Arginine

Last updated
Arginine
Arginin - Arginine.svg
Skeletal formula of arginine
Arginine-from-xtal-3D-bs-17.png
Arginine-from-xtal-3D-sf.png
Names
IUPAC names
Arginine
Other names
2-Amino-5-guanidinopentanoic acid
Identifiers
3D model (JSmol)
3DMet
1725411, 1725412 D, 1725413 L
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.738 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • L:230-571-3
364938 D
KEGG
MeSH Arginine
PubChem CID
RTECS number
  • L:CF1934200 L
UNII
  • 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)/t4-/m0/s1 Yes check.svgY
    Key: ODKSFYDXXFIFQN-BYPYZUCNSA-N Yes check.svgY
  • D/L:Key: ODKSFYDXXFIFQN-UHFFFAOYSA-N
  • D:Key: ODKSFYDXXFIFQN-SCSAIBSYSA-N
  • L:C(C[C@@H](C(=O)O)N)CNC(=N)N
  • D/L:C(CC(C(=O)O)N)CNC(=N)N
  • D:C(C[C@H](C(=O)O)N)CNC(=N)N
  • L HCl:[Cl-].NC(CCCNC(N)=[NH2+])C([O-])=O
  • L Zwitterion:NC(CCCNC(N)=[NH2+])C([O-])=O
Properties
C6H14N4O2
Molar mass 174.204 g·mol−1
AppearanceWhite crystals
Odor Odourless
Melting point 260 °C; 500 °F; 533 K
Boiling point 368 °C (694 °F; 641 K)
14.87 g/100 mL (20 °C)
Solubility slightly soluble in ethanol
insoluble in ethyl ether
log P −1.652
Acidity (pKa)2.18 (carboxyl), 9.09 (amino), 13.8 (guanidino)
Thermochemistry
232.8 J K−1 mol−1 (at 23.7 °C)
Std molar
entropy
(S298)
250.6 J K−1 mol−1
−624.9–−622.3 kJ mol−1
−3.7396–−3.7370 MJ mol−1
Pharmacology
B05XB01 ( WHO ) S
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H319
P305+P351+P338
Lethal dose or concentration (LD, LC):
5110 mg/kg (rat, oral)
Safety data sheet (SDS) L-Arginine
Related compounds
Related alkanoic acids
Related compounds
Supplementary data page
Arginine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino 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 the l-arginine (symbol Arg or R) enantiomer is found naturally. [1] Arg residues are common components of proteins. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. [2] The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide. [3] Like all amino acids, it is a white, water-soluble solid.

Contents

History

Arginine was first isolated in 1886 from yellow lupin seedlings by the German chemist Ernst Schulze and his assistant Ernst Steiger. [4] [5] He named it from the Greek árgyros (ἄργυρος) meaning "silver" due to the silver-white appearance of arginine nitrate crystals. [6] In 1897, Schulze and Ernst Winterstein (1865–1949) determined the structure of arginine. [7] Schulze and Winterstein synthesized arginine from ornithine and cyanamide in 1899, [8] but some doubts about arginine's structure lingered [9] until Sørensen's synthesis of 1910. [10]

Sources

Production

It is traditionally obtained by hydrolysis of various cheap sources of protein, such as gelatin. [11] It is obtained commercially by fermentation. In this way, 25-35 g/liter can be produced, using glucose as a carbon source. [12]

Dietary sources

Arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. [13] Preterm infants are unable to synthesize arginine internally, making the amino acid nutritionally essential for them. [14] Most healthy people do not need to supplement with arginine because it is a component of all protein-containing foods [15] and can be synthesized in the body from glutamine via citrulline. [16] [17] Additional dietary arginine is necessary for healthy individuals under physiological stress, for example during recovery from burns, injury and sepsis, [17] or if the major sites of arginine biosynthesis, the small intestine and kidneys, have reduced function. [3]

Arginine is an essential amino acid for birds, as they do not have a urea cycle. [18] For some carnivores, for example cats, dogs [19] and ferrets, arginine is essential, [3] 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. [20] This is not a problem in practice, because meat contains sufficient arginine to avoid this situation. [20]

Animal sources of arginine include meat, dairy products, and eggs, [21] [22] and plant sources include seeds of all types, for example grains, beans, and nuts. [22]

Biosynthesis

Arginine is synthesized from citrulline in the urea cycle 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.

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.

Arginine biosynthesis. Arginine biosynthesis pathway.png
Arginine biosynthesis.

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. [23]

Function

Arginine plays an important role in cell division, wound healing, removing ammonia from the body, immune function, [24] and the release of hormones. [13] [25] [26] It is a precursor for the synthesis of nitric oxide (NO), [27] making it important in the regulation of blood pressure. [28] [29] Arginine is necessary for T-Cells to function in the body, and can lead to their deregulation if depleted. [30] [31]

Proteins

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, [32] 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. [33] For this reason, it is frequently found at the interface between two proteins. [34] The aliphatic part of the side chain sometimes remains below the surface of the protein. [33]

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. [35] Another post-translational modification of arginine involves methylation by protein methyltransferases. [36]

Precursor

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.

Structure

Delocalization of charge in guanidinium group of
l-Arginine Betaine Arginine.png
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 pKa of 13.8, [37] 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

Growth hormone

Intravenously administered arginine is used in growth hormone stimulation tests [38] because it stimulates the secretion of growth hormone. [39] A review of clinical trials concluded that oral arginine increases growth hormone, but decreases growth hormone secretion, which is normally associated with exercising. [40] 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. [41]

Herpes-Simplex Virus (Cold sores)

Research from 1964 into amino acid requirements of herpes simplex virus in human cells indicated that "...the lack of arginine or histidine, and possibly the presence of lysine, would interfere markedly with virus synthesis", but concludes that "no ready explanation is available for any of these observations". [42]

Further medical evidence indicates that "absorbing more arginine may indirectly cause cold sores by disrupting the body's balance of arginine and another amino acid called lysine." [43] [44]

Further reviews conclude that "lysine's efficacy for herpes 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]

High blood pressure

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. [47]

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. [48]

Schizophrenia

Both liquid chromatography and liquid chromatography/mass spectrometric assays have found that brain tissue of deceased people with schizophrenia shows altered arginine metabolism. Assays also confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine 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]

Raynaud's phenomenon

Oral L-arginine has been shown to reverse digital necrosis in Raynaud syndrome [50]

Safety

L-arginine is recognized as safe (GRAS-status) at intakes of up to 20 grams per day. [51]

See also

Related Research Articles

<span class="mw-page-title-main">Amino acid</span> Organic compounds containing amine and carboxylic groups

Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha amino acids appear in the genetic code.

<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

Methionine is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical role in the metabolism and health of many species, including humans. It is encoded by the codon AUG.

<span class="mw-page-title-main">Lysine</span> Amino acid

Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO form under biological conditions), and a side chain lysyl ((CH2)4NH2), classifying it as a basic, charged (at physiological pH), aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.

<span class="mw-page-title-main">Ornithine</span> Chemical compound

Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.

<span class="mw-page-title-main">Citrulline</span> Chemical compound

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 Yotaro Koga and Ryo Odake 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.

An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life forms, the nine amino acids humans cannot synthesize are phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine.

Agmatine, also known as 4-aminobutyl-guanidine, is an aminoguanidine that was discovered in 1910 by Albrecht Kossel. Agmatine is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism and this provides bases for further research into potential applications.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Lysinuric protein intolerance</span> Medical condition

Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport.

<span class="mw-page-title-main">Argininosuccinate synthase</span> Enzyme

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

<span class="mw-page-title-main">Cyanophycin</span>

Cyanophycin, also known as CGP or multi-L-arginyl-poly, is a non-protein, non-ribosomally produced amino acid polymer composed of an aspartic acid backbone and arginine side groups.

<span class="mw-page-title-main">Asymmetric dimethylarginine</span> Chemical compound

Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health.

<span class="mw-page-title-main">Citrullination</span> Biological process

Citrullination or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline. Citrulline is not one of the 20 standard amino acids encoded by DNA in the genetic code. Instead, it is the result of a post-translational modification. Citrullination is distinct from the formation of the free amino acid citrulline as part of the urea cycle or as a byproduct of enzymes of the nitric oxide synthase family.

<span class="mw-page-title-main">Arginine decarboxylase</span>

The enzyme Acid-Induced Arginine Decarboxylase (AdiA), also commonly referred to as arginine decarboxylase, catalyzes the conversion of L-arginine into agmatine and carbon dioxide. The process consumes a proton in the decarboxylation and employs a pyridoxal-5'-phosphate (PLP) cofactor, similar to other enzymes involved in amino acid metabolism, such as ornithine decarboxylase and glutamine decarboxylase. It is found in bacteria and virus, though most research has so far focused on forms of the enzyme in bacteria. During the AdiA catalyzed decarboxylation of arginine, the necessary proton is consumed from the cell cytoplasm which helps to prevent the over-accumulation of protons inside the cell and serves to increase the intracellular pH. Arginine decarboxylase is part of an enzymatic system in Escherichia coli, Salmonella Typhimurium, and methane-producing bacteria Methanococcus jannaschii that makes these organisms acid resistant and allows them to survive under highly acidic medium.

<span class="mw-page-title-main">Aldehyde dehydrogenase 18 family, member A1</span> Protein-coding gene in the species Homo sapiens

Delta-1-pyrroline-5-carboxylate synthetase (P5CS) is an enzyme that in humans is encoded by the ALDH18A1 gene. This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. As reported by Bruno Reversade and colleagues, ALDH18A1 deficiency or dominant-negative mutations in P5CS in humans causes a progeroid disease known as De Barsy Syndrome.

Arginine alpha-ketoglutarate (AAKG) is a salt of the amino acid arginine and alpha-ketoglutaric acid. It is marketed as a bodybuilding supplement.

<span class="mw-page-title-main">Homoarginine</span> Chemical compound

Homoarginine is an nonproteinogenic alpha-amino acid. It is structurally equivalent to a one-methylene group-higher homolog of arginine and to the guanidino derivative of lysine. L-Homoarginine is the naturally-occurring enantiomer. Physiologically, homoarginine increases nitric oxide (NO) supply and betters endothelial functions in the body, with a particular correlation and effect towards cardiovascular outcome and mortality. At physiological pH, homoarginine is cationic: the guanidino group is protonated.

<span class="mw-page-title-main">Homocitrulline</span> Chemical compound

L-Homocitrulline is an amino acid and a metabolite of ornithine in mammalian metabolism. The amino acid can be detected in larger amounts in the urine of individuals with urea cycle disorders. At present, it is thought that the depletion of the ornithine supply causes the accumulation of carbamyl-phosphate in the urea cycle which may be responsible for the enhanced synthesis of homocitrulline and homoarginine. Both amino acids can be detected in urine. Amino acid analysis allows for the quantitative analysis of these amino acid metabolites in biological fluids such as urine or blood.

Juven is a medical food that is manufactured by Abbott Laboratories and used to provide nutritional support under the care of a physician in individuals with muscle wasting due to AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional. It is a powdered nutritional supplement that contains 3 grams of calcium β-hydroxy β-methylbutyrate, 14 grams of L-arginine, and 14 grams of L-glutamine per two daily servings.

Pre-workout is a generic term for a range of bodybuilding supplement products used by athletes and weightlifters to enhance athletic performance. It is taken to increase endurance, energy, and focus during a workout. Pre-workout supplements contain a variety of ingredients such as caffeine and creatine, ranging by product. It can be taken in a variety of forms including capsules and powder. The first pre-workout entered the market in 1982, and since then they have grown in popularity. Some pre-workouts contain ingredients linked to adverse effects. Although these products are not banned, the Food and Drug Administration (FDA) warns consumers to be cautious when consuming pre-workout.

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