Arginine serves as the formamidine donor for creatine biosynthesis, participates in polyamine biosynthesis, and provides the nitrogen of nitric oxide (NO).

L-Arginine

• L-Arginine can force the blood-brain barrier to open up.

Arginine:

• Precursor for NO and glutamate in IECs and immune cells
• Intestinal growth, structure, and function
• Supports microvasculature of intestinal mucosa
• Increases expression of HSP70 to protect the intestinal mucosa
• Protects against E.coli/LPS-induced damage to the intestinal structure and barrier function
• Facilitates neutrophil and macrophage killing through iNOS-mediated NO production
• Increases intestinal IgA levels
• Lowers inflammatory cytokine levels in intestine
• Increases T-lymphocytes in lamina propria, PPs, intraepithelial spaces

Arginine:

• It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG.
• An alpha-amino acid in the form of nutrient or supplement.
• Nonessential Amino Acid is involved in nitric oxide production, it is the precursor for the biosynthesis of nitric oxide.
• The L-form is one of the 20 most common natural amino acids.
• A semi-essential or conditionally essential amino acid, depending on the developmental stage and health status of the individual.
• Adults can synthesize arginine in the urea cycle.
• Infants are unable to effectively synthesize arginine, making it nutritionally essential for infants.
• Arginine can be considered to be a basic amino acid as the part of the side chain nearest to the backbone is long, carbon-containing and hydrophobic, whereas the end of the side chain is a complex guanidinium group.
• With a pKa of 12.48, the guanidinium group is positively charged in neutral, acidic and even most basic environments.
• Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is delocalized. This group is able to form multiple H-bonds.
• 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.

Biosynthesis:

• 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.
• 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.

Metabolism:

• Some metabolism of L-arginine takes place in the enterocytes.
• L-arginine not metabolized in the enterocytes enters the portal circulation from whence it is transported to the liver, where again some portion of the amino acid is metabolized.

Route of Exposure:

• Absorbed from the lumen of the small intestine into the enterocytes. Absorption is efficient and occurs by an active transport mechanism.

Functions:

• Disposes of ammonia as it is used to make compounds such as nitric oxide, creatine, L-glutamate, L-proline, and it can be converted to glucose and glycogen if needed.
• In large doses, L-arginine also stimulates the release of hormones growth hormone and prolactin.
• Arginine is a known inducer of mTOR (mammalian target of rapamycin) and is responsible for inducing protein synthesis through the mTOR pathway. mTOR inhibition by rapamycin partially reduces arginine-induced protein synthesis.
• Catabolic disease states such as sepsis, injury, and cancer cause an increase in arginine utilization, which can exceed normal body production, leading to arginine depletion.
• Arginine also activates AMP kinase (AMPK) which then stimulates skeletal muscle fatty acid oxidation and muscle glucose uptake, thereby increasing insulin secretion by pancreatic beta-cells.
• Arginine has been seen to increase T lymphocyte 1 (Th1) in response to infection, but increase Th2 in response to injury.

Urea Cycle:

• There are three key amino acids needed for the urea cycle and they function to protect against ammonia toxicity: L-Arginine, L-Citrulline, and L-Ornithine. These are all important but L-Ornithine may be the most critical as it helps remove ammonia from the brain.
• Adequate arginine substitution is essential in the treatment of urea cycle defects as creatine is inefficiently transported into the brain.

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.

Nitric Oxide (NO):

• Molecule-Free radical that reacts in antimicrobial, antitumoral, and neurotransmission activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases.
• L-arginine may have possible anti-atherogenic actions, due to its role as the precursor to nitric oxide.
• NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3,'5' -cyclic guanylate or cyclic GMP.
• The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range.
• Under physiological conditions, NOS is saturated with its L-arginine substrate, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid^would make any difference with regard to NO production.
• The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, supplemental L-arginine could enhance endothelial-dependent vasodilation and NO production.

Supplementing:

• Most healthy people do not need to supplement with arginine because it is a component of all protein-containing foods and can be synthesized in the body from glutamine via citrulline.
• Long-term L-Arginine supplementation increases VIP in the rat small intestine.

Taking Arginine and Ornithine supplement:

• Arginine and ornithine supplements have been shown to increase GH levels in athletes.
  • Arginine suppresses somatostatin secretion, an inhibitor of GH secretion.
  • Taking doses of 500 mg of L-Ornithine in the evening and 500 mg of L-Arginine in the morning can be very helpful to aid ammonia metabolism.

Liver Transplant:

• When optimal treatment fails, or for neonatal onset CPS and OTC deficiency, liver transplant becomes an option.
• Liver transplants have been done successfully as a cure for the disorder (although L-arginine supplementation is still necessary in ASA lyase deficiency posttransplant).
• The transplant alternative must be carefully considered and evaluated with medical professionals to determine the potential of success and benefits compared to the serious risks and potential for new medical concerns, including the possibility of fatal viruses (Epstein-Barr, CMV), risk of developmental delay or lymphoproliferative disease as a side effect of immunosuppression/immunosuppressants.

Drug Treatment:

• Two forms of a drug, phenylbutyrate, are FDA approved for treatment of urea cycle disorders, sodium phenylbutyrate (trade name Buphenyl, powder or pill form) and glycerol phenylbutyrate (trade name Ravicti, liquid form).
• Sodium benzoate is also used in some patients, solely or in combination with phenylbutyrate.
• All three medications serve as “ammonia scavengers” providing alternative pathways for removal of ammonia from the bloodstream and helping to prevent hyperammonemia (elevated blood ammonia).
• Carglumic acid (trade name Carbaglu) is approved for treatment of NAGS deficiency.
• The medications are administered 3-4 times per day as prescribed in order to optimize continual removal of toxic ammonia from the bloodstream.
• Pharmaceutical grade (not over-the-counter) L-citrulline (for OTC and CPS deficiency) or L-arginine free base (ASA and citrullinemia) is also required. These are not to be used in Arginase Deficiency. These supplements help catalyze the urea cycle enzymes and promote optimal removal of ammonia.

Arginine HCl Vs. And Arginine Base:

• Arginine HCl is given intravenously (IV) to UCD patients in the hospital setting.
• Arginine HCl is sometimes used by pharmacists to create a pediatric suspension (liquid) for oral use in UCD children.
• Arginine HCl can cause acidosis. Patients receiving arginine HCl may require additional monitoring for acidosis by their metabolic physician.
• Arginine free base powder is the standard used for daily oral administration for chronic management of some urea cycle disorders. It does not cause acidosis.
• Families should check to ensure the product they are receiving from their pharmacy for oral administration is an arginine free base. If arginine HCl has been substituted by the pharmacy, the metabolic physician needs to be notified in case additional monitoring for acidosis is needed. Even healthcare professionals are not always aware of the difference in these two products.
• With an increasing amount of unregulated dietary supplement products on the market, it is very important to stay vigilant and make sure which form of arginine you are receiving from the pharmacy. Some pharmacies have started distributing Arginine HCl powder instead of Arginine free base powder to patients without notifying the patient/family or treating physician of the substitution.
• Your metabolic physician will determine whether it is safe to continue on arginine HCl and whether additional monitoring is needed. If the physician wishes the patient to receive arginine free base only, the prescription must state explicitly "arginine free base."

Lysine:

• Competes with arginine for absorption and use by the body, if taking will get less than optimal results from arginine, and vice versa.

Citrulline:

• Supplementing with L-citrulline can be effective at raising arginine and nitric oxide levels.

Folate:

• Has nitric oxide-enhancing effects.
• Boosting nitric oxide through L-arginine or l-ornithine, it is imperative to optimize methylation with B12, folate and other methylation cofactors.

Ornithine Transcarbamylase:

• Is an enzyme in the urea cycle. For patients with urea cycle defects, arginine becomes an essential amino acid.

Commonly used:

• By bodybuilders who want to put on weight by increasing body mass. Little proof that improves muscle growth, but may release a growth hormone.
• Can help with coronary heart disease, high blood pressure and preventing muscle breakdown.
• Heart and blood vessel conditions, including angina, congestive heart failure, chest pain, and high blood pressure; age-related cognitive impairment; erectile dysfunction; male infertility; immune support.

Cautions:

• High doses of Arginine may cause nausea and diarrhea.
• People with genital herpes should not take, can increase outbreaks.
• Don’t take if you have asthma, because it increases pulmonary inflammation.
• Consult your doctor before taking if you’re being treated for kidney or liver disease.

Interactions:

• Do not take Lysine at the same time, they can interfere with each other.

Vasopressin:

• Otherwise known as Arginine-Vasopressin (AVP) because in most species it contains Arginine. It’s also called Antidiuretic Hormone (ADH) because it reduces urination (diuresis).

Genetics:

GST/GPX:

• Increase intake of Arginine for those with GST/GPX mutations, additional nutrients needed to support the NOS3 enzyme that the NOS3 gene produces.

Nitric Oxide Synthase 3:

• The enzyme produces nitric oxide from L-arginine which is needed for vasodilation of arterial vessels. Mutations in NOS3 genes can cause nitric oxide deficiencies which can lead to Alzheimer’s, ischemic stroke, myocardial infarction, hypertension, and pre-eclampsia.

Argininosuccinate Lyase Deficiency: rs28941472:

• Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, is characterized by a severe neonatal onset form and a late-onset form.
• There is not enough phosphorus (P) to make creatine phosphate (CP), the amino acid arginine, (which is a main amino acid in the urea cycle), shunts to combine with the amino acid glycine to help make more CP not just for energy but also as a way to rid some of the NH3 through its breakdown into creatinine.
• Having inadequate arginine for the urea cycle and NH3 becomes elevated as the CP is not as efficient in detoxifying NH3 as the urea cycle.
• Taking phosphorus can aid in supporting the creatine pathway more effectively and keep some arginine for the urea cycle.

Involved with:

• Angiotensin-converting enzyme inhibitor
• Antidiabetic
• Anti encephalopathic
• Anti hepatitic
• Antihypertensive
• Anti-impotence
• Anti infertility
• Antioxidant
• Aphrodisiac
• Diuretic
• Hyperammonemia
• Nitric-oxide-genic
• Pituitary stimulant
• Spermatogenic
• Vasodilator

Sources of Arginine:

• Arginine is found in plant and animal proteins, such as dairy products, meat, poultry, fish, and nuts.
• The ratio of L-arginine to lysine is also important-soy and other plant proteins have more L-arginine than animal sources of protein.
• Rich fiber- arugula, bacon, beets, bok choy, celery, Chinese cabbage, cucumber, fennel, leeks, mustard greens, parsley, and watercress.

Arginine is Found in These Foods: Organism Concentration (per 100 grams)

• Sunflower 82000 ppm
• Carob 55460 ppm
• Butternut 50300 ppm
• White lupine 44400 ppm
• Peanut 37022 ppm
• Sesame 34930 ppm
• Soybean 30950 ppm
• Watercress 30000 ppm
• Almond 26098 ppm
• Chives 25250 ppm
• Horseradish tree 24930 ppm
• Brazil nut 24727 ppm
• Common bean 24516 ppm
• Lentils 24400 ppm
• Broad bean 24370 ppm
• Colorado pinyon 23920 ppm
• Pistachio 22740 ppm
• Common walnut 21825 ppm
• Opium poppy 21401 ppm
• Mung bean 20693 ppm
• Winged bean 20576 ppm
• Chickpea 20560 ppm
• Lentils 20365 ppm
• Common pea 20246 ppm
• Jute 20185 ppm
• Swamp cabbage 19655 ppm
• Hyacinth bean 19365 ppm
• Spinach 19239 ppm
• White mustard 18725 ppm
• Asparagus 18452 ppm
• Yardlong bean 18401 ppm
• Mung bean 18383 ppm
• Flaxseed 18000 ppm
• Cashew nut 17711 ppm
• Yardlong bean 16131 ppm
• Lambsquarters 16116 ppm
• Lima bean 15390 ppm
• Taro 15340 ppm
• Soft-neck garlic 15216 ppm
• Evening primrose 15048 ppm
• Common bean 15026 ppm
• Adzuki bean 14834 ppm
• Amaranth 14556 ppm
• Pigeon pea 14530 ppm
• Brussel sprouts 14494 ppm
• Dill 13678 ppm
• Common pea 13254 ppm
• Oat 13000 ppm
• Corn salad 12640 ppm
• Common wheat 12000 ppm
• Common buckwheat 11910 ppm
• Lettuce 11833 ppm
• Kohlrabi 11667 ppm
• Jerusalem artichoke 11627 ppm
• Breadfruit 11300 ppm
• Purslane 10400 ppm
• Sacred lotus 10242 ppm
• Malabar spinach 10145 ppm
• Endive 9984 ppm
• Cassava 9970 ppm
• Winged bean 9671 ppm
• Ginkgo nuts 9366 ppm
• Macadamia nut 9250 ppm
• Cabbage 9225 ppm
• Rye 9130 ppm
• Cucumber 8608 ppm
• Prairie turnip 7976 ppm
• Cucurbita (Gourd) 7910 ppm
• Pepper (C. frutescens) 7834 ppm
• Winged bean 7689 ppm
• Eggplant 7559 ppm
• Common bean 7503 ppm
• Fennel 7460 ppm
• Sesame 7436 g
• Potato 6850 ppm
• Cottonseed 6732 g
• Jicama 6635 ppm
• Sweet basil 6620 ppm
• Peanut 6243 g
• Mountain yam 6035 ppm
• Corn 5450 ppm
• Chayote 5430 ppm
• Cucurbita (Gourd) 5353 g
• Burdock 5250 ppm
• Sunflower 5069 g
• Whelk 4936 g
• Sweet orange 4908 ppm
• Butternut 4862 g
• boars 4841 g
• Bearded seal 4655 g
• boars 4500 mg
• Sacred lotus 4210 ppm
• Spirulina 4147 g
• White lupine 3877 g
• Safflower 3851 g
• whales 3838 g
• Peanut 3800 mg
• fish 3759 g
• Garden tomato 3637 ppm
• Black walnut 3618 g
• Whitefish 3610 g
• Mandarin orange (Clementine, Tangerine) 3546 ppm
• Taro 3510 ppm
• Eumetopias jubatus 3400 g
• Mango 3400 ppm
• Sesame 3300 mg
• Apricot 3300 ppm
• European chestnut 3192 ppm
• Calabash 3140 ppm
• Smelt 3100 g
• Red beetroot 2997 ppm
• Soy bean 2900 mg
• Sweet potato 2835 ppm
• Flaxseed 2600 mg
• Common grape 2520 ppm
• Hazelnut 2500 mg
• Ginger 2486 ppm
• Almond 2483 g
• Fenugreek 2465 g
• Pine nut 2413 g
• Broad bean 2411 g
• Pine nut 2400 mg
• Almond 2400 mg
• Brazil nut 2400 mg
• Salmonidae (Salmon, Trout) 2400 mg
• cuttlefish 2370 g
• Spiny lobster 2303 g
• Bison 2300 g
• Walnut 2300 mg
• Lentils 2300 mg
• turkey 2298 g
• Avocado 2293 ppm
• Common walnut 2278 g
• Colorado pinyon 2251 g
• shrimp 2247 g
• Hazelnut 2222 g
• Highbush blueberry 2210 ppm
• Pistachio 2203 g
• Common pea 2188 g
• sheep 2178 g
• octopus 2176 g
• Deer 2175 g
• Chicken (Cock, Hen, Rooster) 2159 g
• Brazil nut 2148 g
• Chia 2143 g
• Beaver 2141 g
• Cashew nut 2123 g
• Pistachio 2100 mg
• Date 2090 ppm
• Hickory nut 2086 g
• Deer 2073 g
• Snow crab 2068 g
• Rabbit 2040 g
• Sockeye salmon 2010 g
• birds 2009 g
• Bivalvia (Clam, Mussel, Oyster) 2000 g
• Poppy 2000 mg
• Common pea 2000 mg
• Cashew nut 2000 mg
• Lentils 1994 g
• Domestic goat 1989 g
• Allium (Onion) 1950 g
• Dungeness crab 1946 g
• Opium poppy 1945 g
• Mule deer 1938 g
• White mustard 1933 g
• Buffalo 1929 g
• Flaxseed 1925 g
• Crab 1900 mg
• Chickpea 1900 mg
• shrimp 1900 mg
• Moose 1892 g
• Winged bean 1886 g
• European rabbit 1877 g
• Greater sturgeon 1867 g
• Wheat 1867 g
• Greylag goose 1849 g
• horses 1843 g
• Duck 1839 g