The AtlasAmino acidsPositively charged
ArginineArg · R
The substrate for nitric oxide, the hinge of the urea cycle and the start of creatine, and the supplement whose own first pass through the gut undoes most of what is claimed for it.
Molecule · Arg · 12 heavy atoms
Arginine
C6H14N4O2174.20 g/mol
The substrate for nitric oxide, the hinge of the urea cycle and the start of creatine, and the supplement whose own first pass through the gut undoes most of what is claimed for it.
Built fromthe charted ones open their own entry
- Codes
- Arg · R
- Formula
- C6H14N4O2
- Molar mass
- 174.20 g/mol
- Systematic name
- (2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid
- Side chain
- 3-Guanidinopropyl: three carbons ending in a guanidinium group; always positively charged.
- Class
- Positively charged
- In the diet
- Conditionally essential
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 2.17 · α-NH3+ 9.04 · side chain 12.48
- Isoelectric point
- pH 10.76
- Hydropathy
- -4.5 (Kyte–Doolittle)
- Codons
CGUCGCCGACGGAGAAGG- Main transporters
- SLC7A7 (y⁺LAT1, with CD98), SLC3A1, SLC7A9 (rBAT, b⁰,⁺AT)
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
An amino acid whose side chain ends in a guanidinium group, the most strongly basic group in any amino acid: always positively charged, even buried inside a protein 1. The body makes it, mostly from citrulline in the kidney 2.
Why it matters
Arginine is the only substrate of the nitric oxide synthases, a step in the urea cycle, and the source of creatine, polyamines and agmatine 3,4,5. That is why it is sold for blood pressure, erections and exercise, and why it disappoints: a large share of what is swallowed is used up by the gut and liver before it reaches the body 6,7.
Where it runs short
Arginine is conditionally essential: adults make enough, but the newborn, and people with urea cycle disorders or lysinuric protein intolerance, may not 8,9,10.
Where it turns
Inherited arginase 1 deficiency leaves arginine high from birth and causes a slowly progressive spastic weakness of the legs, unlike the other urea cycle disorders 11,12.
The paradox: the body is rarely short of arginine, and the supplement rarely arrives.
The molecule
Arginine’s side chain is three carbons ending in a guanidinium group, a carbon bonded to three nitrogens that shares its positive charge across all of them. Textbooks give its pKa as about 12.5, but a 2015 NMR study measured 13.8, high enough that arginine stays charged even when buried in the core of a protein 1.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.17, α-amino 9.04, side chain 12.48) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
Adults make arginine. The small intestine makes citrulline from glutamine, and the kidney turns that citrulline into arginine and releases it, an intestinal–renal axis 2,13.
Because of that, arginine is conditionally essential, needed in the diet only when synthesis cannot keep up: in newborns, and in strict carnivores, birds and fish 8. In people with urea cycle disorders, arginine itself becomes part of the treatment 9.
Conditionally essentialMade from citrulline that the gut produces and the kidney converts, so adults do not need it in the diet; it is considered conditionally essential in newborns and in several animal species 2,8.
Where it is in food
- Protein foods generally; but much of the arginine in a meal or a capsule is used by the gut and liver on first pass 6.
In the bottle · fermentedMade by fermentation in Corynebacterium glutamicum; strains used for feed-grade arginine in Europe are not genetically modified and the product is at least 98% pure 8,14.
What the body does with it
Nitric oxide is made only from arginine. Endothelial nitric oxide relaxes blood vessels, neuronal nitric oxide signals in the brain and triggers erection, and inducible nitric oxide is a weapon of immune cells 3. In healthy adults, about 16% of the nitrate the body makes each day came from dietary arginine on its first pass through the gut and liver 15.
Arginine is also the last amino acid of the urea cycle: arginase splits it into urea, which is excreted, and ornithine, which goes round again 9. Argininosuccinate lyase, which makes arginine in that cycle, turned out to be needed for nitric oxide production as well; in people with its deficiency, a nitric oxide donor restored blood vessel responses 16.
Creatine synthesis begins by transferring arginine’s guanidino group to glycine. It is a large drain on arginine, glycine and methionine, and vegetarians get almost no creatine from their diet, so they make all of it 5.
Methylated arginines in proteins are released as asymmetric dimethylarginine when those proteins are broken down. It blocks nitric oxide synthase, more than 10 mg of it is excreted daily, and it accumulates when the kidneys fail 4,17.
In three sentences each
The only source of nitric oxide
Three nitric oxide synthases split arginine with oxygen into nitric oxide and citrulline, using NADPH, FAD, FMN and tetrahydrobiopterin; nerve-derived nitric oxide is what drugs like sildenafil depend on 3.
How it is made, moved and broken down
Arginine’s products include nitric oxide, urea, creatine, polyamines, proline, glutamate and agmatine 4. Because so many pathways compete for it, a ratio of arginine to ornithine and citrulline was proposed as a measure of how available it is; in 1,010 people, a low ratio predicted cardiovascular events 19.
Carbon skeleton · glucogenicArginase splits it into ornithine and urea; ornithine can go on to glutamate, proline and polyamines 4.
- Citrulline + aspartate
- Argininosuccinate synthetaseASS1 · ATP
- Argininosuccinate
- Argininosuccinate lyaseASL
- Arginine + fumarate
- Arginine
- Nitric oxide synthaseNOS1, NOS2, NOS3 · BH4, NADPH, O₂
- Nitric oxide + citrulline
- ArginaseARG1, ARG2 · manganese
- Ornithine + urea
- Arginine:glycine amidinotransferaseGATM
- Guanidinoacetate → creatine
Where it matters most
- Kidney
- Makes the body’s arginine from intestinal citrulline 2.
- Liver
- Runs the urea cycle, in which arginase splits arginine into urea and ornithine 9.
- Blood vessels
- Endothelial nitric oxide synthase makes the nitric oxide that relaxes them 3.
- Gut
- Takes up a large share of swallowed arginine before it reaches the circulation 6.
When it goes wrong
Inherited
Arginase 1 deficiency
ARG1 · autosomal recessive
Persistently high arginine drives a progressive spastic diplegia, developmental delay and seizures; across 157 reported cases the mean age at diagnosis was 6.4 years 11,12,22. In the PEACE trial, pegzilarginase, an enzyme that breaks down arginine, lowered plasma arginine from 354 to 86 µmol/L against almost no change on placebo 23.
How it is foundPlasma arginine, then ARG1 sequencing; it is often first mistaken for hereditary spastic paraplegia 12,22.
Inherited
Urea cycle disorders
ASS1, ASL, OTC and others · mostly recessive; OTC X-linked
About one birth in 35,000; half present as newborns with high ammonia. Arginine, or citrulline, is given in several of them to keep the cycle turning 9.
How it is foundAmmonia, plasma amino acids and urinary orotic acid, then genetic testing 9.
Drug
Arginine after a heart attack
In VINTAGE MI, arginine 3 g three times a day did not improve vascular stiffness or heart function, and there were six deaths on arginine against none on placebo; the trial stopped enrolling 24.
Biomarker
ADMA and cardiovascular risk
Across 22 prospective studies and nearly 20,000 people, higher ADMA predicted heart disease and stroke 18. Statins lowered it modestly in a meta-analysis 25.
How it is foundMass spectrometry; immunoassays disagree 26.
Drug
Arginine deprivation in cancer
ASS1
Tumours that lack argininosuccinate synthetase cannot make arginine. Pegargiminase with chemotherapy lengthened survival in 249 people with mesothelioma, with more serious side effects 27; in 635 people with liver cancer it had no effect 28.
How it is foundASS1 status of the tumour, in trials.
Drug
MELAS
MT-TL1 · mitochondrial
Arginine is widely given for the stroke-like episodes of this mitochondrial disease, but a 2022 systematic review found no randomised trial and no demonstrable benefit 29.
How it is measured
Plasma arginine is measured in the amino acid panel and, for arginase 1 deficiency, as the treatment target 23. ADMA is measured in research, but immunoassays and mass spectrometry give different numbers, with immunoassay reading about a third higher in kidney disease 26. Creatine and guanidinoacetate in plasma and urine diagnose the creatine synthesis disorders 30.
- Plasma argininePart of the amino acid panel; high in arginase 1 deficiency and the target of its treatment 12,23.Raised in 82% of reported arginase 1 deficiency cases 12.Arginine and ornithine change in the tube if the sample waits; prompt processing matters 31.
- ADMAAsymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase 17.Research; not a routine clinical test.In 22 prospective studies, people in the top third had 42% more cardiovascular events than the bottom third 18.Immunoassay and mass spectrometry disagree badly, especially in advanced kidney disease, so values are not comparable across methods 26.
- Arginine stimulation testArginine infused to provoke growth hormone release, in testing children for growth hormone deficiency 32.Accepted by consensus for children, alongside the glucagon test 32.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
Uncertainsmall, short, mixed, surrogate or preclinical
- Blood pressure: eleven small trials of 4 to 24 g a day found a fall of about 5 mmHg systolic 33.
- Erectile dysfunction: pooled trials in mild to moderate cases found benefit, more with a PDE5 inhibitor than alone; adverse effects were more common on arginine 34,35.
- Preventing necrotising enterocolitis in preterm babies: three trials in 285 infants showed fewer cases, not enough to change practice 36.
- Sickle cell disease: four trials suggested less pain and fewer crises 37.
Sold asthe claim on the label, against the evidence
- “Arginine boosts nitric oxide and performance.” Much of an oral dose is eliminated before it reaches the circulation, citrulline raises blood arginine more than arginine does, and a widely cited positive meta-analysis of athletic performance was later criticised for errors that distorted its pooled effect 6,7,38,39.
What is strange about it
In the VINTAGE MI trial, 153 people recovering from a heart attack took arginine or placebo for six months. Six died on arginine and none on placebo, and the trial was stopped 24.
Some tumours cannot make their own arginine. An enzyme that destroys arginine in the blood, pegargiminase, added to chemotherapy for mesothelioma, extended median survival from 7.7 to 9.3 months 27; the same approach in liver cancer did nothing 28.
Of the urea cycle disorders, arginase 1 deficiency is the odd one out: babies are healthy at birth, high ammonia is uncommon, and the disease shows itself years later as stiff legs, often first diagnosed as hereditary spastic paraplegia 11,12,22.
Where it connects
In the Atlas
Topics on the map
On the map
A star in Conditional amino acids, one of 14. The substrate for nitric oxide, and mostly destroyed in the gut and liver before it arrives — which is why the supplement disappoints and its precursor does not.
Sources
39 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Fitch CA, Platzer G, Okon M, et al. Arginine: its pKa value revisited.doi:10.1002/pro.2647 · PMID 25808204
pKa 13.8, not about 12; always charged.
- 2van de Poll MCG, Soeters PB, Deutz NEP, et al. Renal metabolism of amino acids: its role in interorgan amino acid exchange.doi:10.1093/ajcn/79.2.185 · PMID 14749222
Kidney makes arginine from intestinal citrulline.
- 3Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function.doi:10.1093/eurheartj/ehr304 · PMID 21890489
Three isoforms; cofactors; nNOS and erection.
- 4Morris SM. Arginine metabolism revisited.doi:10.3945/jn.115.226621 · PMID 27934648
The many products of arginine.
- 5Brosnan JT, Brosnan ME. Creatine: endogenous metabolite, dietary, and therapeutic supplement.doi:10.1146/annurev.nutr.27.061406.093621 · PMID 17430086
Creatine synthesis drains arginine, glycine and methionine.
- 6Castillo L, Chapman TE, Yu YM, et al. Dietary arginine uptake by the splanchnic region in adult humans.doi:10.1152/ajpendo.1993.265.4.E532 · PMID 8238326
About 38% first-pass uptake; small tracer studies.
- 7Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.doi:10.1111/j.1365-2125.2007.02990.x · PMID 17662090
20 volunteers; citrulline raised arginine more; no change in vessel function.
- 8EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Bampidis V, Azimonti G, et al. Assessment of the application for renewal of authorisation of L-arginine produced by fermentation using Corynebacterium glutamicum NITE SD 00285 for all animal species.doi:10.2903/j.efsa.2019.5720 · PMID 32626342
Conditionally essential in neonates and some species; strain and purity.
- 9Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision.doi:10.1002/jimd.12100 · PMID 30982989
Incidence about 1 in 35,000.
- 10Torrents D, Mykkänen J, Pineda M, et al. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.doi:10.1038/6809 · PMID 10080182
The dibasic amino acid exporter.
- 11Diaz GA, Bechter M, Cederbaum SD. The role and control of arginine levels in arginase 1 deficiency.doi:10.1002/jimd.12564 · PMID 36175366
Arginine as the main driver of disease. One author from the drug’s developer.
- 12Bin Sawad A, Pothukuchy A, Badeaux M, et al. Natural history of arginase 1 deficiency and the unmet needs of patients: a systematic review of case reports.doi:10.1002/jmd2.12283 · PMID 35822089
157 patients; diagnosis at a mean 6.4 years.
- 13Marini JC, Agarwal U, Robinson JL, et al. The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig.doi:10.1152/ajpendo.00055.2017 · PMID 28611027
Pigs; the axis exists in the newborn.
- 14Jiang Y, Sheng Q, Wu XY, et al. L-arginine production in Corynebacterium glutamicum: manipulation and optimization of the metabolic process.doi:10.1080/07388551.2020.1844625 · PMID 33153325
Industrial fermentation.
- 15Castillo L, deRojas TC, Chapman TE, et al. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man.doi:10.1073/pnas.90.1.193 · PMID 8419922
About 16% of daily nitrate from first-pass dietary arginine.
- 16Erez A, Nagamani SCS, Shchelochkov OA, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production.doi:10.1038/nm.2544 · PMID 22081021
ASL is part of the NOS complex; NO donor helped patients’ vessels.
- 17Vallance P, Leone A, Calver A, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.doi:10.1016/0140-6736(92)90865-z · PMID 1347093
ADMA discovered; accumulates in kidney failure.
- 18Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies.doi:10.1161/JAHA.115.001833 · PMID 26021436
19,842 people; top third against bottom, RR 1.42.
- 19Tang WHW, Wang Z, Cho L, et al. Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk.doi:10.1016/j.jacc.2009.02.036 · PMID 19477356
1,010 people; low arginine ratio, hazard ratio 1.98.
- 20Servais A, Thomas K, Dello Strologo L, et al. Cystinuria: clinical practice recommendation.doi:10.1016/j.kint.2020.06.035 · PMID 32918941
The basic amino acid transporter of the kidney.
- 21Fernandes-Pires G, Azevedo MD, Lanzillo M, et al. Rescue of myocytes and locomotion through AAV-driven intracisternal gene therapy in a rat model of creatine transporter deficiency.doi:10.1016/j.omtm.2024.101251 · PMID 38745894
Creatine synthesis defects treatable with creatine; transporter deficiency not. Rat study.
- 22McNutt MC, Foreman N, Gotway G. Arginase 1 deficiency in patients initially diagnosed with hereditary spastic paraplegia.doi:10.1002/mdc3.13612 · PMID 36698992
Misdiagnosis as hereditary spastic paraplegia.
- 23Sanchez Russo R, Gasperini S, Bubb G, et al. Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.doi:10.1016/j.eclinm.2023.102405 · PMID 38292042
32 patients; arginine normalised in 90.5%.
- 24Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.doi:10.1001/jama.295.1.58 · PMID 16391217
153 patients; six deaths on arginine, none on placebo.
- 25Zinellu A, Mangoni AA. An updated systematic review and meta-analysis of the effect of statins on asymmetric dimethylarginine.doi:10.1016/j.niox.2022.01.001 · PMID 35032642
23 studies; modest fall.
- 26Pecchini P, Malberti F, Mieth M, et al. Measuring asymmetric dimethylarginine (ADMA) in CKD: a comparison between enzyme-linked immunosorbent assay and liquid chromatography-electrospray tandem mass spectrometry.doi:10.5301/jn.5000085 · PMID 22322824
126 patients; ELISA 0.78 against 0.59 µmol/L by mass spectrometry.
- 27Szlosarek PW, Creelan BC, Sarkodie T, et al. Pegargiminase plus first-line chemotherapy in patients with nonepithelioid pleural mesothelioma: the ATOMIC-Meso randomized clinical trial.doi:10.1001/jamaoncol.2023.6789 · PMID 38358753
249 patients; median survival 9.3 against 7.7 months. Manufacturer-sponsored.
- 28Abou-Alfa GK, Qin S, Ryoo BY, et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.doi:10.1093/annonc/mdy101 · PMID 29659672
635 patients; no survival difference.
- 29Stefanetti RJ, Ng YS, Errington L, et al. L-arginine in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes: a systematic review.doi:10.1212/WNL.0000000000200299 · PMID 35428733
37 articles, no randomised trials; no demonstrable benefit.
- 30Liu N, Sun Q. Laboratory diagnosis of cerebral creatine deficiency syndromes by determining creatine and guanidinoacetate in plasma and urine.doi:10.1007/978-1-0716-2565-1_12 · PMID 36127584
The diagnostic method.
- 31Xia T, Gao S, Shu C, et al. Analysis of amino acids in human blood using UHPLC-MS/MS: potential interferences of storage time and vacutainer tube in pre-analytical procedure.doi:10.1016/j.clinbiochem.2016.09.018 · PMID 27693603
Storage and tube effects on plasma amino acids.
- 32Arlien-Søborg MC, Radovick S, Boguszewski MCS, et al. Consensus and controversies about diagnosing GH deficiency: a Delphi survey by the GH research society.doi:10.1007/s11102-025-01526-z · PMID 40335774
Arginine and glucagon tests accepted in children.
- 33Dong JY, Qin LQ, Zhang Z, et al. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials.doi:10.1016/j.ahj.2011.09.012 · PMID 22137067
11 trials, 387 people; systolic −5.4 mmHg.
- 34Rhim HC, Kim MS, Park YJ, et al. The potential role of arginine supplements on erectile dysfunction: a systemic review and meta-analysis.doi:10.1016/j.jsxm.2018.12.002 · PMID 30770070
10 trials, 540 men; adverse effects 8.3% against 2.3%.
- 35Barbonetti A, Tienforti D, Antolini F, et al. Nutraceutical interventions for erectile dysfunction: a systematic review and network meta-analysis.doi:10.1093/jsxmed/qdae123 · PMID 39279185
15 trials; best with tadalafil.
- 36Shah PS, Shah VS, Kelly LE. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants.doi:10.1002/14651858.CD004339.pub4 · PMID 28399330
Three trials, 285 infants; RR 0.38; not enough for a recommendation.
- 37Orsi BC, Gorski D, Krul NE, et al. The effects of nutritional supplementation for children and adolescents with sickle cell disease: a systematic review and meta-analyses.doi:10.1016/j.clnu.2025.02.016 · PMID 40022955
Four arginine trials among 20.
- 38Viribay A, Burgos J, Fernández-Landa J, et al. Effects of arginine supplementation on athletic performance based on energy metabolism: a systematic review and meta-analysis.doi:10.3390/nu12051300 · PMID 32370176
Positive pooled effect with very high heterogeneity.
- 39Trexler ET. Common errors in sports nutrition meta-analyses lead to distortion of pooled effect estimates.doi:10.3390/nu17142375 · PMID 40733000
Commentary identifying errors in the arginine meta-analysis.
This is education, not medical advice. Nothing on this page is written with knowledge of your history, your medications or your risks, and nothing here is a dose. Do not start or stop any treatment on the basis of it — talk to your own physician. Read the full medical disclaimer.