Arginine

Arginine
Names
	Other names 2-Amino-5-guanidinopentanoic acid
Identifiers
CAS Number	7200-25-1 ; 157-06-2 R ; 74-79-3 S ;
3D model (JSmol)	Interactive image; Interactive image;
3DMet	B01331
Beilstein Reference	1725411, 1725412 R, 1725413 S
ChEBI	CHEBI:29016 ;
ChEMBL	ChEMBL212301 ; ChEMBL1485 ;
ChemSpider	227 ; 64224 R ; 6082 S ;
DrugBank	DB00125 ;
ECHA InfoCard	100.000.738
EC Number	230-571-3
Gmelin Reference	364938 R
IUPHAR/BPS	721;
KEGG	C02385 ;
MeSH	Arginine
PubChem CID	232; 71070 R; 6322 S;
RTECS number	CF1934200 S
UNII	94ZLA3W45F ;
	InChI InChI=1S/C6H14N4O2/c7-4(5(11)12)2-1-3-10-6(8)9/h4H,1-3,7H2,(H,11,12)(H4,8,9,10) Key: ODKSFYDXXFIFQN-UHFFFAOYSA-N ;
	SMILES NC(CCCNC(N)=N)C(O)=O ; NC(CCC[nH]:c(:[nH]):[nH2])c(:[o]):[oH] ;
Properties
Chemical formula	C6H14N4O2
Molar mass	174.20 g·mol−1
Appearance	White crystals
Odor	Odourless
Melting point	260 °C; 500 °F; 533 K
Boiling point	368 °C (694 °F; 641 K)
Solubility in water	14.87 g/100 mL (20 °C)
Solubility	slightly soluble in ethanol; insoluble in ethyl ether
log P	−1.652
Acidity (pKa)	12.488
Basicity (pKb)	1.509
Thermochemistry
Specific; heat capacity (C)	232.8 J K−1 mol−1 (at 23.7 °C)
Std molar; entropy (So298)	250.6 J K−1 mol−1
Std enthalpy of; formation (ΔfHo298)	−624.9–−622.3 kJ mol−1
Std enthalpy of; combustion (ΔcHo298)	−3.7396–−3.7370 MJ mol−1
Pharmacology
ATC code	B05XB01 (WHO) S
Hazards
Safety data sheet	See: data page; sigma-aldrich
GHS pictograms
GHS signal word	WARNING
GHS hazard statements	H319
GHS precautionary statements	P305+351+338
	Lethal dose or concentration (LD, LC):
LD50 (median dose)	5110 mg/kg (rat, oral)
Related compounds
Related alkanoic acids	N-Methyl-D-aspartic acid; beta-Methylamino-L-alanine; Guanidinopropionic acid; Theanine; Pantothenic acid;
Related compounds	Panthenol;
Supplementary data page
Structure and; properties	Refractive index (n),; Dielectric constant (εr), etc.
Thermodynamic; data	Phase behaviour; solid–liquid–gas
Spectral data	UV, IR, NMR, MS
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is ?)
	Infobox references

Arginine (symbol Arg or R)^[1] is an α-amino acid that is used in the biosynthesis of proteins.^[2] It contains an α-amino group, an α-carboxylic acid group, and a side chain consisting of a 3-carbon aliphatic straight chain ending in a guanidino group. At physiological pH, the carboxylic acid is deprotonated (−COO⁻), the amino group is protonated (−NH₃⁺), and the guanidino group is also protonated to give the guanidinium form (-C-(NH₂)₂⁺), making arginine a charged, aliphatic amino acid.^[3] It is the precursor for the biosynthesis of nitric oxide, it is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG.

In humans, arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual.^[4] Preterm infants are unable to synthesize or create arginine internally, making the amino acid nutritionally essential for them.^[5] Most healthy people do not need to supplement with arginine because it is a component of all protein-containing foods^[6] and can be synthesized in the body from glutamine via citrulline.^[7]

History[edit]

Arginine was first isolated in 1886 from lupin and pumpkin seedlings by the German chemist Ernst Schulze^[8] and his assistant Ernst Steiger;^[9] in 1897, Ernst Schulze and Ernst Winterstein (1865–1949) determined the structure of arginine.^[10] Schulze and Winterstein synthesized arginine from ornithine and cyanamide in 1899,^[11] but some doubts about arginine's structure lingered^[12] until Sørensen's synthesis of 1910.^[13]

Sources[edit]

Dietary sources[edit]

Arginine is a conditionally essential amino acid in humans and rodents,^[14] as it may be required depending on the health status or lifecycle of the individual, for example, while healthy adults can supply their own requirement for arginine, immature and rapidly growing individuals require arginine in their diet,^[15] and it is also essential under physiological stress, for example during recovery from burns, injury, and sepsis,^[15] or when the small intestine and kidneys, which are the major sites of arginine biosynthesis, have been damaged.^[14] It is, however, an essential amino acid for birds, as they do not have a urea cycle,^[16] for some carnivores, for example cats, dogs^[17] and ferrets, arginine is essential,^[14] because after a meal, their highly efficient protein catabolism produces large quantities of ammonia which need to be processed through the urea cycle, and if not enough arginine is present, the resulting ammonia toxicity can be lethal.^[18] This is not a problem in practice, because meat contains sufficient arginine to avoid this situation.^[18]

Animal sources of arginine include meat, dairy products, and eggs,^[19]^[20] and plant sources include seeds of all types, for example grains, beans, and nuts.^[20]

Biosynthesis[edit]

Arginine is synthesized from citrulline in arginine and proline metabolism by the sequential action of the cytosolic enzymes argininosuccinate synthetase and argininosuccinate lyase. This is an energetically costly process, because for each molecule of argininosuccinate that is synthesized, one molecule of adenosine triphosphate (ATP) is hydrolyzed to adenosine monophosphate (AMP), consuming two ATP equivalents.

Citrulline can be derived from multiple sources:

from arginine itself via nitric oxide synthase, as a byproduct of the production of nitric oxide for signaling purposes
from ornithine through the breakdown of proline or glutamine/glutamate
from asymmetric dimethylarginine via DDAH

The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net use or production of these amino acids is highly dependent on cell type and developmental stage.

On a whole-body basis, synthesis of arginine occurs principally via the intestinal–renal axis: the epithelial cells of the small intestine produce citrulline, primarily from glutamine and glutamate, which is carried in the bloodstream to the proximal tubule cells of the kidney, which extract citrulline from the circulation and convert it to arginine, which is returned to the circulation. This means that impaired small bowel or renal function can reduce arginine synthesis, increasing the dietary requirement.

Synthesis of arginine from citrulline also occurs at a low level in many other cells, and cellular capacity for arginine synthesis can be markedly increased under circumstances that increase the production of inducible NOS, this allows citrulline, a byproduct of the NOS-catalyzed production of nitric oxide, to be recycled to arginine in a pathway known as the citrulline-NO or arginine-citrulline pathway. This is demonstrated by the fact that, in many cell types, NO synthesis can be supported to some extent by citrulline, and not just by arginine, this recycling is not quantitative, however, because citrulline accumulates in NO-producing cells along with nitrate and nitrite, the stable end-products of NO breakdown.^[21]

Function[edit]

Arginine plays an important role in cell division, wound healing, removing ammonia from the body, immune function,^[22] and the release of hormones.^[4]^[23]^[24] It is a precursor for the synthesis of nitric oxide (NO),^[25] making it important in the regulation of blood pressure.^[26]^[27]^[28]

Proteins[edit]

Arginine's side chain is amphipathic, because at physiological pH it contains a positively charged guanidinium group, which is highly polar, at the end of a hydrophobic aliphatic hydrocarbon chain, because globular proteins have hydrophobic interiors and hydrophilic surfaces,^[29] arginine is typically found on the outside of the protein, where the hydrophilic head group can interact with the polar environment, for example taking part in hydrogen bonding and salt bridges.^[30] For this reason, it is frequently found at the interface between two proteins,^[31] the aliphatic part of the side chain sometimes remains below the surface of the protein.^[30]

Arginine residues in proteins can be deiminated by PAD enzymes to form citrulline, in a post-translational modification process called citrullination.This is important in fetal development, is part of the normal immune process, as well as the control of gene expression, but is also significant in autoimmune diseases.^[32]^:275 Another post-translational modification of arginine involves methylation by protein methyltransferases.^[32]^:176

Precursor[edit]

Arginine is the immediate precursor of NO, an important signaling molecule which can act as a second messenger, as well as an intercellular messenger which regulates vasodilation, and also has functions in the immune system's reaction to infection.

Arginine is also a precursor for urea, ornithine, and agmatine; is necessary for the synthesis of creatine; and can also be used for the synthesis of polyamines (mainly through ornithine and to a lesser degree through agmatine, citrulline, and glutamate. The presence of asymmetric dimethylarginine (ADMA), a close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker for vascular disease, just as L-arginine is considered a sign of a healthy endothelium.

Safety[edit]

L-arginine is generally recognized as safe (GRAS-status) at intakes of up to 20 grams per day.^[33]

Structure[edit]

Delocalization of charge in guanidinium group of L-Arginine

The amino acid side-chain of arginine consists of a 3-carbon aliphatic straight chain, the distal end of which is capped by a guanidinium group, which has a pK_a of 12.48, and is therefore always protonated and positively charged at physiological pH. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is delocalized, enabling the formation of multiple hydrogen bonds.

Research[edit]

Growth hormone[edit]

Intravenously-administered arginine is used in growth hormone stimulation tests^[34] because it stimulates the secretion of growth hormone.^[35] A review of clinical trials concluded that oral arginine increases growth hormone.^[36] However, a more recent trial reported that although oral arginine increased plasma levels of L-arginine it did not cause an increase in growth hormone.^[37]

High blood pressure[edit]

A meta-analysis showed that L-arginine reduces blood pressure with pooled estimates of 5.4 mmHg for systolic blood pressure and 2.7 mmHg for diastolic blood pressure.^[28]

Supplementation with L-arginine reduces diastolic blood pressure and lengthens pregnancy for women with gestational hypertension, including women with high blood pressure as part of pre-eclampsia. It did not lower systolic blood pressure or improve weight at birth.^[38]

References[edit]

^ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
^ IUPAC-IUBMB Joint Commission on Biochemical Nomenclature. "Nomenclature and Symbolism for Amino Acids and Peptides". Recommendations on Organic & Biochemical Nomenclature, Symbols & Terminology etc. Archived from the original on 29 May 2007. Retrieved 2007-05-17.
^ Glasel, Jay A.; Deutscher, Murray P. (1995-11-20). Introduction to Biophysical Methods for Protein and Nucleic Acid Research. Academic Press. p. 456. ISBN 9780080534985.
^ ^a ^b Tapiero H, Mathé G, Couvreur P, Tew KD (November 2002). "L-Arginine". (review). Biomedicine & Pharmacotherapy. 56 (9): 439–445. doi:10.1016/s0753-3322(02)00284-6.
^ Wu G, Jaeger LA, Bazer FW, Rhoads JM (Aug 2004). "Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications". (review). The Journal of Nutritional Biochemistry. 15 (8): 442–51. doi:10.1016/j.jnutbio.2003.11.010. PMID 15302078.
^ "Drugs and Supplements Arginine". Retrieved 15 January 2015.
^ Skipper, Annalynn (1998). Dietitian's Handbook of Enteral and Parenteral Nutrition. Jones & Bartlett Learning. p. 76. ISBN 9780834209206.
^ Apel, Frank (July 2015). "Biographie von Ernst Schulze" (PDF). Retrieved 2017-11-06.
^ Schulze, Ernst; Steiger, Ernst (1887). "Ueber das Arginin" [On arginine]. Zeitschrift für physiologische Chemie. 11 (1–2): 43–65.
^ Schulze, Ernst; Winterstein, Ernst (1897). "Ueber ein Spaltungsproduct des Arginins" [On a cleavage product of arginine]. Berichte der Deutschen Chemischen Gesellschaft (in German). 30: 2879–2882. The structure for arginine is presented on p. 2882.
^ Schulze, E.; Winterstein, E. (1899). "Ueber die Constitution des Arginins" [On the constitution of arginine]. Berichte der Deutschen Chemischen Gesellschaft (in German). 32: 3191–3194.
^ Cohen, Julius Berend (1919). Organic Chemistry for Advanced Students, Part 3 (2nd ed.). New York, New York, USA: Longmans, Green & Co. p. 140.
^ Sörensen, S.P.L. (1910). "Über die Synthese des dl-Arginins (α-Amino-δ-guanido-n-valeriansäure) und der isomeren α-Guanido-δ-amino-n-valeriansäure"" [On the synthesis of racemic arginine (α-amino-δ-guanido-n-valeric acid) and of the isomeric α-guanido-δ-amino-n-valeric acid]. Berichte der Deutschen Chemischen Gesellschaft (in German). 43: 643–651.
^ ^a ^b ^c Ignarro, Louis J. (2000-09-13). Nitric Oxide: Biology and Pathobiology. Academic Press. p. 189. ISBN 9780080525037.
^ ^a ^b Borlase, Bradley C. (1994). Enteral Nutrition. Jones & Bartlett Learning. p. 48. ISBN 9780412984716.
^ Freedland, Richard Allan; Briggs, Stephanie (2012-12-06). A Biochemical Approach to Nutrition. Springer Science & Business Media. p. 45. ISBN 9789400957329.
^ Nutrient Requirements of Dogs. National Academies Press. 1985. p. 65. ISBN 9780309034968.
^ ^a ^b Wortinger, Ann; Burns, Kara (2015-06-11). Nutrition and Disease Management for Veterinary Technicians and Nurses. John Wiley & Sons. p. 232. ISBN 9781118811085.
^ Spano, Marie A.; Kruskall, Laura J.; Thomas, D. Travis (2017-08-30). Nutrition for Sport, Exercise, and Health. Human Kinetics. p. 240. ISBN 9781450414876.
^ ^a ^b Watson, Ronald Ross; Zibadi, Sherma (2012-11-28). Bioactive Dietary Factors and Plant Extracts in Dermatology. Springer Science & Business Media. p. 75. ISBN 9781627031677.
^ Morris SM (Oct 2004). "Enzymes of arginine metabolism". (review). The Journal of Nutrition. 134 (10 Suppl): 2743S–2747S; discussion 2765S–2767S. doi:10.1093/jn/134.10.2743S. PMID 15465778.
^ Mauro, Claudio; Frezza, Christian (2015-07-13). The Metabolic Challenges of Immune Cells in Health and Disease. Frontiers Media SA. p. 17. ISBN 9782889196227.
^ Stechmiller JK, Childress B, Cowan L (Feb 2005). "Arginine supplementation and wound healing". (review). Nutrition in Clinical Practice. 20 (1): 52–61. doi:10.1177/011542650502000152. PMID 16207646.
^ Witte MB, Barbul A (2003). "Arginine physiology and its implication for wound healing". (review). Wound Repair and Regeneration. 11 (6): 419–23. doi:10.1046/j.1524-475X.2003.11605.x. PMID 14617280.
^ Andrew PJ, Mayer B (Aug 1999). "Enzymatic function of nitric oxide synthases". (review). Cardiovascular Research. 43 (3): 521–31. doi:10.1016/S0008-6363(99)00115-7. PMID 10690324.
^ Gokce N (Oct 2004). "L-arginine and hypertension". (review). The Journal of Nutrition. 134 (10 Suppl): 2807S–2811S; discussion 2818S–2819S. doi:10.1093/jn/134.10.2807S. PMID 15465790.
^ Rajapakse NW, De Miguel C, Das S, Mattson DL (Dec 2008). "Exogenous L-arginine ameliorates angiotensin II-induced hypertension and renal damage in rats". (primary). Hypertension. 52 (6): 1084–90. doi:10.1161/HYPERTENSIONAHA.108.114298. PMC 2680209 . PMID 18981330.
^ ^a ^b Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, Zhang W (Dec 2011). "Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials". review. American Heart Journal. 162 (6): 959–965. doi:10.1016/j.ahj.2011.09.012. PMID 22137067.
^ Mathews, Christopher K.,; Van Holde, Kensal Edward; Ahern, Kevin G. (2000). Biochemistry (3rd ed.). San Francisco, Calif.: Benjamin Cummings. p. 180. ISBN 0805330666. OCLC 42290721.
^ ^a ^b Barnes, Michael R. (2007-04-16). Bioinformatics for Geneticists: A Bioinformatics Primer for the Analysis of Genetic Data. John Wiley & Sons. p. 326. ISBN 9780470026199.
^ Kleanthous, Colin (2000). Protein-protein Recognition. Oxford University Press. p. 13. ISBN 9780199637607.
^ ^a ^b Griffiths, John R.; Unwin, Richard D. (2016-10-12). Analysis of Protein Post-Translational Modifications by Mass Spectrometry. John Wiley & Sons. ISBN 9781119250883.
^ Shao A, Hathcock JN (2008). "Risk assessment for the amino acids taurine, L-glutamine and L-arginine". Regul Toxicol Pharmacol. 50 (3): 376–399. doi:10.1016/j.yrtph.2008.01.004. PMID 18325648.
^ U.S. National Library of Medicine (September 2009 Growth hormone stimulation test
^ Alba-Roth J, Müller OA, Schopohl J, von Werder K (Dec 1988). "Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion". The Journal of Clinical Endocrinology and Metabolism. 67 (6): 1186–9. doi:10.1210/jcem-67-6-1186. PMID 2903866.
^ Kanaley JA (2008). "Growth hormone, arginine and exercise". Curr Opin Clin Nutr Metab Care. 11 (1): 50–4. doi:10.1097/MCO.0b013e3282f2b0ad. PMID 18090659.
^ Forbes SC, Bell GJ (2011). "The acute effects of a low and high dose of oral L-arginine supplementation in young active males at rest". Appl Physiol Nutr Metab. 36 (3): 405–11. doi:10.1139/h11-035. PMID 21574873.
^ Gui S, Jia J, Niu X, Bai Y, Zou H, Deng J, Zhou R (Mar 2014). "Arginine supplementation for improving maternal and neonatal outcomes in hypertensive disorder of pregnancy: a systematic review". (review). Journal of the Renin-Angiotensin-Aldosterone System. 15 (1): 88–96. doi:10.1177/1470320313475910. PMID 23435582.