1912 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Simon, L. Plies, A. Habermeier, U. Martine, M. Reining, and E. I. Closs Role of Neutral Amino Acid Transport and Protein Breakdown for Substrate Supply of Nitric Oxide Synthase in Human Endothelial Cells Circ. Res., October 31, 2003; 93(9): 813 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R P Mookerjee, S Sen, N A Davies, S J Hodges, R Williams, and R Jalan Tumour necrosis factor {alpha} is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis Gut, August 1, 2003; 52(8): 1182 - 1187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Toda and T. Okamura The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels Pharmacol. Rev., June 1, 2003; 55(2): 271 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Afshar, L. L. Gibson, I. S. Yuhanna, T. S. Sherman, J. D. Kerecman, P. H. Grubb, B. A. Yoder, D. C. McCurnin, and P. W. Shaul Pulmonary NO synthase expression is attenuated in a fetal baboon model of chronic lung disease Am J Physiol Lung Cell Mol Physiol, May 1, 2003; 284(5): L749 - L758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ueda, S. Kato, H. Matsuoka, M. Kimoto, S. Okuda, M. Morimatsu, and T. Imaizumi Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine: Role of Dimethylarginine Dimethylaminohydrolase Circ. Res., February 7, 2003; 92(2): 226 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Knipp, O. Braun, P. M. Gehrig, R. Sack, and M. Vasak Zn(II)-free Dimethylargininase-1 (DDAH-1) Is Inhibited upon Specific Cys-S-Nitrosylation J. Biol. Chem., January 24, 2003; 278(5): 3410 - 3416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Loscalzo L-Arginine in Atherosclerosis: Consequences of Methylation Stress in a Complex Catabolism? Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 3 - 5. [Full Text] [PDF]
|
|
|
|
|
|
C. Hermenegildo, P. Medina, M. Peiro, G. Segarra, J. M. Vila, J. Ortega, and S. Lluch Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Hyperthyroid Patients J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5636 - 5640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Haslett, D. Sanoudou, A. T. Kho, R. R. Bennett, S. A. Greenberg, I. S. Kohane, A. H. Beggs, and L. M. Kunkel Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle PNAS, November 12, 2002; 99(23): 15000 - 15005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Nijveldt, P. A. M. van Leeuwen, C. van Guldener, C. D. A. Stehouwer, J. A. Rauwerda, and T. Teerlink Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans Nephrol. Dial. Transplant., November 1, 2002; 17(11): 1999 - 2002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Leiper, J. Murray-Rust, N. McDonald, and P. Vallance S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: Further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase PNAS, October 15, 2002; 99(21): 13527 - 13532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Paiva, J. Laakso, H. Laine, R. Laaksonen, J. Knuuti, and O. T. Raitakari Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1241 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Cardounel and J. L. Zweier Endogenous Methylarginines Regulate Neuronal Nitric-oxide Synthase and Prevent Excitotoxic Injury J. Biol. Chem., September 6, 2002; 277(37): 33995 - 34002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Maas, E. Schwedhelm, J. Albsmeier, and R. H Boger The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function Vascular Medicine, August 1, 2002; 7(3): 213 - 225. [Abstract] [PDF]
|
|
|
|
|
|
V. Achan, C. T.L. Tran, F. Arrigoni, G. St.J. Whitley, J. M. Leiper, and P. Vallance all-trans-Retinoic Acid Increases Nitric Oxide Synthesis by Endothelial Cells: A Role for the Induction of Dimethylarginine Dimethylaminohydrolase Circ. Res., April 19, 2002; 90(7): 764 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Stuhlinger, F. Abbasi, J. W. Chu, C. Lamendola, T. L. McLaughlin, J. P. Cooke, G. M. Reaven, and P. S. Tsao Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthase Inhibitor JAMA, March 20, 2002; 287(11): 1420 - 1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Walker, E. McGing, I. Fisher, R. H. Boger, S. M. Bode-Boger, G. Jackson, J. M. Ritter, and P. J. Chowienczyk Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: Lack of effect of oral l-arginine on endothelial function, oxidative stress and exercise performance J. Am. Coll. Cardiol., August 1, 2001; 38(2): 499 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Chambers, D. O. Haskard, and J. S. Kooner Vascular endothelial function and oxidative stress mechanisms in patients with Behcet's syndrome J. Am. Coll. Cardiol., February 1, 2001; 37(2): 517 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Channon, H. Qian, and S. E. George Nitric Oxide Synthase in Atherosclerosis and Vascular Injury : Insights From Experimental Gene Therapy Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1873 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Shah, P. Vallance, and D. Harrison NO in the cardiovascular system Cardiovasc Res, August 15, 1999; 43(3): 507 - 508. [Full Text] [PDF]
|
|
|
|
|
|
M. Knipp, J. M. Charnock, C. D. Garner, and M. Vasak Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain. Zn(II) RELEASE ACTIVATES DDAH-1 J. Biol. Chem., October 26, 2001; 276(44): 40449 - 40456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Achan, C. T.L. Tran, F. Arrigoni, G. St.J. Whitley, J. M. Leiper, and P. Vallance all-trans-Retinoic Acid Increases Nitric Oxide Synthesis by Endothelial Cells: A Role for the Induction of Dimethylarginine Dimethylaminohydrolase Circ. Res., April 19, 2002; 90(7): 764 - 769. [Abstract] [Full Text] [PDF]
|
|