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Information about Asymmetric Dimethylarginine

Asymmetric dimethylarginine

Systematic (IUPAC) name
2-amino-5-[(amino-dimethylamino-methylidene)amino]
pentanoic acid
Identifiers
PubChem        123831
Chemical data
FormulaC8H18N4O2 
Mol. weight202.25
SMILESCN(C)C(=NCCCC(C(=O)O)N)N
Complete data
Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide, a key chemical to endothelial and hence cardiovascular health.

Discovery

Patrick Vallance and his London co-workers first noted the interference role for asymmetric dimethylarginine;[1] today biochemical and clinical research continues into its role in cardiovascular disease, diabetes mellitus, erectile dysfunction and certain forms of kidney disease. The nitric oxide pathway is very important and ADMA appears significant to it.

Synthesis and regulation in the body

Enlarge picture
Cardiovascular effects have been linked to ADMA
Asymmetric dimethylarginine is created in protein methylation, a common mechanism of post-translational protein modification. This reaction is catalyzed by an enzyme set called S-adenosylmethionine protein N-methyltransferases (protein methylases I and II).[2] The methyl groups transferred to create ADMA are derived from the methyl group donor S-adenosylmethionine, an intermediate in the metabolism of homocysteine. (Homocysteine is an important blood chemical, because it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellular space and thence into blood plasma. Asymmetric dimethylarginine is measured using high performance liquid chromatography.

ADMA concentrations are substantially elevated by native or oxidized LDL cholesterol.[3] Thus a spiralling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote vasodilation. The elimination of ADMA occurs through urine excretion and metabolism by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. Polyphenol antioxidants also play a role in down-regulating homocysteine.

ADMA and suggested lines of therapeutic research

Enlarge picture
ADMA may play a role in certain forms of kidney disease
With raised levels of ADMA seemingly to be associated with adverse human health consequences for cardiovascular disease, metabolic diseases and also a wide range of diseases of the elderly, the possible lowering of ADMA levels may have important therapeutic effects. However it has yet to be established whether ADMA levels can be manipulated and, more importantly, if this results in useful clinical benefits.

The association of ADMA with abnormalities of lipid regulation suggested that supplements of free fatty acids might manipulate ADMA levels. However research has failed to show that these have an effect.[4][5]

ADMA role has been linked with elevated levels of homocysteine.[6][7][8] Whilst approaches at modifying the later with oral supplements of folic acid were strongly suggested, studies have shown this fails to give any clinical benefit and suggested that B vitamins might instead increase some cardiovascular risks.[9][10]<ref anme="NEJM2006-Bonna>Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K (2006). "Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction". N Engl J Med. PMID 16531614. 

Direct alteration of ADMA levels with supplements of L-arginine have been suggested.[11][12] The hope is that such intervention might not only improve endothelial function but also reduce clinical symptoms of overt cardiovascular disease.[13][14] However studies show inconsistency in results in a clinical context,[15] and the recent results with manipulating homocysteine levels warrant extreme care with what clinical outcomes might arise from this approach.

Statins, as well as affecting circulating cholesterol levels, also increase nitric oxide levels and so have a direct effect on blood supply to the heart. Elevated levels of ADMA seems to modify this effect and so may have consequences for patients' responsiveness to taking statins.[16]

See also

Notes

1. ^ Vallance P., Leone A., Calver A., Collier J., Moncada S. (1992). "Endogenous dimethyl-arginine as an inhibitor of nitric oxide synthesis". J. Cardiovasc. Pharmacol 20 (Suppli. 12): S60-S62. 
2. ^ Rawal N, Rajpurohit R, Lischwe MA, Williams KR, Paik WK, Kim S (1995). "Structural specificity of substrate for S-adenosylmethionine:protein arginine N-methyltransferases". Biochim Biophys Acta 1248 (1): 11-8. PMID 7536038. 
3. ^ Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM (2000). "LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases". Circ Res 87 (2): 99-105. PMID 10903992. 
4. ^ Eid HM, Arnesen H, Hjerkinn EM, Lyberg T, Ellingsen I, Seljeflot I (2006). "Effect of diet and omega-3 fatty acid intervention on asymmetric dimethylarginine". Nutr Metab (Lond) 3: 4. PMID 16396682. 
5. ^ Namiranian K, Mittermayer F, Artwohl M, Pleiner J, Schaller G, Mayer BX, Bayerle-Eder M, Roden M, Baumgartner-Parzer S, Wolzt M (2005). "Free fatty acids do not acutely increase asymmetrical dimethylarginine concentrations". Horm Metab Res 37 (12): 768-72. PMID 16372232. 
6. ^ Krzyzanowska K, Mittermayer F, Krugluger W, Schnack C, Hofer M, Wolzt M, Schernthaner G (2006). "Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes". Atherosclerosis. PMID 16414052. 
7. ^ Dayal S, Lentz SR (2005). "ADMA and hyperhomocysteinemia". Vasc Med 10 Suppl 1: S27-33. PMID 16444866. 
8. ^ Stuhlinger MC, Stanger O (2005). "Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction". Curr Drug Metab 6 (1): 3-14. PMID 15720202. 
9. ^ Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ (2006). "Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial". J Am Coll Cardiol 47 (6): 1108-16. PMID 16545638. 
10. ^ (2006) "Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease". N Engl J Med. PMID 16531613. 
11. ^ Bode-Boger SM, Muke J, Surdacki A, Brabant G, Boger RH, Frolich JC (2003). "Oral L-arginine improves endothelial function in healthy individuals older than 70 years". Vasc Med 8 (2): 77-81. PMID 14518608. 
12. ^ John P. Cooke (2002). The Cardiovascular Cure. Random House. ISBN 0-7679-0881-3. 
13. ^ Rector TS, Bank AJ, Mullen KA, Tschumperlin LK, Sih R, Pillai K, Kubo SH (1996). "Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure". Circulation 93 (12): 2135-41. PMID 8925582. 
14. ^ Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K (1997). "Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris". Am J Cardiol 80 (3): 331-3. PMID 9264427. 
15. ^ Loscalzo J (2004). "L-arginine and atherothrombosis". J Nutr 134 (10 Suppl): 2798S-2800S; discussion 2818S-2819S. PMID 15465788. 
16. ^ Janatuinen T, Laakso J, Laaksonen R, Vesalainen R, Nuutila P, Lehtimaki T, Raitakari OT, Knuuti J (2003). "Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults". Vasc Med 8 (3): 185-9. PMID 14989559. 

External links

IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. It is developed and kept up to date under the auspices of the International Union of Pure and Applied Chemistry (IUPAC).
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PubChem is a database of chemical molecules. The system is maintained by the National Center for Biotechnology Information (NCBI), a component of the National Library of Medicine, which is part of the United States National Institutes of Health (NIH).
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A chemical formula is a concise way of expressing information about the atoms that constitute a particular chemical compound. A chemical formula is also a short way of showing how a chemical reaction occurs.
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4, 2
(mildly acidic oxide)
Electronegativity 2.55 (Pauling scale)
Ionization energies
(more) 1st: 1086.5 kJmol−1
2nd: 2352.6 kJmol−1
3rd: 4620.5 kJmol−1

Atomic radius 70 pm
Atomic radius (calc.
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1, −1
(amphoteric oxide)
Electronegativity 2.20 (Pauling scale) More

Atomic radius 25 pm
Atomic radius (calc.) 53 pm
Covalent radius 37 pm
Van der Waals radius 120 pm
Miscellaneous

Thermal conductivity (300 K) 180.
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3, 5, 4, 2
(strongly acidic oxide)
Electronegativity 3.04 (Pauling scale)
Ionization energies
(more) 1st: 1402.3 kJmol−1
2nd: 2856 kJmol−1
3rd: 4578.1 kJmol−1

Atomic radius 65 pm
Atomic radius (calc.
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2, −1
(neutral oxide)
Electronegativity 3.44 (Pauling scale)
Ionization energies
(more) 1st: 1313.9 kJmol−1
2nd: 3388.3 kJmol−1
3rd: 5300.5 kJmol−1

Atomic radius 60 pm
Atomic radius (calc.
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molecular mass (abbreviated Mr) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12).
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smiles

File extension: .smi
Type of format: chemical file format

The simplified molecular input line entry specification or SMILES
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Blood plasma is the liquid component of blood, in which the blood cells are suspended. It makes up about 55% of total blood volume. Blood plasma is prepared simply by spinning a tube of fresh blood in a centrifuge until the blood cells fall to the bottom of the tube.
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Metabolism is the complete set of chemical reactions that occur in living cells. These processes are the basis of life, allowing cells to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories.
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A by-product is a secondary or incidental product deriving from a manufacturing process, a chemical reaction or a biochemical pathway, and is not the primary product or service being produced. A by-product can be useful and marketable, or it can have severe ecological consequences.
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Proteins are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues.
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Cytoplasm is a gelatinous, semi-transparent fluid that fills most cells. Eukaryotic cells contain a nucleus that is kept separate from the cytoplasm by a double membrane layer. The cytoplasm has three major elements; the cytosol, organelles and inclusions.
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Arginine (abbreviated as Arg or R)[1] is an α-amino acid. The L -form is one of the 20 most common natural amino acids. Its codons are CGU, CGC, CGA and CGG.
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amino acid is a molecule that contains both amine and carboxyl functional groups. In biochemistry, this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent.
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Nitric oxide or Nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals including humans and is an extremely important intermediate in the chemical industry.
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endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary.
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Circulatory System is a psychedelic rock musical ensemble formed by musician/painter Will Cullen Hart, and featuring Hannah Jones, Derek Almstead, Peter Erchick, John Fernandes, and Heather McIntosh.
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London
Canary Wharf is the centre of London's modern office towers
London shown within England
Coordinates:
Sovereign state United Kingdom
Constituent country England
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MeSH D002318 Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins). While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to
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Diabetes mellitus
Classification & external resources

ICD-10 E 10. –E 14.
ICD-9 250

MedlinePlus 001214
eMedicine med/546   emerg/134

MeSH C18.452.394.
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MeSH D007172 Erectile dysfunction (ED or (male) impotence) is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis.
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The kidneys are organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. The medical field that studies the kidneys and diseases of the kidney is called nephrology[1].
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Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. This term is commonly used in chemistry, biochemistry, and the biological sciences.
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Enzymes are proteins that catalyze (i.e. accelerate) chemical reactions.[1] In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products.
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In chemistry, a methyl group is a hydrophobic alkyl functional group derived from methane (CH4). It has the formula -CH3 and is very often abbreviated as -Me in the structure of a molecule. This hydrocarbon unit can be found in many organic compounds.
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Homocysteine is a chemical compound with the formula HSCH2CH2CH(NH2)CO2H. It is a homologue of the naturally-occurring amino acid cysteine, differing in that its side-chain contains an additional methylene (-CH2
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A genetic marker is a known DNA sequence that can be identified by a simple assay.

It can be described as some sort of variation present can arise due to mutation or alteration in the genomic loci that can be observed.
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Synthesis (from the ancient Greek σύνθεσις σύν (with) and θεσις
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