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The synthesis and metabolism of asymmetric dimethylarginine (ADMA)

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Abstract

Numerous reports have indicated that the plasma concentration of endogenously produced inhibitors of nitric oxide synthase are elevated in human disease states. In this review we discuss recent advances in our understanding of the enzymes responsible for the synthesis and metabolism of these inhibitors.

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References

  1. Kakimoto Y, Akazawa S (1970) Isolation and identification of N G,N G and N G,N′G dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. J Biol Chem 245:5751–5758

    PubMed  CAS  Google Scholar 

  2. Palmer RM, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666

    Article  PubMed  CAS  Google Scholar 

  3. Rees DD, Palmer RM, Hodson HF, Moncada S (1989) A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 96:418–424

    PubMed  CAS  Google Scholar 

  4. Whittle BJ, Lopez-Belmonte J, Rees DD (1989) Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol 98:646–652

    PubMed  CAS  Google Scholar 

  5. Aisaka K, Gross SS, Griffith OW, Levi R (1989) N G-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo? Biochem Biophys Res Commun 160:881–886

    Article  PubMed  CAS  Google Scholar 

  6. Vallance P, Collier J, Moncada S (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2:997–1000

    Article  PubMed  CAS  Google Scholar 

  7. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575

    Article  PubMed  CAS  Google Scholar 

  8. Clarke S (1993) Protein methylation. Curr Opin Cell Biol 5:977–983

    Article  PubMed  CAS  Google Scholar 

  9. Aletta JM, Cimato TR, Ettinger MJ (1998) Protein methylation: a signal event in post-translational modification. Trends Biochem Sci 23:89–91

    Article  PubMed  CAS  Google Scholar 

  10. Paik WK, Kim S (1968) Protein methylase I. Purification and properties of the enzyme. J Biol Chem 243:2108–2114

    PubMed  CAS  Google Scholar 

  11. Ghosh SK, Paik WK, Kim S (1988) Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein- and histone-specific enzyme. J Biol Chem 263:19024–19033

    PubMed  CAS  Google Scholar 

  12. Boffa LC, Karn J, Vidali G, Allfray VG (1977) Distribution of N G,N G-dimethylarginine in nuclear protein fractions. Biochem Biophys Res Commun 74:969–976

    Article  PubMed  CAS  Google Scholar 

  13. Brahms H, Raymackers J, Union A, de Keyser F, Meheus L, Luhrmann R (2000) The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J Biol Chem 275:17122–17129

    Article  PubMed  CAS  Google Scholar 

  14. Baldwin GS, Carnegie PR (1971) Isolation and partial characterization of methylated arginines from the encephalitogenic basic protein of myelin. Biochem J 123:69–74

    PubMed  CAS  Google Scholar 

  15. Miyake M, Kakimoto Y (1976) Synthesis and degradation of methylated proteins of mouse organs: correlation with protein synthesis and degradation. Metabolism 25:885–896

    Article  PubMed  CAS  Google Scholar 

  16. Garlick PJ, Waterlow JC, Swick RW (1976) Measurement of protein turnover in rat liver. Analysis of the complex curve for decay of label in a mixture of proteins. Biochem J 156:657–663

    PubMed  CAS  Google Scholar 

  17. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson J (1994) Molecular biology of the cell, 3rd edn. Garland Publishing, New York

    Google Scholar 

  18. Inoue R, Miyake M, Kanazawa A, Sato M, Kakimoto Y (1979) Decrease of 3-methylhistidine and increase of N G,N G -dimethylarginine in the urine of patients with muscular dystrophy. Metabolism 28:801–804

    Article  PubMed  CAS  Google Scholar 

  19. Millward DJ (1970) Protein turnover in skeletal muscle. II. The effect of starvation and a protein-free diet on the synthesis and catabolism of skeletal muscle proteins in comparison to liver. Clin Sci 39:591–603

    PubMed  CAS  Google Scholar 

  20. Goldberg AL, St John AC (1976) Intracellular protein degradation in mammalian and bacterial cells: part 2. Annu Rev Biochem 45:747–803

    Article  PubMed  CAS  Google Scholar 

  21. Dice JF, Walker CD (1979) Protein degradation in metabolic and nutritional disorders. Ciba Found Symp 75:331–350

    PubMed  Google Scholar 

  22. Parag HA, Raboy B, Kulka RG (1987) Effect of heat shock on protein degradation in mammalian cells: involvement of the ubiquitin system. EMBO J 6:55–61

    PubMed  CAS  Google Scholar 

  23. McDermott JR (1976) Studies on the catabolism of N G-methylarginine, N G,N G-dimethylarginine and N G,N′G-dimethylarginine in the rabbit. Biochem J 154:179–184

    PubMed  CAS  Google Scholar 

  24. Ogawa T, Kimoto M, Watanabe H, Sasaoka K (1987) Metabolism of N G,N G-and N G,N′G -dimethylarginine in rats. Arch Biochem Biophys 252:526–537

    Article  PubMed  CAS  Google Scholar 

  25. Ogawa T, Kimoto M, Sasaoka K (1989) Purification and properties of a new enzyme, N G,N G-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 264:10205–10209

    PubMed  CAS  Google Scholar 

  26. Kimoto M, Tsuji H, Ogawa T, Sasaoka K (1993) Detection of N G,N G-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch Biochem Biophys 300:657–662

    Article  PubMed  CAS  Google Scholar 

  27. Tojo A, Welch WJ, Bremer V, Kimoto M, Kimura K, Omata M, Ogawa T, Vallance P, Wilcox C (1997) Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 52:1593–1601

    Article  PubMed  CAS  Google Scholar 

  28. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell R, Hodson H, Whitley G, Vallance P (1996) Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540

    PubMed  CAS  Google Scholar 

  29. Kimoto M, Miyatake S, Sasagawa T, Yamashita H, Okita M, Oka T, Ogawa T, Tsuji H (1998) Purification, cDNA cloning and expression of human N G,N G-dimethylarginine dimethylaminohydrolase. Eur J Biochem 258:863–868

    Article  PubMed  CAS  Google Scholar 

  30. Leiper JM, Santa Maria J, Chubb A, MacAllister R, Charles I, Whitley G, Vallance P (1999) Identification of two human dimethylarginine dimethyl-aminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 343:209–214

    Article  PubMed  CAS  Google Scholar 

  31. Kimoto M, Sasakawa T, Tsuji H, Miyatake S, Oka T, Nio N, Ogawa T (1997) Cloning and sequencing of cDNA encoding N G,N G-dimethylarginine dimethylaminohydrolase from rat kidney. Biochim Biophys Acta 1337:6–10

    PubMed  CAS  Google Scholar 

  32. Santa Maria J, Vallance P, Charles IG, Leiper J (1999) Identification of microbial dimethylarginine dimethylaminohydrolase enzymes. Mol Microbiol 33:1278–1279

    Article  PubMed  CAS  Google Scholar 

  33. Adak S, Aulak KS, Stuehr DJ (2002) Direct evidence for nitric oxide production by a nitric-oxide synthase-like protein from Bacillus subtilis. J Biol Chem 277:16167–16171

    Article  PubMed  CAS  Google Scholar 

  34. Murray-Rust J, Leiper J, McAlister M, Phelan J, Tilley S, Santa Maria J, Vallance P, McDonald N (2001) Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Biol 8:679–683

    Article  PubMed  CAS  Google Scholar 

  35. Leiper J, Murray-Rust J, McDonald N, Vallance P (2002) S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A 99:13527–13532

    Article  PubMed  CAS  Google Scholar 

  36. Hand MF, Haynes WG, Webb DJ (1998) Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. Kidney Int 53:1068–1077

    Article  PubMed  CAS  Google Scholar 

  37. Cross JM, Donald AE, Kharbanda R, Deanfield J, Woolfson R, MacAllister R (2001) Acute administration of L-arginine does not improve arterial endothelial function in chronic renal failure. Kidney Int 60:2318–2323

    Article  PubMed  CAS  Google Scholar 

  38. Zoccali C, Bode-Böger SM, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frölich JC, Böger RH (2001) Plasma concentrations of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113–2117

    Article  PubMed  CAS  Google Scholar 

  39. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon M (1997) Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 15:901–909

    Article  PubMed  CAS  Google Scholar 

  40. Chen BM, Xia LW, Zhao RQ (1997) Determination of N G,N G-dimethylarginine in human plasma by high-performance liquid chromatography. J Chromatogr B 692:467–471

    Article  CAS  Google Scholar 

  41. Holden DP, Fickling SA, Whitley GS, Nussey S (1998) Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 178:551–556

    Article  PubMed  CAS  Google Scholar 

  42. Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y, Yasukawa H, Iwami G, Okuda S, Imaizumi T (1997) Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension 29(1 Pt 2):242–247

    PubMed  CAS  Google Scholar 

  43. Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer H (2001) Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 37:489–492

    Article  PubMed  CAS  Google Scholar 

  44. Böger RH, Bode-Böger SM, Kienke S, Stan A, Nafe R, Frölich JC (1998) Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis 136:67–77

    Article  PubMed  Google Scholar 

  45. Böger RH, Bode-Böger SM, Szuba A, Tsao P, Chan J, Tangphao O, Blaschke T, Cooke JP (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98:1842–1847

    PubMed  Google Scholar 

  46. Bode-Böger SM, Böger RH, Kienke S, Junker W, Frölich JC (1996) Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun 219:598–603

    Article  PubMed  Google Scholar 

  47. Herlitz H, Petersson A, Sigstrom L, Wennmalm A, Westberg G (1997) The arginine-nitric oxide pathway in thrombotic microangiopathy. Scand J Urol Nephrol 31:477–479

    Article  PubMed  CAS  Google Scholar 

  48. Azuma H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S (1995) Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharmacol 115:1001–1004

    PubMed  CAS  Google Scholar 

  49. Usui M, Matsuoka H, Miyazaki H, Udea S, Okuda S, Imaizumi T (1998) Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci 62:2425–2430

    Article  PubMed  CAS  Google Scholar 

  50. Feng Q, Lu X, Fortin AJ, Pettersson A, Hedner T, Kline R, Arnold J (1998) Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure. Cardiovasc Res 37:667–675

    Article  PubMed  CAS  Google Scholar 

  51. Piatti P, Fragasso G, Monti LD, Setola E, Lucotti P, Fermo I, Paroni R, Galluccio E, Pozza G, Chierchia S, Margonato A (2003) Acute intravenous L-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms: correlation with asymmetric dimethylarginine levels. Circulation 107:429–436

    Article  PubMed  CAS  Google Scholar 

  52. Masuda H, Goto M, Tamaoki S, Azuma H (1999) Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol 126:211–218

    Article  PubMed  CAS  Google Scholar 

  53. Abbasi F, Asagmi T, Cooke JP, Lamendola C, McLaughlin T, Teaven G, Stuehlinger M, Tsao P (2001) Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 88:1201–1203

    Article  PubMed  CAS  Google Scholar 

  54. Böger RH, Bode-Böger SM, Sydow K, Heistad D, Lentz S (2000) Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol 20:1557–1564

    PubMed  Google Scholar 

  55. Böger RH, Lentz SR, Bode-Böger SM, Knapp H, Haynes W (2001) Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci 100:161–167

    Article  PubMed  Google Scholar 

  56. Yoo JH, Lee SC (2001) Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 158:425–430

    Article  PubMed  CAS  Google Scholar 

  57. Masuda H, Tsujii T, Okuno T, Kihara K, Goto M, Azuma H (2001) Involvement of accumulated endogenous NOS inhibitors and decreased NOS activity in the impaired neurogenic relaxation of the rabbit proximal urethra with ischaemia. Br J Pharmacol 133:97–106

    Article  PubMed  CAS  Google Scholar 

  58. Hermenegildo C, Medina P, Peiro M, Segarra G, Vila J, Ortega J, Lluch S (2002) Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J Clin Endocrinol Metab 87:5636–5640

    Article  PubMed  CAS  Google Scholar 

  59. Das I, Khan NS, Puri BK, Hirsch S (1996) Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. Neurosci Lett 215:209–211

    Article  PubMed  CAS  Google Scholar 

  60. Rawal N, Lee YJ, Whitaker JN, Park J, Paik W, Kim S (1995) Urinary excretion of N G-dimethylarginines in multiple sclerosis patients: preliminary observations. J Neurol Sci 129:186–191

    Article  PubMed  CAS  Google Scholar 

  61. Fandriks L, von Bothmer C, Johansson B, Holm M, Bolin I, Pettersson A (1997) Water extract of Helicobacter pylori inhibits duodenal mucosal alkaline secretion in anesthetized rats. Gastroenterology 113:1570–1575

    Article  PubMed  CAS  Google Scholar 

  62. Abe T, Tohgi H, Murata T, Isobe C, Sato C (2001) Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during aging and in patients with Alzheimer’s disease. Neurosci Lett 312:177–179

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was funded by British Heart Foundation Programme grant PG20007.

Note added in proof

Recently Wang et al. (Science 2004; 306:279–283) demonstrated that histone arginine methylation can be reversed by the action of human protein arginine deiminase 4.

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  1. Centre for Clinical Pharmacology and Therapeutics, BHF Laboratories, Division of Medicine, University College London, 5 University Street, London, WC1E 6JJ, UK

    James M. Leiper & Patrick Vallance

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  1. James M. Leiper
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Correspondence to James M. Leiper.

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Leiper, J.M., Vallance, P. The synthesis and metabolism of asymmetric dimethylarginine (ADMA). Eur J Clin Pharmacol 62 (Suppl 1), 33–38 (2006). https://doi.org/10.1007/s00228-005-0013-y

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