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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__777899595342094__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__777899595342094__) 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:6203","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__777899595342094__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"777899595342094","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__777899595342094__ 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 11160710503D starting HoverWatcher_5 Time for openFile( Marvin 11160710503D 25 24 0 0 0 0 999 V2000 -1.2234 -2.4455 -2.4851 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.7869 -3.3717 -1.9536 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.5972 -2.6257 -3.6587 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.2231 -1.0879 -1.8313 C 0 0 1 0 0 0 0 0 0 0 0 0 -2.4522 -0.9229 -1.0460 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.0082 -0.9645 -0.9113 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.0082 0.4124 -0.2475 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2063 0.5369 0.6733 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2067 1.8564 1.3089 N 0 0 0 0 0 0 0 0 0 0 0 0 2.1899 2.1916 2.1671 C 0 0 0 0 0 0 0 0 0 0 0 0 3.0761 1.3977 2.4148 O 0 0 0 0 0 0 0 0 0 0 0 0 2.1899 3.4045 2.7520 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.5971 -3.4963 -4.0778 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1769 -0.3151 -2.5988 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4533 -1.6548 -0.3513 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3631 -0.0501 -0.5461 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0552 -1.7369 -0.1435 H 0 0 0 0 0 0 0 0 0 0 0 0 0.9036 -1.0869 -1.4941 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0380 1.1852 -1.0151 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9208 0.5353 0.3356 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1601 -0.2360 1.4409 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1189 0.4140 0.0902 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4989 2.4894 1.1113 H 0 0 0 0 0 0 0 0 0 0 0 0 2.8974 3.6455 3.3702 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4826 4.0382 2.5550 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 0 0 0 1 3 1 0 0 0 0 1 4 1 0 0 0 0 3 13 1 0 0 0 0 4 5 1 0 0 0 0 4 6 1 0 0 0 0 4 14 1 0 0 0 0 5 15 1 0 0 0 0 5 16 1 0 0 0 0 6 7 1 0 0 0 0 6 17 1 0 0 0 0 6 18 1 0 0 0 0 7 8 1 0 0 0 0 7 19 1 0 0 0 0 7 20 1 0 0 0 0 8 9 1 0 0 0 0 8 21 1 0 0 0 0 8 22 1 0 0 0 0 9 10 1 0 0 0 0 9 23 1 0 0 0 0 10 11 2 0 0 0 0 10 12 1 0 0 0 0 12 24 1 0 0 0 0 12 25 1 0 0 0 0 M END): 17 ms reading 25 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 25 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1914 by Japanese researchers Yatarō Koga (古賀彌太郎) and Ryō Ōtake (大嶽了) and further codified by Mitsunori Wada of Tokyo Imperial University in 1930.
It has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase. |
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Read full article at Wikipedia
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| InChI=1S/C6H13N3O3/c7-4(5(10)11)2-1-3-9-6(8)12/h4H,1-3,7H2,(H,10,11)(H3,8,9,12)/t4-/m0/s1 |
| RHGKLRLOHDJJDR-BYPYZUCNSA-N |
| N[C@@H](CCCNC(N)=O)C(O)=O |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Arabidopsis thaliana
(NCBI:txid3702)
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See:
PubMed
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Saccharomyces cerevisiae
(NCBI:txid4932)
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Source: yeast.sf.net
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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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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Saccharomyces cerevisiae metabolite
Any fungal metabolite produced during a metabolic reaction in Baker's yeast (Saccharomyces cerevisiae ).
micronutrient
Any nutrient required in small quantities by organisms throughout their life in order to orchestrate a range of physiological functions.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
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).
Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
Daphnia magna metabolite
A Daphnia metabolite produced by the species Daphnia magna.
(via citrulline )
hapten
Any substance capable of eliciting an immune response only when attached to a large carrier such as a protein. Examples include dinitrophenols; oligosaccharides; peptides; and heavy metals.
(via citrulline )
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nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
protective agent
Synthetic or natural substance which is given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent.
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View more via ChEBI Ontology
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(2S)-2-amino-5-(carbamoylamino)pentanoic acid
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L-citrulline
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N5-carbamoyl-L-ornithine
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(S)-2-Amino-5-ureidopentanoic acid
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HMDB
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2-Amino-5-ureidovaleric acid
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KEGG COMPOUND
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α-amino-δ-ureidovaleric acid
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ChemIDplus
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Cit
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ChemIDplus
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CITRULLINE
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PDBeChem
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Citrulline
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KEGG COMPOUND
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δ-ureidonorvaline
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ChemIDplus
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L-2-Amino-5-ureidovaleric acid
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HMDB
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L-Citrulline
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KEGG COMPOUND
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N5-(aminocarbonyl)-L-ornithine
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ChemIDplus
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N5-(Aminocarbonyl)ornithine
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DrugBank
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N5-carbamoylornithine
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DrugBank
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Nδ-carbamylornithine
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ChemIDplus
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1725416
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Reaxys Registry Number
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Reaxys
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372-75-8
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CAS Registry Number
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ChemIDplus
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6055157
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Beilstein Registry Number
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Beilstein
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774677
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Gmelin Registry Number
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Gmelin
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Figueroa A, Sanchez-Gonzalez MA, Wong A, Arjmandi BH (2012)
Watermelon extract supplementation reduces ankle blood pressure and carotid augmentation index in obese adults with prehypertension or hypertension.
American journal of hypertension 25, 640-643 [PubMed:22402472]
[show Abstract]
BackgroundAnkle-brachial index (ABI) and ankle blood pressure (BP) are associated with increased carotid wave reflection (augmentation index, AIx). Oral L-citrulline and L-arginine from synthetic or watermelon sources have reduced brachial BP, aortic BP, and aortic AIx. A directly measured carotid AIx (cAIx) rather than aortic AIx has been proposed as a better measurement of central AIx. We evaluated the effects of watermelon extract on ankle BP and cAIx in individuals with normal ABI and prehypertension or stage 1 hypertension.MethodsAnkle and brachial systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), cAIx, ABI, and heart rate (HR) were evaluated in the supine position in 14 adults (11 women/3 men, age 58 ± 1 years) with prehypertension or stage 1 hypertension (153 ± 4 mm Hg). Subjects were randomly assigned to 6 weeks of watermelon extract supplementation (L-citrulline/L-arginine, 6 g daily) or placebo followed by a 2-week washout period and then crossover.ResultsAnkle and brachial SBP (-11.5 ± 3.8 and -15.1 ± 2.8 mm Hg), DBP (-7.8 ± 2.3 and -7.6 ± 1.8 mm Hg), and MAP (-9.8 ± 2.6 and -7.3 ± 1.8 mm Hg), and cAIx (-8.8 ± 2.6 %) decreased significantly (P < 0.05) after watermelon supplementation compared to placebo. Watermelon supplementation had no significant effect (P > 0.05) on ABI and HR.ConclusionsThis study shows that watermelon extract supplementation reduces ankle BP, brachial BP, and carotid wave reflection in obese middle-aged adults with prehypertension or stage 1 hypertension and normal ABI, which may reflect improved arterial function. | Agrawal V, Woo JH, Mauldin JP, Jo C, Stone EM, Georgiou G, Frankel AE (2012)
Cytotoxicity of human recombinant arginase I (Co)-PEG5000 in the presence of supplemental L-citrulline is dependent on decreased argininosuccinate synthetase expression in human cells.
Anti-cancer drugs 23, 51-64 [PubMed:21955999]
[show Abstract]
Human recombinant arginase I cobalt [HuArgI (Co)] coupled with polyethylene glycol 5000 [HuArgI (Co)-PEG5000] has shown potent in-vitro depletion of arginine from tissue culture medium. We now show that HuArgI (Co)-PEG5000 is toxic to almost all cancer cell lines and to some normal primary cells examined. In contrast, HuArgI (Co)-PEG5000 in combination with supplemental L-citrulline is selectively cytotoxic to a fraction of human cancer cell lines in tissue culture, including some melanomas, mesotheliomas, acute myeloid leukemias, hepatocellular carcinomas, pancreas adenocarcinomas, prostate adenocarcinomas, lung adenocarcinomas, osteosarcomas, and small cell lung carcinomas. Unfortunately, a subset of normal human tissues is also sensitive to HuArgI (Co)-PEG5000 with L-citrulline supplementation, including umbilical endothelial cells, bronchial epithelium, neurons, and renal epithelial cells. We further show that cell sensitivity is predicted by the level of cellular argininosuccinate synthetase protein expression measured by immunoblots. By comparing a 3-day and 7-day exposure to HuArgI (Co)-PEG5000 with supplemental L-citrulline, some tumor cells sensitive on short-term assay are resistant in the 7-day assay consistent with the induction of argininosuccinate synthetase expression. On the basis of these results, we hypothesize that HuArgI (Co)-PEG5000 in combination with L-citrulline supplementation may be an attractive therapeutic agent for some argininosuccinate synthetase-deficient tumors. These in-vitro findings stimulate further development of this molecule and may aid in the identification of tissue toxicities and better selection of patients who will potentially respond to this combination therapy. | Yi L, Lingshan G, Cui Y, Xiaoxing Y, Junnian Z (2012)
A preliminary study on protective effect of L-citrulline against ischemia-reperfusion induced gastric mucosal lesions in rat.
Indian journal of pharmacology 44, 31-35 [PubMed:22345866]
[show Abstract]
ObjectivesThis study was designed to investigate the gastroprotective effect of L-citrulline against gastric ischemia-reperfusion injury.Materials and methodsSodium pentobarbital-anesthetized rats underwent occlusion of the celiac artery for 30 min, followed by 60 min of reperfusion. Sixty minutes before ischemia, L-citrulline at doses of 300, 600, 900 mg/kg was administered intragastrically. Based on this animal model of gastric ischemia-reperfusion injury, the gastroprotective effect of L-citrulline was assessed by determining and comparing the ulcerative index and the estimation of myeloperoxidase (MPO) activity and malondialdehyde (MDA) level in the gastric mucosal tissues. Moreover, the expression of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) protein was also determined.ResultsIntragastric administration of L-citrulline (600 and 900 mg/kg) 60 min before ischemia significantly ameliorated the gastric mucosal damage and inhibited the increase in MPO and MDA contents. Also, the increase in expression of iNOS protein was also prevented by L-citrulline. The expression of nNOS and eNOS was not affected significantly by I/R or L-citrulline.ConclusionThe results suggest that L-citrulline, administered exogenously, exhibits gastric protection by inhibition of neutrophil infiltration in rats, which may be related in prevention of the increase in iNOS activity. | Ochiai M, Hayashi T, Morita M, Ina K, Maeda M, Watanabe F, Morishita K (2012)
Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men.
International journal of cardiology 155, 257-261 [PubMed:21067832]
[show Abstract]
BackgroundNitric oxide (NO) plays a key role in the maintenance of vascular tone, contributing to the functional regulation of arterial stiffness. Although oral L-citrulline could become the effective precursor of L-arginine (substrate for endothelial NO synthase) via the L-citrulline/ L-arginine pathway, little is known about the efficacy of L-citrulline application on arterial stiffness.ObjectiveWe examined the short-term effects of L-citrulline supplementation on arterial stiffness in humans.MethodsIn a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (baPWV; index of arterial stiffness >1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days. baPWV and various clinical parameters were measured before (baseline) and after oral supplementation of L-citrulline or placebo.ResultsCompared with the placebo group, baPWV was significantly reduced in the L-citrulline group (p<0.01). No significant differences in blood pressure (BP) were found between the two groups, and no correlation was observed between BP and baPWV. The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group (p<0.05). Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group (p<0.05, p<0.01, p<0.05, respectively). Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (r=-0.553, p<0.05).ConclusionThese findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans. | Salard-Arnaud I, Stuehr D, Boucher JL, Mansuy D (2012)
Spectroscopic, catalytic and binding properties of Bacillus subtilis NO synthase-like protein: comparison with other bacterial and mammalian NO synthases.
Journal of inorganic biochemistry 106, 164-171 [PubMed:22119809]
[show Abstract]
Genome sequencing has shown the presence of genes coding for NO-synthase (NOS)-like proteins in bacteria. The roles and properties of these proteins remain unclear. UV-visible spectroscopy was used to characterize the recombinant NOS-like protein from Bacillus subtilis (bsNOS) in its ferric and ferrous states in the presence of various Fe(III)- and Fe(II)-heme-ligands and of a series of L-arginine (L-arg) analogs. BsNOS exhibited several spectroscopic and binding properties in common with Bacillus anthracis NOS (baNOS) that were clearly different from those of tetrahydrobiopterin (H4B)-free mammalian NOS oxygenase domains (mNOS(oxys)) and of Staphylococcus aureus NOS (saNOS). Interestingly, bsNOS and baNOS that do not contain H4B exhibited properties much closer to those of H4B-containing mNOS(oxys). Moreover, bsNOS was found to efficiently catalyze the oxidation of L-arginine into L-citrulline by H(2)O(2), whereas H4B-free mNOS(oxys) exhibited low activities for this reaction. | Camacho ME, Carrion MD, Lopez-Cara LC, Entrena A, Gallo MA, Espinosa A, Escames G, Acuna-Castroviejo D (2012)
Melatonin synthetic analogs as nitric oxide synthase inhibitors.
Mini reviews in medicinal chemistry 12, 600-617 [PubMed:22512552]
[show Abstract]
Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease. | Ogier de Baulny H, Schiff M, Dionisi-Vici C (2012)
Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder.
Molecular genetics and metabolism 106, 12-17 [PubMed:22402328]
[show Abstract]
Lysinuric protein intolerance (LPI) is an inherited defect of cationic amino acid (lysine, arginine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y(+)LAT1 protein. LPI has long been considered a relatively benign urea cycle disease, when appropriately treated with low-protein diet and l-citrulline supplementation. However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome. Specifically, immune dysfunction potentially attributable to nitric oxide (NO) overproduction secondary to arginine intracellular trapping (due to defective efflux from the cell) might be a crucial pathophysiological route explaining many of LPI complications. The latter comprise severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis with subsequent activation of macrophages, various auto-immune disorders and an incompletely characterized immune deficiency. These results have several therapeutic implications, among which lowering the l-citrulline dosage may be crucial, as excessive citrulline may worsen intracellular arginine accumulation. | Rubio-Texeira M, Van Zeebroeck G, Thevelein JM (2012)
Peptides induce persistent signaling from endosomes by a nutrient transceptor.
Nature chemical biology 8, 400-408 [PubMed:22388927]
[show Abstract]
The yeast Gap1 transceptor mediates amino acid activation of the protein kinase A pathway and undergoes endocytic internalization following amino acid transport. We identified three specific γ-glutamyl dipeptides that cause persistent cyclic AMP-independent activation of protein kinase A, prevent Gap1 vacuolar sorting and cause Gap1 accumulation in endosomes. To our knowledge, these are the first examples of persistent agonists of a transceptor. In yeast mutants blocked in multivesicular body sorting, L-citrulline mimicked persistent signaling, further supporting that the internalized Gap1 transceptor keeps signaling. Unexpectedly, these dipeptides were transported by Gap1 and not by the regular dipeptide transporters. Their uptake was unusually sensitive to external pH and caused transient intracellular acidification. High external pH, NHA1 deletion or V-ATPase inhibition overcame the vacuolar sorting defect. Hence, this work has identified specific dipeptides that cause enhanced proton influx through the Gap1 symporter, resulting in its defective vacuolar sorting, and independently transform it into a persistently signaling transceptor. | Rushaidhi M, Jing Y, Kennard JT, Collie ND, Williams JM, Zhang H, Liu P (2012)
Aging affects L-arginine and its metabolites in memory-associated brain structures at the tissue and synaptoneurosome levels.
Neuroscience 209, 21-31 [PubMed:22387109]
[show Abstract]
L-arginine, one of the most metabolically versatile amino acids, can be metabolized to form a number of bioactive molecules. The present study systematically investigated age-related changes in L-arginine and its metabolites in the hippocampus, parahippocampal region, and prefrontal cortex at the tissue (crude homogenates) and synaptoneurosome (a subcellular preparation enriched for synaptic material) levels. As aging leads to reduced water content in the brain, age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level were compared. There were significant differences in L-arginine, L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, and glutamate, but not GABA, in the CA1, CA2/3, and dentate gyrus sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, and postrhinal cortices in 24 (aged) and 4 (young) months old rats in a region-specific manner. The overall pattern of age-related changes in amino acids (L-arginine, L-citrulline, L-ornithine, glutamate, and GABA) was largely similar between homogenates and synaptoneurosomes, whereas the pattern for the amines (agmatine, putrescine, spermidine, and spermine) was quite different. Furthermore, the pattern of age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level was very similar for all 9 neurochemicals measured. These findings suggest that there are differential effects of aging on L-arginine metabolism at the tissue and synaptoneurosome levels and that the way of data normalization (tissue weight vs. protein level) has no or very minor effects on 9 neurochemicals measured. | Pradilla G, Garzon-Muvdi T, Ruzevick JJ, Bender M, Edwards L, Momin EN, Thompson RC, Tamargo RJ (2012)
Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage.
Neurosurgery 70, 747-56; discussion 756-7 [PubMed:21915076]
[show Abstract]
BackgroundNitric oxide (NO) depletion and periadventitial inflammation contribute to the pathogenesis of cerebral vasospasm. L-Citrulline increases L-arginine levels, thereby raising NO synthesis. Transgenic C57Bl6 mice with a haptoglobin (Hp) 2-2 genotype develop more severe vasospasm than wild-type (Hp 1-1) mice after subarachnoid hemorrhage (SAH).ObjectiveTo evaluate the toxicity of systemic L-citrulline and its effect on basilar artery (BA) vasospasm, neurobehavioral scores, and inducible NO synthase (iNOS)/endothelial NO synthase (eNOS) expression after SAH in Hp 2-2 mice.MethodsThe Hp 2-2 genotypes were confirmed by reverse-transcriptase polymerase chain reaction. Toxicity was assessed with escalating L-citrulline doses. To test efficacy, Hp 1-1 and Hp 2-2 mice (n = 64) were divided into 4 groups (n = 32 per genotype): sham surgery (n = 8), SAH with no treatment (n = 8), SAH + vehicle (n = 8), and SAH + L-citrulline (200 mg/kg IP every 8 hours; n = 8). Post-SAH neurobehavioral scores were recorded at 24 hours; animals were perfused; and BAs were processed for analysis. Expression of iNOS and eNOS was determined by reverse-transcriptase polymerase chain reaction.ResultsThe administration of L-citrulline resulted in higher BA lumen patencies in both genotypes (Hp 1-1: SAH + vehicle, 77.8 ± 3.2% vs SAH + L-citrulline, 91.8 ± 5.9% [mean ± SEM]; P < .05; Hp 2-2: SAH + vehicle, 67.1 ± 2.0% vs SAH + L-citrulline, 86.9 ± 2.2%; P < .001). Neurobehavioral scores were higher in Hp 2-2 mice treated with L-citrulline (SAH + vehicle, 1.2 ± 0.2 vs SAH + L-citrulline, 2.4 ± 0.2; P < .01). Expression of iNOS and eNOS increased in Hp 2-2 mice after L-citrulline treatment, but limited sample sizes prevented further statistical analysis. L-Citrulline was not toxic even at the highest dose.ConclusionL-Citrulline is safe; increases BA patency, neurobehavioral scores, and NOS expression in Hp 2-2 mice after SAH; and is a potential agent for treatment of vasospasm after SAH. | Mauldin JP, Zeinali I, Kleypas K, Woo JH, Blackwood RS, Jo CH, Stone EM, Georgiou G, Frankel AE (2012)
Recombinant human arginase toxicity in mice is reduced by citrulline supplementation.
Translational oncology 5, 26-31 [PubMed:22348173]
[show Abstract]
Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 (HuArg I [Co]-PEG5000) achieved potent in vitro depletion of arginine from tissue culture medium and cytotoxicity to many cancer cell lines. The recombinant enzyme also produced tumor growth inhibition of hepatocellular carcinoma and pancreatic carcinoma xenografts. Although these results were promising, the therapeutic index was narrow. Toxicities were seen in normal cells in tissue culture. In vivo normal tissue injury occurred at doses twice the effective dose. The current study was conducted to define, in greater detail, the maximum tolerated dose (MTD), pharmacodynamics, and dose-limiting toxicities (DLTs) of twice-weekly intraperitoneal HuArg I [Co]-PEG5000 in Balb/c mice. Animal weight and survival were monitored, serum arginine levels measured, and complete blood cell counts, chemistries, necropsies, and histologies were performed. In addition, methods to ameliorate the HuArg I [Co]-PEG5000 adverse effects were tested. Supplemental l-citrulline was given concurrently with the arginase drug. The HuArg I [Co]-PEG5000 MTD in mice was 5 mg/kg twice weekly, and DLTs included weight loss and marrow necrosis. No other organ damage or changes in blood cell counts or chemistries were observed. Arginase reduced serum arginine levels from 60 µM to 4 to 6 µM. Supplemental l-citrulline given per os or daily subcutaneously reduced and delayed toxicities, and l-citrulline given twice daily subcutaneously completely prevented animal toxicities. On the basis of these results, we hypothesize that HuArg I [Co]-PEG5000, particularly with supplemental l-citrulline, may be an attractive therapeutic agent for argininosuccinate synthetase-deficient tumors. | Liu P, Jing Y, Collie ND, Chary S, Zhang H (2009)
Memory-related changes in L-citrulline and agmatine in the rat brain.
Hippocampus 19, 597-602 [PubMed:19173225]
[show Abstract]
L-citrulline, L-ornithine, and agmatine are the metabolites of L-arginine by nitric oxide synthase (NOS), arginase, and arginine decarboxylase (ADC), respectively. In contrast to the NOS and arginase pathways, the role of the ADC-agmatine pathway in learning and memory has only been paid attention lately. Recent evidence suggests a potential involvement of agmatine in learning and memory processing. The present study further addressed this issue by comparing the levels of agmatine, as well as L-arginine, L-citrulline, and L-ornithine, in the hippocampus, parahippocampal region, prefrontal cortex, vestibular nucleus, and cerebellum in rats that were trained in the delayed nonmatch to position task in the T-maze with their yoked controls. There were significantly increased agmatine levels in the prefrontal, entorhinal, and perirhinal cortices and increased L-citrulline concentrations in the dentate gyrus (DG) and prefrontal cortex in the T-maze training group relative to the control one. L-arginine and L-ornithine levels were not significantly different between groups in the brain regions examined. These results demonstrate T-maze training-induced region-specific increases in L-citrulline and agmatine. Significant positive correlations between prefrontal and perirhinal agmatine levels and animals' performance in the T-maze further suggest the direct involvement of agmatine in learning and memory processing. | Timóteo MA, Oliveira L, Campesatto-Mella E, Barroso A, Silva C, Magalhães-Cardoso MT, Alves-do-Prado W, Correia-de-Sá P (2008)
Tuning adenosine A1 and A2A receptors activation mediates L-citrulline-induced inhibition of [3H]-acetylcholine release depending on nerve stimulation pattern.
Neurochemistry international 52, 834-845 [PubMed:18022291]
[show Abstract]
The influence of nerve stimulation pattern on transmitter release inhibition by L-citrulline, the co-product of NO biosynthesis by nitric oxide synthase (NOS), was studied in the rat phrenic nerve-hemidiaphragm. We also investigated the putative interactions between NOS pathway and the adenosine system. L-citrulline (10-470 microM), the NOS substrate L-arginine (10-470 microM) and the NO donor 3-morpholinylsydnoneimine (SIN-1, 1-10 microM), concentration-dependently inhibited [(3)H]-acetylcholine ([(3)H]-ACh) release from rat motor nerve endings. Increasing stimulus frequency from 5 Hz-trains to 50 Hz-bursts enhanced [(3)H]-ACh release inhibition by l-arginine (47 microM) and L-citrulline (470 microM), whereas the effect of SIN-1 (10 microM) remained unchanged. NOS inhibition with N(omega)-nitro-L-arginine (100 microM) prevented the effect of L-arginine, but not that of L-citrulline. Adenosine deaminase (2.5 U/ml) and the adenosine transport inhibitor, S-(p-nitrobenzyl)-6-thioinosine (10 microM), attenuated release inhibition by L-arginine and L-citrulline. With 5 Hz-trains, blockade of A(1) receptors with 1,3-dipropyl-8-cyclopentyl xanthine (2.5 nM), but not of A(2A) receptors with ZM241385 (10nM), reduced the inhibitory action of l-arginine and L-citrulline; the opposite was verified with 50 Hz-bursts. Blockade of muscarinic M(2) autoreceptors with AF-DX116 (10 nM) also attenuated the effects of L-arginine and L-citrulline with 50 Hz-bursts. L-citrulline (470 microM) increased basal adenosine outflow via the equilibrative nucleoside transport system sensitive to NBTI (10 microM), without significantly (P>0.05) changing the nucleoside release subsequent to nerve stimulation. Data indicate that NOS-derived L-citrulline negatively modulates [(3)H]-ACh release by increasing adenosine outflow channelling to A(1) and A(2A) receptors activation depending on the stimulus paradigm. While adenosine acts predominantly at inhibitory A(1) receptors during 5 Hz-trains, inhibition of ACh release by L-citrulline at 50 Hz-bursts depends on the interplay between adenosine A(2A) and muscarinic M(2) receptors. | Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD, Connor SC, Griffin JL (2007)
A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.
Physiological genomics 29, 99-108 [PubMed:17190852]
[show Abstract]
Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker (fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression. | Nakaki T, Hishikawa K (2002)
[The arginine paradox].
Nihon yakurigaku zasshi. Folia pharmacologica Japonica 119, 7-14 [PubMed:11862757]
[show Abstract]
L-Arginine has attracted major interest because it has been identified as the natural substrate of nitric oxide synthase and is now recognized as a major player in the regulation of biological function. The arginine paradox refers to the phenomenon that exogenous L-arginine causes NO-mediated biological effects despite the fact that nitric oxide synthases (NOS) are theoretically saturated with the substrate L-arginine. There have been several explanations for this phenomenon, although none of them can explain the arginine paradox fully: (1) L-arginine-induced insulin, which has vasodilatory actions. (2) Neither extracellular nor intracellular concentration determines the NOS activity but rather the L-arginine amount transported across the plasma membrane may do so. (3) Endogenous NOS inhibitors reduce the enzyme sensitivity to L-arginine. These inhibitors include, NG, NG-dimethyl-L-arginine, L-citrulline, argininosuccinic acid and agmatine. (4) Intracellular L-citrulline, an NOS product, is a potent inhibitor of NOS so that the cells may need extra L-arginine to compete with L-citrulline inhibition. |
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