Arginine is theamino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features aguanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the amino and guanidino groups are protonated, resulting in a cation. Only thel-arginine (symbolArg orR) enantiomer is found naturally.[1] Arg residues are common components ofproteins. It isencoded by thecodons CGU, CGC, CGA, CGG, AGA, and AGG.[2] The guanidine group in arginine is theprecursor for the biosynthesis ofnitric oxide.[3] Like all amino acids, it is a white, water-soluble solid.
The one-letter symbol R was assigned to arginine for its phonetic similarity.[4]
Arginine was first isolated in 1886 fromyellow lupin seedlings by the German chemistErnst Schulze and his assistant Ernst Steiger.[5][6] He named it from the Greekárgyros (ἄργυρος) meaning "silver" due to the silver-white appearance of arginine nitrate crystals.[7] In 1897, Schulze and Ernst Winterstein (1865–1949) determined the structure of arginine.[8] Schulze and Winterstein synthesized arginine fromornithine andcyanamide in 1899,[9] but some doubts about arginine's structure lingered[10] untilSørensen's synthesis of 1910.[11]
It is traditionally obtained byhydrolysis of various sources of protein, such asgelatin.[12] It is obtained commercially by fermentation. In this way, 25-35 g/liter can be produced, using glucose as a carbon source.[13]
Arginine is classified as a semiessential or conditionallyessential amino acid, depending on the developmental stage and health status of the individual.[14] Preterm infants are unable to synthesize arginine internally, making the amino acid nutritionally essential for them.[15] Most healthy people do not need to supplement with arginine because it is a component of all protein-containing foods[16] and can be synthesized in the body fromglutamine viacitrulline.[17][18] Additional, dietary arginine is necessary for otherwise healthy individuals temporarily under physiological stress, for example during recovery from burns, injury or sepsis,[18] or if either of the major sites of arginine biosynthesis, thesmall intestine andkidneys, have reduced function, because the small bowel does the first step of the synthesizing process and the kidneys do the second.[3]
Arginine is an essential amino acid for birds, as they do not have aurea cycle.[19] For some carnivores, for example cats, dogs[20] and ferrets, arginine is essential,[3] because after a meal, their highly efficientprotein catabolism produces large quantities ofammonia which need to be processed through the urea cycle, and if not enough arginine is present, the resulting ammonia toxicity can be lethal.[21] This is not a problem in practice, because meat contains sufficient arginine to avoid this situation.[21]
Animal sources of arginine include meat, dairy products, and eggs,[22][23] and plant sources include seeds of all types, for example grains, beans, and nuts.[23]
The pathways linking arginine,glutamine, andproline are bidirectional. Thus, the net use or production of these amino acids is highly dependent on cell type and developmental stage.[citation needed]
Arginine biosynthesis
Arginine is made by the body as follows. Theepithelial cells of thesmall intestine produce citrulline, primarily fromglutamine andglutamate, which is secreted into the bloodstream which carries it to theproximal tubule cells of thekidney, which extract the citrulline and convert it to arginine, which is returned to the blood. This means that impaired small bowel or renal function can reduce arginine synthesis and thus create a dietary requirement for arginine. For such a person, arginine would become "essential".
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 ofinducible nitric oxide synthase (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 to nitric oxide (citrulline-NO) or arginine-citrulline pathway. This is demonstrated by the fact that, in many cell types, nitric oxide synthesis can be supported to some extent by citrulline, and not just by arginine. This recycling is not quantitative, however, because citrulline accumulates in nitric oxide producing cells along withnitrate andnitrite, the stable end-products of nitric oxide breakdown.[24]
Arginine's side chain isamphipathic, because at physiological pH it contains a positively charged guanidinium group, which is highly polar, at the end of a hydrophobicaliphatic hydrocarbon chain. Because globular proteins have hydrophobic interiors and hydrophilic surfaces,[33] 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 inhydrogen bonding andsalt bridges.[34] For this reason, it is frequently found at the interface between two proteins.[35] The aliphatic part of the side chain sometimes remains below the surface of the protein.[34]
Arginine residues in proteins can be deiminated by PAD enzymes to form citrulline, in apost-translational modification process calledcitrullination.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 inautoimmune diseases.[36] Another post-translational modification of arginine involvesmethylation by proteinmethyltransferases.[37]
Arginine is the immediate precursor of nitric oxide, an important signaling molecule which can act as asecond messenger, as well as an intercellular messenger which regulates vasodilation, and also has functions in the immune system's reaction to infection.[citation needed]
Arginine is also a precursor forurea,ornithine, andagmatine; is necessary for the synthesis ofcreatine; and can also be used for the synthesis ofpolyamines (mainly through ornithine and to a lesser degree through agmatine, citrulline, and glutamate). The presence ofasymmetric dimethylarginine (ADMA), a close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker forvascular disease, just asL-arginine is considered a sign of a healthyendothelium.[38]
Delocalization of charge in guanidinium group ofl-Arginine
Theamino acidside-chain of arginine consists of a 3-carbonaliphatic straight chain, the distal end of which is capped by aguanidinium group, which has apKa of 13.8,[39] and is therefore always protonated and positively charged at physiological pH. Because of theconjugation between the double bond and the nitrogenlone pairs, the positive charge is delocalized, enabling the formation of multiplehydrogen bonds.
Intravenously administered arginine is used in growth hormone stimulation tests[40] because it stimulates the secretion ofgrowth hormone.[41] A review of clinical trials concluded that oral arginine increases growth hormone, but decreases growth hormone secretion, which is normally associated with exercising.[42] However, a more recent trial reported that although oral arginine increased plasma levels ofL-arginine it did not cause an increase in growth hormone.[43]
Research from 1964 into amino acid requirements ofherpes simplex virus in human cells indicated that "...the lack of arginine orhistidine, and possibly the presence oflysine, would interfere markedly with virus synthesis", but concludes that "no ready explanation is available for any of these observations".[44]
Further reviews conclude that "lysine's efficacy forherpes labialis may lie more in prevention than treatment." and that "the use of lysine for decreasing the severity or duration of outbreaks" is not supported, while further research is needed.[45] A 2017 study concludes that "clinicians could consider advising patients that there is a theoretical role of lysine supplementation in the prevention of herpes simplex sores but the research evidence is insufficient to back this. Patients with cardiovascular or gallbladder disease should be cautioned and warned of the theoretical risks."[46]
A meta-analysis showed thatL-arginine reduces blood pressure with pooled estimates of 5.4 mmHg for systolic blood pressure and 2.7 mmHg for diastolic blood pressure.[47]
Both liquid chromatography and liquid chromatography/mass spectrometric assays have found that brain tissue of deceased people withschizophrenia shows altered arginine metabolism. Assays also confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increasedagmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between L-ornithine level and the duration of illness. Moreover, cluster analyses revealed that L-arginine and its main metabolites L-citrulline, L-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. Despite this, the biological basis of schizophrenia is still poorly understood, a number of factors, such as dopamine hyperfunction, glutamatergic hypofunction, GABAergic deficits, cholinergic system dysfunction, stress vulnerability and neurodevelopmental disruption, have been linked to the aetiology and/or pathophysiology of the disease.[49]
L-arginine is recognized as safe (GRAS-status) at intakes of up to 20 grams per day.[51] L-arginine is found in many foods, such as fish, poultry, and dairy products, and is used as a dietary supplement.[52] It may interact with variousprescription drugs and herbal supplements.[52]
^Forbes SC, Bell GJ (June 2011). "The acute effects of a low and high dose of oral L-arginine supplementation in young active males at rest".Applied Physiology, Nutrition, and Metabolism.36 (3):405–11.doi:10.1139/h11-035.PMID21574873.
^Shao A, Hathcock JN (April 2008). "Risk assessment for the amino acids taurine, L-glutamine and L-arginine".Regulatory Toxicology and Pharmacology.50 (3):376–99.doi:10.1016/j.yrtph.2008.01.004.PMID18325648.
^ab"L-Arginine". MedlinePlus, US National Institutes of Health. 13 October 2021. Retrieved2021-05-27.
