CITRULLINE

Citrulline is an α-amino acid.
Citrulline's 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.

CAS Number: 372-75-8
EC Number: 206-759-6
IUPAC Name: 2-Amino-5-(carbamoylamino)pentanoic acid
Chemical Formula: C6H13N3O3

Other names: DL-Citrulline, 627-77-0, 2-Amino-5-ureidopentanoic acid, Citrullin, DL-2-Amino-5-ureidovaleric acid, 2-amino-5-(carbamoylamino)pentanoic acid, citrulina, Citrulline, (+/-)-, 1OYO2NV4NM, CITRULLINE, (DL), DL-Ornithine, N5-(aminocarbonyl)-, Ornithine, N5-carbamoyl-, DL-, EINECS 211-012-2, MFCD00007955, NSC-46711, DL-Ornithine, N(5)-(aminocarbonyl)-, N(5)-carbamoyl-DL-ornithine, N(5)-(aminocarbonyl)ornithine, CHEBI:18211, NSC27425, NSC46711, N(5)-(aminocarbonyl)-DL-ornithine, NSC 46711, N5-carbamoylornithine, H-D-Orn(carbamoyl)-OH, NORVALINE, 5-((AMINOCARBONYL)AMINO)-, N(5)-carbamoylornithine, N5-carbamoyl-L-ornithine, 2-Amino-5-uredovaleric acid, cit, H-Orn(carbamoyl)-OH;L-Citrulline, MFCD00216469, Citrulline,(l), citrulline (DL-form), Spectrum_000037, .delta.-Ureidonorvaline, CITRULLINE, DL-, SpecPlus_000523, L(+)CITRULLINE, Spectrum2_001371, Spectrum3_001045, Spectrum4_001185, Spectrum5_001792, UNII-1OYO2NV4NM, N.delta.-Carbamylornithine, bmse000209, Epitope ID:141797, SCHEMBL20587, BSPBio_002570, KBioGR_001849, KBioSS_000397, N(.delta.)-Carbamylornithine, DivK1c_006619, SPBio_001322, SGCUT00061, SCHEMBL13282334, KBio1_001563, KBio2_000397, KBio2_002965, KBio2_005533, KBio3_001790, DTXSID40861910, to_000034, BBL027668, CCG-38847, NSC206276, s5124, STK802460, STL455121, AKOS005622468, L-(+)-2-Amino-5-ureidovaleric acid, L-CITRULLINE (1.12117), N5-[hydroxy(imino)methyl]ornithine, CS-W017450, HY-W016734, PB48354, SDCCGMLS-0066976.P001, 2aAminoa5a(carbamoylamino)pentanoic acid, 2-azaniumyl-5-(carbamoylamino)pentanoate, NCGC00178596-01, .alpha.-Amino-.delta.-ureidovaleric acid, AS-60168, SY023288, SY032853, SY048344, DB-049088, DB-054282, NS00013538, D89239, EN300-1168657, L000975, SR-05000002410, SR-05000002410-1, BRD-A12237696-001-04-2, Q27102910

Citrulline has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. 
Citrulline 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.

Biosynthesis
Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. 
Citrulline is also produced from arginine as a byproduct of the reaction catalyzed by NOS family
Citrulline is made from arginine by the enzyme trichohyalin at the inner root sheath and medulla of hair follicles.
Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide.

Citrulline is also made by enterocytes of the small intestine.

Function
Several proteins contain citrulline as a result of a posttranslational modification. 
These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination with the help of calcium ion. 
Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation.

Circulating citrulline concentration is a biomarker of intestinal functionality.

Chemical Properties    
White powder

Originator    
StaminO2,ErgoPharm

Uses:
An amino acid, Citrulline can be used in the treatment of asthenia and as an essential intermediate in the biosynthesis of nitric oxide.

Uses:
An essential intermediate in the biosynthesis of nitric oxide.

Manufacturing Process
Citrulline is obtained as a result of a reaction of L-arginine hydrochloride with sodium hydroxide, copper oxide and hydrogen sulfide.
In practice it is usually used as malate salt

Therapeutic Function    
Stimulant, Detoxicant

Purification Methods    
Likely impurities are arginine and ornithine. 
Crystallise S-citrulline from water by adding 5 volumes of EtOH. Also crystallise it from water by addition of MeOH. 
[Ellenbogen J Am Chem Soc 74 5198 1952, Greenstein & Winitz The Chemistry of the Amino Acids J. Wiley, Vol 3 pp 2491-2494 1961, Beilstein 4 IV 2647.]

Citrulline is an amino acid found in watermelon. 
Citrulline is also made in the body. 
The body changes citrulline into another amino acid called L-arginine.

The name citrulline comes from Citrullus vulgaris, the Latin term for watermelon. 
Unlike some amino acids, citrulline isn't used to make protein, but it might help increase other chemicals the body needs to make protein. 
Citrulline might also help improve blood flow and reduce blood pressure.

People use citrulline for athletic performance, sickle cell disease, erectile dysfunction (ED), high blood pressure in the lungs, heart disease, and many other conditions, but there is no good scientific evidence to support most of these uses.

Possibly Effective for
Athletic performance. 
Taking citrulline by mouth might help improve some types of exercise performance such as weight lifting. 
But its effects on aerobic exercises such as running are unclear.
There is interest in using Citrulline for a number of other purposes, but there isn't enough reliable information to say whether it might be helpful.

Citrulline is a natural supplement that is considered a non-essential amino acid. 
This means that the body can make its own citrulline; it can also be found in some foods (such as watermelon). 
Citrulline is synthesized (made) in the liver and intestine; its function is to detoxify ammonia and act as a vasodilator (dilating the blood vessels). 
Citrulline is also said to have an antioxidant effect.

There are two forms of citrulline, available as a supplement; these include Citrulline and citrulline malate. 
The primary difference between the two types of citrulline is that Citrulline is simply citrulline without any other substance, and citrulline malate is comprised of Citrulline, plus DL-malate (a compound that may be instrumental in converting food to energy.)

What Is Citrulline Used For?
Although there is very little scientific research evidence to back many of the claims of Citrulline health benefits, the natural supplement is said to have several health promoting properties, and is used for health conditions, including:

Enhancing physical exercise
Improving athletic performance
Helping with erectile dysfunction
Lowering high blood pressure
Treating sickle cell anemia

How it Works
In the body, Citrulline is transformed into a different amino acid, called L-arginine, which is converted into a chemical called nitric oxide. 
Citrulline is thought that Citrulline may help to supply the body with the raw material it requires to make specific proteins. 
Citrulline may also act as a vasodilator (a substance that widens the veins and arteries to help improve blood flow while lowering blood pressure).

Preparation and Dosage
Preparation
citrulline is commonly available in a powder form that can be mixed with liquid or added to nutritional shakes.

For exercise performance enhancement, 2 to 5 grams of Citrulline per day is an average dose. 
Studies have shown that doses of 3 to 6 grams per day of Citrulline and 8 grams of citrulline malate can be taken with no side effects. 
In fact, one study, conducted in France, discovered that taking up to 15 grams of citrulline was safe and well-tolerated by the study participants. 
No side effects were reported, even when supplement doses of up to 20 grams of citrulline malate were taken.

What to Look For
Natural supplements (such as citrulline) are not regulated by the Food and Drug Administration (FDA) or any other governmental agency, like prescription and over-the-counter drugs. 
What this indicates is that the burden to ensure a person is buying a safe, pure and effective product, is on the consumer. 
Simply reading the label may not provide enough information to make a well-informed buying decision on products such as citrulline.

It’s important to purchase a product that is organic, and one that has been certified by a third-party agency, such as the U.S. Pharmacopeia, NSF International. 
These organizations evaluate and report on a product’s level of safety, purity, and potency.

Citrulline is a non-essential amino acid, which means you don’t necessarily have to get it from foods because the body can produce it as needed. 
Citrulline is found naturally in various foods including watermelon, pumpkins, cucumber and bitter melon, but taking it as a supplement can increase your levels significantly. 
Higher levels have been shown to have benefits for health and particularly exercise performance.

Effects on the Body
The amino acid is known to play a key role in the Urea cycle, which helps eliminate harmful compounds from the body. 

But Citrulline has other effects on the body. One of the ways it can improve exercise performance is by increasing vasodilation. 
This means it helps widen the arteries and veins and increases blood flow. 
Consuming Citrulline may also boost levels of another amino acid Arginine which is converted into nitric oxide. 
Increasing nitric oxide also improves blood flow which may be one of the reasons why it improves exercise performance.

Weight Training
Research shows that supplementing with Citrulline can improve both your resistance and endurance training.

Studies have shown that taking about 8g of Citrulline malate (which provides about 4.5 grams of Citrulline ) before weight training can significantly increase the number of reps you can perform and reduce post workout muscle soreness and fatigue.

Citrulline helps to increase protein synthesis and boost levels of growth hormone after exercise making it useful for increasing muscle mass and maintaining healthy levels of muscle mass as we age.

Aerobic Power
Want more energy and less fatigue when working out?  
Taking 6g Citrulline for 7 days has been shown to increase cellular energy production (ATP) during exercise by 34%, which increases your capacity for aerobic output and intensity. 
This makes is perfect for gym classes, circuits or interval training.

Endurance Exercise
If you looking to build up your endurance training, then Citrulline may be particularly helpful. 
Taking supplements for several weeks has been shown to increase the oxygen content in muscle tissue – this allows you to become more efficient at using oxygen and in turn can improve performance.

One study showed supplementation of 6g Citrulline for 1 week enabled cyclists to significantly cycle for longer than those taking a placebo. 
Similar studies have shown it improves power output improving performance in time trials and reduces muscle fatigue immediately after exercise.

Another benefit of Citrulline for exercise performance appears to be due to its antioxidant properties. When we exercise we increase oxidative stress on the body and the production of free radicals. 
Free radicals can cause damage to the body and contribute to muscle soreness. 
Studies have shown that Citrulline can reduce the number of these free radicals produced during exercise.

Benefits For Exercise
Improved circulation
Increased muscle mass
Improved endurance
More power, more energy during workouts
Decreased muscle soreness and less fatigue

Additional Benefits
Heart Health
As Citrulline can improve blood flow and lower blood pressure it can also be helpful for heart health. 
Studies have shown that taking supplements for over 1 week can benefit those who are at risk of heart disease, suffer with arterial stiffness or have angina by helping to widen the arteries and improving blood flow.

Erectile Dysfunction
As it can improve blood flow studies have confirmed it may also be helpful for erectile dysfunction.

Using Supplements
Citrulline is generally found in two forms in dietary supplements. 
Citrulline and Citrulline malate. Both are effective for exercise performance.

Citrulline is an amino acid. 
Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. 
Citrulline is also produced from arginine as a by-product of the reaction catalyzed by NOS family. 
Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.

A non-essential amino acid and a precursor of arginine. 
Citrulline supplements have been claimed to promote energy levels, stimulate the immune system and help detoxify ammonia (a cell toxin). 
Citrulline is made from L-ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. 
Citrulline is also produced from L-arginine as a by-product of the reaction catalyzed by the enzyme NO synthase.

Citrulline, while being an amino acid, is not involved in protein synthesis and is not one of the amino acids coded for by DNA. 
Although citrulline cannot be incorporated in proteins during protein synthesis, several proteins are known to contain citrulline as an amino acid. 
These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert the amino acid arginine into citrulline. 
Proteins that contain citrulline residues include myelin basic protein (MBP), fillagrin and several histone proteins.

Citrulline is converted to L-arginine by argininosuccinate synthase. 
L-arginine is in turn responsible for citrulline's therapeutic affects. 
Many of L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. 
NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. 

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. 
NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. 
Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase.

NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. 
Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. 
The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. 
The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. 
iNOS may be expressed constitutively in select tissues such as lung epithelium.

All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. 
Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. 

eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. 
In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. 
The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. 
What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate.

In other words, 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, L-arginine could enhance endothelial-dependent vasodilation and NO production.

Citrulline is a non-essential amino acid. 
In hepatocytes, Citrulline is synthesized in the urea cycle by the addition of carbon dioxide and ammonia to ornithine. 
Citrulline is converted into L-arginine by the enzymes argininosuccinate synthetase and argininosuccinate lyase in the presence of L-aspartate and ATP. 
Subsequently, L-arginine is converted to nitric oxide by nitric oxide synthase and Citrulline is regenerated as a by-product.

Citrulline is the L-enantiomer of citrulline. 
Citrulline has a role as an EC 1.14.13.39 (nitric oxide synthase) inhibitor, a protective agent, a nutraceutical, a micronutrient, a human metabolite, an Escherichia coli metabolite, a Saccharomyces cerevisiae metabolite and a mouse metabolite. 
Citrulline is an enantiomer of a D-citrulline. 
Citrulline is a tautomer of a Citrulline zwitterion.

Citrulline is an amino acid. 
Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. 
Citrulline is also produced from arginine as a by-product of the reaction catalyzed by NOS family. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.

Citrulline, also known as Cit or δ-ureidonorvaline, belongs to the class of organic compounds known as l-alpha-amino acids. 
These are alpha amino acids which have the L-configuration of the alpha-carbon atom. 
Citrulline has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. 
Citrulline exists in all living species, ranging from bacteria to humans. 
Within humans, citrulline participates in a number of enzymatic reactions. 

In particular, citrulline can be biosynthesized from carbamoyl phosphate and ornithine which is catalyzed by the enzyme ornithine carbamoyltransferase. 
In addition, citrulline and L-aspartic acid can be converted into argininosuccinic acid through the action of the enzyme argininosuccinate synthase. 

In humans, citrulline is involved in the metabolic disorder called argininemia. 
Citrulline has also been found to be associated with several diseases such as ulcerative colitis, rheumatoid arthritis, and citrullinemia type II. 
Citrulline has also been linked to several inborn metabolic disorders including argininosuccinic aciduria and fumarase deficiency. 

Outside of the human body, citrulline is found, on average, in the highest concentration in a few different foods such as wheats, oats, and cucumbers and in a lower concentration in swiss chards, yellow wax beans, and potato. 
Citrulline has also been detected, but not quantified in several different foods, such as epazotes, lotus, common buckwheats, strawberry guava, and italian sweet red peppers. 
Citrulline is a potentially toxic compound. 

Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation. 
Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase. 
Citrulline is also produced from arginine as a byproduct of the reaction catalyzed by NOS family (NOS; EC1.14.13.39).

Citrulline is a non-essential amino acid produced in the liver and intestine. 
This means that the body can make its own citrulline; it can also be found in some foods (such as watermelon) and supplements (such as BalanceDocs Stamina). 
The body converts Citrulline to L-arginine, another type of amino acid that improves blood flow and is shown to help people with heart disease, clogged arteries, and erectile dysfunction (ED).

Below are six benefits of using an Citrulline supplement:

Increased exercise capacity
Several research studies show that healthy adults who started taking Citrulline saw an increase in exercise capacity. 
This is due to its ability to utilize oxygen better which boosts your workout and endurance ability.

Increased blood flow
Nitric oxide plays an important role in regulating blood flow. 
Since higher levels of Citrulline have been shown to increase nitric oxide levels, you could say there is a positive correlation between Citrulline and the increase of blood flow throughout the body. 
Increased blood flow also helps improve symptoms of erectile dysfunction (ED). 
In one study, this increase in blood flow appeared to decrease symptoms of mild ED and improve the ability to maintain an erection. 
At this time, there have not been studies on the use of Citrulline in moderate to severe cases of ED.

Decreased blood pressure
We live in a time of information overload and a constant state of “being busy” which many people perceive as “stress.” When we get in these states of stress, we breathe shallow, which results in our blood pressure going up and our bodies getting tense. 
Over time, this becomes the new normal and we live with consistently sky-high blood pressure.

Many studies have shown that Citrulline helps decrease high blood pressure and increase nitric oxide levels. 
Nitric oxide causes blood vessels to dilate which lowers blood pressure. 
In turn, the blood pressure will decrease. 
This is especially important for people who appear healthy and fit on the outside but experience higher blood pressure.

Improved cardiac function and erectile dysfunction
There have been direct links that show Citrulline improves the function of both the right and left ventricles, as well as endothelial function. 
There is often an improvement in erectile dysfunction due to the increase in blood and oxygen utilization.

Enhanced cognition & brain performance
The most common killer of cells is a lack of oxygen in our bodies. 
As previously mentioned, Citrulline helps utilize and maximize oxygen and blood flow throughout our bodies. 
When we utilize more oxygen, our cognitive function goes up and our brains perform at a higher level.

Boosted immunity
Citrulline supplementation has been linked to the ability to fight infection by boosting the immune system and help fight foreign invaders naturally.

Citrulline is an amino acid produced in the intestine and in the liver, but the liver does not contribute significantly to circulating citrulline concentrations. 
The intestine is thus the only organ that normally releases significant amounts of citrulline into the blood. 

The investigators have designed a study looking at the value of measuring plasma citrulline concentration in patients with Crohn's disease and short bowel or normal intestinal length. 
Measuring the plasma citrulline concentration in short bowel patients may help to distinguish between patients who need permanent parenteral feeding from patients with just transient intestinal dysfunction.

Citrulline may also help the investigators in understanding the small bowel intestinal length remaining and the absorptive integrity. 
In patients with normal intestinal length and Crohn's disease, it may be a reliable marker of small bowel damage and could be applied to establish therapeutic improvements. 
Citrulline has been demonstrated to strongly correlate (inversely) with severity on intestinal biopsies.