Dimethylarginine

Figure 13.1 (a) Trimethyllysine 4 and dimethylarginine 2 at histone H3 from X-ray structure [4]. (b) Chemical structure of the methylating agent S-adenosyl-L-methionine. 

Figure 13.2 (a) Sequential methylation and demethylation of lysines catalyzed by histone methyl transferases (HMTs) and histone demethylases (HDMs), respectively, (b) Sequential methylation and demethylation of arginines catalyzed by HMTs and HDMs, respectively, leading to symmetric and asymmetric dimethylarginines. 

Homocysteine decreases the bioavailability of nitrous oxide (NO) via a mechanism involving glutathione peroxidase (37). Tawakol et al. (38) reported that hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Homocysteine impairs the NO synthase pathway both in cell culture (39) and in monkeys with hyperhomocysteinemia, by increasing the levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor (40). Elevation of ADMA may mediate endothelial dysfunction during experimental hyperhomocysteinemia in humans (41). However, Jonasson et al. (42) did not find increased ADMA levels in patients with coronary heart disease and hyperhomocysteinemia, nor did vitamin supplementation have any effect on ADMA levels in spite of substantial plasma tHcy reduction,... 

Stuhlinger MC, et al. Homocysteine impairs the nitric oxide synthase pathway role of asymmetric dimethylarginine, Circulation 2001 104(21 ) 2569-2575. 

Boger RH, et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia [In Process Citation], Arterioscler Thromb Vase Biol 2000 20(6) 1557-1564. 

Boger RH, et al, Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci (Colch) 2001 ... 

Jonasson Tp et al. Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease, Eur J Clin Invest 2003 33(7) 543-549. 

Maas R, Wenske S, Zabel M, et al. Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction. Eur Urol 2005 48 1004-1012. 

ElesberAA, Solomon H, Lennon RJ, etal. Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur HeartJ 2006 27 824-83 I. 

Serum DN with macroalbuminuria and diabetic patients without albuminuria DN patients 78 CE-TOF MS Creatinine, aspartic acid, y-bulyrobetaine, citrulline, symmetric dimethylarginine, kynurenine, azelaic acid, and galactaric acid (55)... 

Let s start with this one because arginine is the raw material, the substrate, from which NO is made in the endothelium. To get the job done, you must have an adequate amount of eNOS, the enzyme that acts as a catalyst in the production process, and enough of the amino acid arginine. But the process can be blocked by high levels of asymmetric dimethylarginine (ADMA), a known inhibitor of NO synthesis. 

In the focus of a renewed interest are histone MTases. They produce monomethylarginine, symmetrical and nnsymmetrical dimethylarginine, and all possible lysine e-amino gronp methy-lation states. Such post-translational modifications of the histones determines whether chromatin adopts a compacted structure and is associated with silenced DNA-heterochromatin, or if it seems to be an extended structure and is associated with transcriptionally active DNA-euchromatin (20). Arginine MTases seem to methylate even more substrates, but the modification effects are not well nnderstood (21). As in DNA, the above-described examples of methylated residnes can be viewed as steric marks designed for recognition by highly specific proteins. 

Friesen WJ, Massenet S, Paushkin S, Wyce A, Dreyfuss G. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol. Cell 2001 7 1111-1117. 

ADMA is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine [70,83]. Two isoforms of this enzyme have been characterized and cloned to date. DDAH I predominates in tissues that express neuronal NOS and DDAH II predominates in tissues expressing endothelial NOS [70,84]. Activity of DDAH has been shown to be decreased by oxidized low density lipoprotein (LDL) or tumor necrosis factor-a (TNF-a) in vitro yielding increased levels of ADMA. Plasma levels of ADMA were found elevated in hyperhomo-cysteinemia, hypercholesterolemia and in hypertensive patients on a high salt diet [70,72,73]. 

J. T. Kielstein, S. M. Bode-B5ger, J. C. Frolich, H. Haller and R. H. Boger, Relationship of Asymmetric Dimethylarginine to Dialysis Treatment and Atherosclerotic Disease. Kidney International 59(Suppl. 78) (2001) 9-13. 

R. J. Chan, R. H. BOger. S. M. Bode-B6ger, O. Tangphao. P. S. Tsao, T. F. Blaschke and J. P. Cooke, Asymmetric Dimethylarginine Increases Mononuclear Cell Adhesiveness in Hypercholesterolemic Humans, Arteriosclerosis. Thrombosis, and Va.scular Biology 20 ( 2000) 1040-1056. 

P. Vallance, A. Leone, A. Calver, J. Collier and S. Moncada, Endogenous Dimethylarginine as an Inhibitor of Nitric Oxide Synthesis. Journal of Cardiovascular Pharmacology 20(Suppl. 12) (1992)... 

S. A. Fickling, A. Leone, S. Nussey, P. Vallance and G. Whitley, Synthesis of NG.NG-Dimethylarginine By Human Endothelial Cells, Endothelium 1 (1993) 137-140. 

Y. Kakimoto and S. Akazawa, Isolation and Identification ofNG, NG-Dimethylarginine, N-Epsilon-Mono-, Di-, and Trimethyllysine, and Glucosylgalactosyl- and Galactosyl-Delta-Hydroxylysine From Human Urine, Journal of Biological Chemistry 245 (1970) 5751 -5758. 

M. Kimoto, G. S. Whitley. H. Tsuji and T. Ogawa, Detection of NG.NG-Dimethylarginine Dimethylaminohydrolase in Human Tissues Using a Monoclonal NnUhoA v. Journal of Biochemistry 117(1995)237-238. 

J. M. Leiper, J. Santa-Maria. A. Chubb, R. J. MacAlIister, 1. G. Charles, G. S. Whitley and P. Vallance, Identification of Two Human Dimethylarginine Dimethylaminohydrolases with Distinct Tissue Distributions and Homology w ith Microbial. Arginine Deiminases. Biochemical Journal 343... 

J. T. Kielstein, R. H. BSger, S. M. Bode-B6ger, J. Schaeffer, M. Barbey, K. M. Koch and J. C. Frdhlich, Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease Relationship to Treatment Method and Atherosclerotic Disease, Journal of American Society of Nephrology 10 (1999) 594-600. 

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