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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__559819880756596__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__559819880756596__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:25682","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__559819880756596__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"559819880756596","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__559819880756596__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Marvin 04191111403D starting HoverWatcher_5 Time for openFile( Marvin 04191111403D 32 31 0 0 0 0 999 V2000 1.5980 0.7920 -2.9920 N 0 0 0 0 0 0 0 0 0 0 0 0 0.5470 -0.2330 -2.9580 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.3220 -0.0300 -1.7160 C 0 0 0 0 0 0 0 0 0 0 0 0 0.5450 -0.1460 -0.4610 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3240 0.0560 0.7800 C 0 0 0 0 0 0 0 0 0 0 0 0 0.5060 -0.0550 1.9820 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.0760 -0.0100 3.2270 C 0 0 0 0 0 0 0 0 0 0 0 0 0.6470 -0.2100 4.2920 N 0 0 0 0 0 0 0 0 0 0 0 0 2.0990 -0.3690 4.1720 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4210 0.2450 3.3480 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.0410 0.2930 4.6740 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3070 -0.1180 -4.1940 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.4600 0.9550 -4.7250 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.8970 -1.2100 -4.7050 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.4460 -1.1360 -5.4980 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0050 -1.2210 -2.9230 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1310 1.6850 -3.0240 H 0 0 0 0 0 0 0 0 0 0 0 0 2.0770 0.7460 -2.1050 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1020 -0.7910 -1.6900 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7800 0.9580 -1.7500 H 0 0 0 0 0 0 0 0 0 0 0 0 1.3250 0.6140 -0.4870 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0030 -1.1350 -0.4260 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1040 -0.7040 0.8060 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7820 1.0440 0.7460 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4660 -0.1600 1.8990 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9590 0.3940 2.5550 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5400 -0.4390 5.1670 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3200 -1.2780 3.6120 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5170 0.4900 3.6490 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1050 0.5060 4.5700 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9100 -0.6670 5.1710 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5700 1.0760 5.2680 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 0 0 0 1 17 1 0 0 0 0 1 18 1 0 0 0 0 2 3 1 0 0 0 0 2 12 1 0 0 0 0 2 16 1 0 0 0 0 3 4 1 0 0 0 0 3 19 1 0 0 0 0 3 20 1 0 0 0 0 4 5 1 0 0 0 0 4 21 1 0 0 0 0 4 22 1 0 0 0 0 5 6 1 0 0 0 0 5 23 1 0 0 0 0 5 24 1 0 0 0 0 6 7 1 0 0 0 0 6 25 1 0 0 0 0 7 8 2 0 0 0 0 7 10 1 0 0 0 0 8 9 1 0 0 0 0 9 27 1 0 0 0 0 9 28 1 0 0 0 0 9 29 1 0 0 0 0 10 11 1 0 0 0 0 10 26 1 0 0 0 0 11 30 1 0 0 0 0 11 31 1 0 0 0 0 11 32 1 0 0 0 0 12 13 2 0 0 0 0 12 14 1 0 0 0 0 14 15 1 0 0 0 0 M END): 16 ms reading 32 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 32 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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InChI=1S/C8H18N4O2/c1- 10-8(11-2)12-5-3-4-6(9)7(13)14/h6H,3-5,9H2,1-2H3,(H,13,14)(H2,10,11,12)/t6-/m0/s1 |
| HVPFXCBJHIIJGS-LURJTMIESA-N |
| CN\C(NCCC[C@H](N)C(O)=O)=N\C |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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EC 1.14.13.39 (nitric oxide synthase) inhibitor
An EC 1.14.13.* (oxidoreductase acting on paired donors, incorporating 1 atom of oxygen, with NADH or NADPH as one donor) inhibitor that interferes with the action of nitric oxide synthase (EC 1.14.13.39).
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View more via ChEBI Ontology
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Outgoing
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Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
has role
EC 1.14.13.39 (nitric oxide synthase) inhibitor
(CHEBI:61908)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is a
L-arginine derivative
(CHEBI:83965)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is a
dimethylarginine
(CHEBI:86468)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is a
guanidines
(CHEBI:24436)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is a
non-proteinogenic L-α-amino acid
(CHEBI:83822)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is conjugate base of
Nω,N'ω-dimethyl-L-argininium(1+)
(CHEBI:197308)
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
is tautomer of
Nω,N'ω-dimethyl-L-arginine zwitterion
(CHEBI:61914)
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Incoming
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Nω,N'ω-dimethyl-L-argininium(1+)
(CHEBI:197308)
is conjugate acid of
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
Nω,N'ω-dimethyl-L-argininyl residue
(CHEBI:61916)
is substituent group from
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
Nω,N'ω-dimethyl-L-arginine zwitterion
(CHEBI:61914)
is tautomer of
Nω,N'ω-dimethyl-L-arginine
(CHEBI:25682)
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N5-(N,N'-dimethylcarbamimidoyl)-L-ornithine
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(2S)-2-amino-5-(N',N''-dimethylcarbamimidamido)pentanoic acid
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IUPAC
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(S)-2-amino-5-(N',N''-dimethylguanidino)pentanoic acid
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ChEBI
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Guanidino-N(1),N(2)-dimethylarginine
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ChemIDplus
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N(G1),N(G2)-Dimethylarginine
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ChemIDplus
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N,N'-Dimethylarginine
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ChemIDplus
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N3,N4-dimethyl-L-arginine
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ChEBI
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N3,N4-dimethylarginine
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ChEBI
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N5-((methylamino)(methylimino)methyl)-L-ornithine
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ChemIDplus
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N5-(N,N'-dimethylamidino)-L-ornithine
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ChEBI
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N5-(N,N'-dimethylcarbamimidoyl)-L-ornithine
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ChEBI
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N5-[bis(methylamino)methylene]-L-ornithine
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ChEBI
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NG,N'G-dimethyl-L-arginine
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ChEBI
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NG,N'G-dimethylarginine
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ChEBI
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SDMA
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HMDB
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symmetric dimethylarginine
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ChEBI
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30344-00-4
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CAS Registry Number
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ChemIDplus
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7973080
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Reaxys Registry Number
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Reaxys
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7973080
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Beilstein Registry Number
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Beilstein
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Grasemann H, Al-Saleh S, Scott JA, Shehnaz D, Mehl A, Amin R, Rafii M, Pencharz P, Belik J, Ratjen F (2011)
Asymmetric dimethylarginine contributes to airway nitric oxide deficiency in patients with cystic fibrosis.
American journal of respiratory and critical care medicine 183, 1363-1368 [PubMed:21278301]
[show Abstract]
RationaleAirway nitric oxide is reduced in cystic fibrosis airways. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that may contribute to nitric oxide deficiency in cystic fibrosis.ObjectivesTo test the hypothesis that asymmetric dimethylarginine is increased in cystic fibrosis and contributes to nitric oxide deficiency and airway obstruction.MethodsThe concentrations of asymmetric dimethylarginine, symmetric dimethylarginine, and l-arginine were measured in sputum of clinically stable patients with cystic fibrosis, in patients with cystic fibrosis before and after treatment for a pulmonary exacerbation, and in healthy control subjects, using liquid chromatography-tandem mass spectrometry.Measurements and main resultsAsymmetric dimethylarginine was increased in cystic fibrosis compared with control sputum, and the l-arginine/asymmetric dimethylarginine ratio was decreased. Symmetric dimethylarginine exceeded asymmetric dimethylarginine concentrations in control sputum, but this ratio was reversed in cystic fibrosis. Treatment for pulmonary exacerbation resulted in a decrease in sputum asymmetric dimethylarginine and an improved l-arginine/asymmetric dimethylarginine ratio. The treatment-related decrease in asymmetric dimethylarginine correlated significantly with an increase in sputum nitric oxide metabolites and improvement in pulmonary function. The activity of the asymmetric dimethylarginine-metabolizing enzyme, dimethylarginine dimethylaminohydrolase, was higher in cystic fibrosis sputum before rather than after treatment, suggesting that the accumulation of asymmetric dimethylarginine is caused by increased production, not decreased degradation, of asymmetric dimethylarginine.ConclusionsAsymmetric dimethylarginine is increased in cystic fibrosis airways and may contribute to airway obstruction in patients with cystic fibrosis by reducing nitric oxide formation. | Tsikas D, Beckmann B, Gutzki FM, Jordan J (2011)
Simultaneous gas chromatography-tandem mass spectrometry quantification of symmetric and asymmetric dimethylarginine in human urine.
Analytical biochemistry 413, 60-62 [PubMed:21303648]
[show Abstract]
Previously, we demonstrated the utility of a gas chromatography-tandem mass spectrometry (GC-MS/MS) method for the quantitative determination of asymmetric dimethylarginine (ADMA) in biological samples. Here we report the extension of this method to symmetric dimethylarginine (SDMA) in human urine. SDMA and ADMA were simultaneously quantitated in urine by using their in situ prepared trideuteromethyl esters as internal standards. The GC-MS/MS method was validated for SDMA and ADMA in spot urine samples of 19 healthy adults. In these samples, the creatinine-corrected excretion rate was 3.23±0.63 μmol/mmol for SDMA and 3.14±0.98 μmol/mmol for ADMA. | Gad MZ, Hassanein SI, Abdel-Maksoud SM, Shaban GM, Abou-Aisha K, Elgabarty HA (2010)
Assessment of serum levels of asymmetric dimethylarginine, symmetric dimethylarginine and L-arginine in coronary artery disease.
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 15, 746-752 [PubMed:20936901]
[show Abstract]
Serum asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-arginine, and C-reactive protein (hsCRP) levels were assessed in 100 Egyptian male 35-50-year-old patients with coronary artery disease (CAD), classified into: patients under conservative medical treatment, patients directed for percutaneous coronary interventions, patients directed for coronary artery bypass graft operation and patients suffering from acute myocardial infarction. Age- and sex-matched controls (n=100) were included. Correlation between serum levels of biomarkers and dimethylarginine dimethylaminohydrolase-2 (DDAH-2) genotypes was studied. No association between biomarkers and carriage of the specific DDAH2 SNP2 (-449C/G, rs805305) genotype was detected. Further studies are required to confirm the contribution of the biomarkers in the predisposition of CAD. | Mangoni AA (2009)
The emerging role of symmetric dimethylarginine in vascular disease.
Advances in clinical chemistry 48, 73-94 [PubMed:19803415]
[show Abstract]
Asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits the activity of the enzyme endothelial nitric oxide synthase (eNOS), with consequent reduced synthesis of nitric oxide (NO). An increased synthesis and/or a reduced catabolism of ADMA might contribute to the onset and progression of atherosclerosis and thrombosis. The detrimental effects of ADMA on endothelial function, cardiovascular homeostasis, and cardiovascular outcomes have been extensively investigated. However, little attention has been paid to another methylated form of L-arginine, symmetric dimethylarginine (SDMA), as a potential modulator of vascular homeostasis and vascular disease. The first part of this chapter discusses the synthesis, transport, and metabolism of ADMA and SDMA and summarizes the evidence linking ADMA with vascular disease and adverse cardiovascular outcomes. The second part describes the results of recent studies highlighting the important role of SDMA in modulating vascular homeostasis and vascular damage. Suggestions for future research directions on SDMA are also discussed. | Shaw GM, Vollset SE, Carmichael SL, Yang W, Finnell RH, Blom H, Ueland PM (2009)
Nested case-control study of one-carbon metabolites in mid-pregnancy and risks of cleft lip with and without cleft palate.
Pediatric research 66, 501-506 [PubMed:19668105]
[show Abstract]
Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with cleft lip with/without cleft palate (CLP). A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and CLP by measuring nutrient analytes in mid-pregnancy sera. This study included data from a repository of women's mid-pregnancy serum specimens collected in California from 2003-04. Each woman's specimen was linked with delivery information to determine whether her fetus had CLP or another structural malformation, or was nonmalformed. We identified 89 CLP cases. We randomly selected 409 specimens as controls. Specimens were tested for homocysteine, methylmalonic acid, folate, vitamin B12, pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, choline, betaine, methionine, methionine sulfoxide, cysteine, cystathionine, arginine, and asymmetric and symmetric dimethylarginine. We observed three analytes with odds ratios unlikely to be explained by random variation, i.e., elevated CLP risks were observed for low levels and for high levels of pyridoxal phosphate (vitamin B6), higher levels of choline, and low levels of symmetric dimethylarginine. These data did not show meaningful differences between cases and controls for any other analytes. | Sayegh J, Clarke SG (2008)
Hsl7 is a substrate-specific type II protein arginine methyltransferase in yeast.
Biochemical and biophysical research communications 372, 811-815 [PubMed:18515076]
[show Abstract]
The Saccharomyces cerevisiae protein Hsl7 is a regulator of the Swe1 protein kinase in cell cycle checkpoint control. Hsl7 has been previously described as a type III protein arginine methyltransferase, catalyzing the formation of omega-monomethylarginine residues on non-physiological substrates. However, we show here that Hsl7 can also display type II activity, generating symmetric dimethylarginine residues on calf thymus histone H2A. Symmetric dimethylation is only observed when enzyme and the methyl-accepting substrate were incubated for extended times. We confirmed the Hsl7-dependent formation of symmetric dimethylarginine by amino acid analysis and thin layer chromatography with wild-type and mutant recombinant enzymes expressed from both bacteria and yeast. This result is significant because no type II activity has been previously demonstrated in S. cerevisiae. We also show that Hsl7 has little or no activity on GST-GAR, a commonly used substrate for protein arginine methyltransferases, and only minimal activity on myelin basic protein. This enzyme thus may only recognize only a small subset of potential substrate proteins in yeast, in contrast to the situation with Rmt1, the major type I methyltransferase. | Weaving G, Rocks BF, Bailey MP, Titheradge MA (2008)
Arginine and methylated arginines in human plasma and urine measured by tandem mass spectrometry without the need for chromatography or sample derivatisation.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 874, 27-32 [PubMed:18815077]
[show Abstract]
A method for the simultaneous analysis of asymmetric dimethylarginine, symmetric dimethylarginine, monomethylarginine and arginine in human plasma and urine, with short analysis time and isotopic internal standardisation for each analyte is described. The method requires neither sample derivatisation nor the need for chromatographic separation of analytes. The method described shows good precision and accuracy and is suited for both research purposes and implementation in the busy, routine clinical laboratory. In addition the synthesis and utilisation of isotopically labelled symmetric dimethylarginine and monomethylarginine is described for the first time, avoiding the use of surrogates such as homoarginine for internal standardisation. | Gonsalvez GB, Tian L, Ospina JK, Boisvert FM, Lamond AI, Matera AG (2007)
Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins.
The Journal of cell biology 178, 733-740 [PubMed:17709427]
[show Abstract]
Small nuclear ribonucleoproteins (snRNPs) are core components of the spliceosome. The U1, U2, U4, and U5 snRNPs each contain a common set of seven Sm proteins. Three of these Sm proteins are posttranslationally modified to contain symmetric dimethylarginine (sDMA) residues within their C-terminal tails. However, the precise function of this modification in the snRNP biogenesis pathway is unclear. Several lines of evidence suggest that the methyltransferase protein arginine methyltransferase 5 (PRMT5) is responsible for sDMA modification of Sm proteins. We found that in human cells, PRMT5 and a newly discovered type II methyltransferase, PRMT7, are each required for Sm protein sDMA modification. Furthermore, we show that the two enzymes function nonredundantly in Sm protein methylation. Lastly, we provide in vivo evidence demonstrating that Sm protein sDMA modification is required for snRNP biogenesis in human cells. | Lluch P, Mauricio MD, Vila JM, Segarra G, Medina P, Del Olmo JA, Rodrigo JM, Serra MA (2006)
Accumulation of symmetric dimethylarginine in hepatorenal syndrome.
Experimental biology and medicine (Maywood, N.J.) 231, 70-75 [PubMed:16380646]
[show Abstract]
In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no-HRS). Plasma levels of NO, ADMA, SDMA, and l-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 +/- 0.25 vs. 0.38 +/- 0.06 and 0.29 +/- 0.04 microM, respectively; P < 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 +/- 0.26, 1.11 +/- 0.1, and 0.53 +/- 0.06 microM, respectively; P < 0.05; NOx, 94 +/- 9.1, 95.5 +/- 9.54, and 37.67 +/- 4.62 microM, respectively; P < 0.05). In patients with HRS there was a positive correlation between serum creatinine and plasma SDMA (r2 =0.765, P < 0.001) but not between serum creatinine and ADMA or NOx. The results suggest that renal dysfunction is a main determinant of elevated SDMA concentration in HRS. Accumulation of ADMA as a result of impaired hepatic removal may be the causative factor initiating renal vasoconstriction and SDMA retention in the kidney. | Pedersen LG, Tarnow I, Olsen LH, Teerlink T, Pedersen HD (2006)
Body size, but neither age nor asymptomatic mitral regurgitation, influences plasma concentrations of dimethylarginines in dogs.
Research in veterinary science 80, 336-342 [PubMed:16182327]
[show Abstract]
Asymmetric dimethylarginine (ADMA) is a marker of various cardiovascular diseases in man. The aim of the present study was to test if Cavalier King Charles Spaniels (CKCS) with varying degrees of mitral regurgitation (MR) had increased plasma concentration of ADMA and furthermore, characterize the plasma level of ADMA and symmetric dimethylarginine (SDMA) in normal dogs. Seventy-six dogs were included (44 CKCS and 32 dogs of other breeds). The CKCS had various degrees of MR, whereas the remaining dogs had either no or minimal MR. Apart from cardiac murmurs, no dogs showed signs of cardiac or systematic disease. The degree of MR had no significant influence on ADMA (P = 0.33). Body weight was directly associated with ADMA (P = 0.0004) and creatinine was directly associated with SDMA (P<0.0001). Furthermore, the plasma concentration of ADMA was three to four times higher than found in healthy humans. | Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, Aigner C, Fink L, Muyal JP, Weissmann N, Grimminger F, Seeger W, Schermuly RT (2005)
Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19, 1175-1177 [PubMed:15827267]
[show Abstract]
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and has been implicated in endothelial dysfunction. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), with DDAH2 representing the predominant endothelial DDAH isoform. Symmetric dimethylarginine (SDMA), also originating from arginine methylation by protein arginine methyltransferases, is an inhibitor of intracellular arginine uptake. In both chronic pulmonary hypertensive rats and patients suffering from idiopathic pulmonary arterial hypertension (IPAH; NYHA class III and IV), a marked increase in plasma ADMA and SDMA levels, as well as tissue levels of asymmetric and symmetric dimethylated proteins, was observed. Moreover, when comparing lung tissue from pulmonary hypertensive rats and IPAH patients to corresponding normal lung tissue, expression of DDAH2 was found to be reduced at both the mRNA and the protein level with no significant changes in DDAH1 expression. These findings were further supported by demonstrating a decrease in DDAH2 function in the experimental pulmonary hypertension model. Immunohistochemistry in human and rat control tissue demonstrated both isoforms of DDAH in the endothelial layer and in the alveolar epithelium. In contrast, in pulmonary hypertensive tissue, the immunoreactivity of DDAH2 in pulmonary endothelium was significantly decreased compared with DDAH1. Therefore, altogether we can conclude that enhanced dimethylarginine levels may contribute to vascular abnormalities in pulmonary arterial hypertension. Suppression of endothelial DDAH2 expression and function represents an important underlying mechanism. | Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, Gunderson SI, Felix AM, Herth N, Hoffmann R, Pestka S (2005)
PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine.
The Journal of biological chemistry 280, 3656-3664 [PubMed:15494416]
[show Abstract]
The cDNA for PRMT7, a recently discovered human protein-arginine methyltransferase (PRMT), was cloned and expressed in Escherichia coli and mammalian cells. Immunopurified PRMT7 actively methylated histones, myelin basic protein, a fragment of human fibrillarin (GAR) and spliceosomal protein SmB. Amino acid analysis showed that the modifications produced were predominantly monomethylarginine and symmetric dimethylarginine (SDMA). Examination of PRMT7 expressed in E. coli demonstrated that peptides corresponding to sequences contained in histone H4, myelin basic protein, and SmD3 were methylated. Furthermore, analysis of the methylated proteins showed that symmetric dimethylarginine and relatively small amounts of monomethylarginine and asymmetric dimethylarginine were produced. SDMA was also formed when a GRG tripeptide was methylated by PRMT7, indicating that a GRG motif is by itself sufficient for symmetric dimethylation to occur. Symmetric dimethylation is reduced dramatically compared with monomethylation as the concentration of the substrate is increased. The data demonstrate that PRMT7 (like PRMT5) is a Type II methyltransferase capable of producing SDMA modifications in proteins. | Marra M, Bonfigli AR, Testa R, Testa I, Gambini A, Coppa G (2003)
High-performance liquid chromatographic assay of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine in human plasma by derivatization with naphthalene-2,3-dicarboxaldehyde.
Analytical biochemistry 318, 13-17 [PubMed:12782025]
[show Abstract]
Asymmetric dimethylarginine (ADMA) is an emerging cardiovascular risk factor. Its increased levels have been hypothesized to be a cause of endothelial dysfunction in pathological conditions such as hypertension, dyslipidemia, renal failure, hyperglycemia, and hyperhomocysteinemia. It acts as a potent competitive inhibitor of nitric oxide synthase. Methods using ortho-phthaldialdehyde (OPA) as derivatization reagent are widely performed in HPLC determination of ADMA, but they produce derivatives whose fluorescence rapidly decreases during time. Moreover, these methods do not allow a clear separation of ADMA from its stereoisomer symmetric dimethylarginine (SDMA). Our work describes a new method to determine ADMA, SDMA, and arginine that uses, as derivatizing reagent, naphthalene-2,3-dicarboxaldehyde (NDA). Chromatograms with low background, showing a complete separation of ADMA and SDMA, are obtained. NDA derivatives are considerably more stable than the OPA derivatives. The calibration curves of ADMA and SDMA are linear within the range of 0.01-16.0 microM. Coefficients of variation are less than 1.7% for within day and less then 2.3% for day to day. Absolute mean recoveries from supplemented samples are between 100 and 104%. These characteristics make this method reliable and easily manageable for large routine analyses. | Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA (2002)
Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography.
Analytical biochemistry 303, 131-137 [PubMed:11950212]
[show Abstract]
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), may be related to reduced biosynthesis of nitric oxide in diseases associated with accelerated atherosclerosis. The closely related compound symmetric dimethylarginine (SDMA) does not inhibit NOS, but may compete with arginine for cellular uptake, thereby limiting substrate availability for NOS. We report on a method for the simultaneous measurement of arginine, ADMA, and SDMA as a tool to gain insight in the role of these compounds in the regulation of NOS activity. Sample cleanup was performed by solid-phase extraction on polymeric cation-exchange columns using monomethylarginine as internal standard. After derivatization with ortho-phthaldialdehyde reagent containing 3-mercaptopropionic acid, analytes were separated by isocratic reversed-phase HPLC with fluorescence detection. The stable derivatives were separated with near baseline resolution. Using a sample volume of 0.2 ml, linear calibration curves were obtained with limits of quantification of 0.08 microM for arginine and 0.01 microM for ADMA and SDMA. Analytical recovery was 98-102%, and interassay CV was better than 3%. Plasma from healthy volunteers (n = 53) contained 94 +/- 26 microM arginine, 0.42 +/- 0.06 microM ADMA, and 0.47 +/- 0.08 microM SDMA. Due to its high precision and sensitivity this method is a valuable tool in research on the metabolism of dimethylated arginines and their role in the regulation of NOS activity. | Hermenegildo C, Medina P, Peiró M, Segarra G, Vila JM, Ortega J, Lluch S (2002)
Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients.
The Journal of clinical endocrinology and metabolism 87, 5636-5640 [PubMed:12466365]
[show Abstract]
Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine plasma levels in the hypothyroid group were similar to those of the control group; whereas in hyperthyroidism, these values were significantly increased. However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NO(x) production. When all subjects were analyzed together, free T(4) levels were directly correlated with ADMA and inversely correlated with NO(x). | Ellis J, Wennerholm UB, Bengtsson A, Lilja H, Pettersson A, Sultan B, Wennergren M, Hagberg H (2001)
Levels of dimethylarginines and cytokines in mild and severe preeclampsia.
Acta obstetricia et gynecologica Scandinavica 80, 602-608 [PubMed:11437716]
[show Abstract]
BackgroundThe objectives were 1. to evaluate if the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine was altered in mild and severe forms of preeclampsia, and 2. to assess the relationship between dimethylarginines and the cytokine response in preeclampsia.MethodsAsymmetric and symmetric dimethylarginine were measured with high performance liquid chromatography in women with mild (n=13) and severe (n=32) preeclampsia and in normotensive pregnant controls (n=20). Interleukin-4, -6, -8, -10 and tumor necrosis factor-alpha were analyzed by immunoassays in women with mild (n=8) and severe (n=17) preeclampsia and in normotensive pregnant controls (n=14). The Mann Whitney U-test and Spearman Rank test were used for statistical analysis.ResultsThe plasma levels of dimethylarginine were increased in preeclamptic subjects. The elevation of symmetric dimethylarginine was more pronounced than that of asymmetric dimethylarginine. The control levels of interleukin-6, -8 and -10 were significantly higher at term than at gestational week 32-36. Interleukin-6 and -8 were significantly elevated in subjects with severe, but not mild, preeclampsia, whereas TNF-alpha and IL-10 were not significantly altered. Symmetric dimethylarginine levels correlated significantly with arterial blood pressure and serum levels of creatinine and uric acid. Dimethylarginine levels in plasma were, however, not related to the cytokine response.ConclusionsPlasma concentrations of both asymmetric and symmetric dimethylarginine were significantly elevated both in mild and severe preeclampsia. Symmetric, but not asymmetric, dimethylarginine correlated to the severity of the condition. Plasma levels of interleukin-6 and -8 were also elevated in severe preeclampsia but no direct correlations were found between these cytokines and dimethylarginines. |
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