A crystalline amino acid C6H13N3O3 formed specifically as an intermediate in the conversion of ornithine to arginine. [1]


Citrulline is an intermediate metabolic amino acid produced mainly by enterocytes of the small intestine. Levels of citrulline have actually been associated with chemotherapeutically reduced enterocyte mass, independent of nutritional and inflammatory status. [2]


Citrulline can be originated from:.

  • from arginine by means of 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 through DDAH

Citrulline is made from ornithine and carbamoyl phosphate in one of the main reactions in the urea cycle. It is also produced from arginine as a byproduct of the response catalyzed by NOS household. It 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. [3]


Although citrulline is not coded for by DNA straight, numerous proteins are known to contain citrulline as a result of a posttranslational adjustment. These citrulline residues are created by a family of enzymes called peptidylarginine deiminases (PADs), which transform arginine into citrulline in a procedure called citrullination or deimination. Proteins that normally contain citrulline residues consist of myelin fundamental protein (MBP), filaggrin, and numerous histone proteins, whereas other proteins, such as fibrin and vimentin are vulnerable to citrullination throughout cell death and tissue inflammation.

Clients with rheumatoid arthritis frequently (at least 80% of them) establish an immune response against proteins consisting of citrulline. Although the origin of this immune response is not known, detection of antibodies reactive with citrulline containing proteins or peptides is now ending up being an important assistance in the diagnosis of rheumatoid arthritis. [4]

Citrulline malate vs. L-citrulline

When you’re purchasing supplements that contain Citrulline, you’ll likely observe that various supplements use different types of this amino acid. The two main kinds in which you can consume it are Citrulline Malate and L-Citrulline.

Citrulline Malate: Citrulline Malate is made up of Citrulline plus Malic Acid. Malic Acid is a natural supplement discovered in fruits like apples that assists to promote the development of energy for your cells.

L-Citrulline (totally free type): L-Citrulline is an isolated kind of Citrulline. There is absolutely nothing else contributed to the amino acid when you take supplements which contain L-Citrulline.

In regards to efficiency, there’s very little of a difference between these two types. Both deal benefits and can help you see substantial results.

However, some individuals argue that Citrulline Malate may be more useful because of the extra health advantages that originate from Malic Acid. For example, it may assist with hydration and protect the body from free radicals thanks to its antioxidant homes.

There’s not a great deal of research study comparing the two, however. Whether you’re supplementing with Citrulline Malate or L-Citrulline, you’ll likely experience comparable health and efficiency advantages, so, for most people, there’s no requirement to split hairs over which form you’re taking in. [5]

Mechanism of action

L-citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine remains in turn responsible for citrulline’s therapeutic impacts. 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 functions in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine through the enzyme nitric oxide synthase or synthetase (NOS), and the results of NO are primarily mediated by 3′,5′ -cyclic guanylate or cyclic GMP. NO triggers the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is transformed to guanylic acid by means of the enzyme cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. A number of isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS discovered in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The type of NOS caused by immunological or inflammatory stimuli is known as iNOS. iNOS may be revealed constitutively in choose tissues such as lung epithelium. All the nitric oxide synthases utilize NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, along with the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Surprisingly, ascorbic acid appears to boost NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS manufacture NO in response to an increased concentration of calcium ions or sometimes in action to calcium-independent stimuli, such as shear stress. In vitro research studies of NOS show that the Km of the enzyme for L-arginine remains in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma remains in the millimolar variety. What this implies is that, under physiological conditions, NOS is filled with its L-arginine substrate. To put it simply, 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 supplements of the amino acid would make any distinction with regard to NO production. The response would appear to have actually reached its maximum level. However, in vivo research studies have actually demonstrated that, under particular conditions, e.g. hypercholesterolemia, L-arginine could enhance endothelial-dependent vasodilation and NO production. [6]

Leading L-citrulline food sources

Since it’s produced from the fermentation of arginine, it’s most prevalent in specific fruits. Nuts like almonds and walnuts, and beans like chickpeas, can include it however in smaller amount.

Yellow watermelon

Citrulline comes from the Latin word citrullus, which means watermelon. That is the first food it was found in; separated in 1914 and completely determined in 1930.

Just how much citrulline there remains in watermelon varies by part and color. Yellow watermelon has the most. Its content is 3.5 mg per gram for the flesh and 1.5 mg per gram for the skin.

Orange watermelon

After yellow, orange watermelon is the second greatest in L citrulline content. There’s 1.8 mg/g for the flesh and 1.5 mg/g for the skin.

Red watermelon

Red, which is the most typical type of watermelon, has the least amount of citrulline; 1 mg for the flesh and 0.8 mg per gram for the skin.

Despite color, watermelon rind has less citrulline than the edible fruit flesh. When both are dried, the skin has a greater concentration.

While you can eat watermelon rind, its hard and fibrous texture is difficult to chew and absorb. It’s better to drink it, by juicing it.

Watermelon leaves

Watermelon leaves are edible and they’re one of the richest natural sources of citrulline. When grown in drought conditions, such as the Kalahari Desert where they’re native, they produce large quantities of citrulline in the leaves; to act as an antioxidant, for countering the higher oxidative stress.


The citrulline content in cucumber is 0.146 mg/g for the fresh fruit or vegetable (if you care to call it that). Persian cucumbers will be equivalent. While the quantity is lower than watermelon, the advantage is that you can drink cucumber juice in high quantity, without the worry of high sugar and calories.


There’s minimal research study which measures the amount of L-citrulline in pumpkins, though it has lower material than watermelon.

Pumpkin leaves

Similar to watermelon, the leaves of the pumpkin plant are a cheap and readily available dietary source when in-season.


Commonly called a cantaloupe in the US and Canada, muskmelon ranks high amongst the L citrulline entire foods.


Like pumpkins, squash are cultivars of the Cucurbitaceae household. All of those fruits/vegetables include this amino acid.


Gourds, squash, and pumpkin are all in the exact same family.


Also referred to as the African horned melon, for everything about it check out our piece on the kiwano.


A popular organic treatment for impotence is raw cold processed cocoa powder and other potent sources, like dark chocolate. There’s science to support this advantage; the citrulline in chocolate may trigger much better nitric oxide levels, which in turn, might help increase blood circulation to the penis. [7]

Benefits of L-citrulline

Below are 6 benefits of using an L-Citrulline supplement:.

Increased exercise capacity

A number of research studies show that healthy adults who started taking L-citrulline saw a boost in workout capability. This is because of its capability to make use of oxygen much better which improves your workout and endurance ability.

Increased blood circulation

Nitric oxide plays an essential role in managing blood circulation. Given that greater levels of L-Citrulline have actually been revealed to increase nitric oxide levels, you could state there is a positive connection in between L-Citrulline and the boost of blood circulation throughout the body. Increased blood flow likewise assists improve signs of impotence (ED). In one research study, this increase in blood flow appeared to reduce symptoms of mild ED and enhance the capability to maintain an erection. At this time, there have not been studies on using L-citrulline in moderate to severe cases of ED.

Reduced high blood pressure

We live in a time of details overload and a constant state of “being busy” which lots of people view as “stress.” When we get in these states of tension, we breathe shallow, which leads to our blood pressure increasing and our bodies getting tense. Over time, this becomes the brand-new regular and we deal with regularly sky-high high blood pressure.

Lots of research studies have shown that L-citrulline assists decrease hypertension and increase nitric oxide levels. Nitric oxide causes blood vessels to dilate which lowers blood pressure. In turn, the blood pressure will reduce. This is specifically important for individuals who appear healthy and fit on the outside however experience greater high blood pressure.

Improved cardiac function and erectile dysfunction

There have been direct links that show L-citrulline improves the function of both the right and left ventricles, along with endothelial function. There is often an enhancement in erectile dysfunction due to the increase in blood and oxygen utilization.

Enhanced cognition and brain performance

The most typical killer of cells is an absence of oxygen in our bodies. As previously discussed, L-Citrulline assists make use of and make the most of oxygen and blood circulation throughout our bodies. When we use more oxygen, our cognitive function goes up and our brains perform at a greater level.

Boosted immunity

L-citrulline supplementation has actually been connected to the ability to fight infection by increasing the immune system and aid combat foreign invaders naturally. [8]

10 advantages of l-citrulline for males

Regardless of being thought about a non-essential amino acid, L-citrulline has promising applications in health and illness. Here’s a list of the leading 10 L citrulline benefits for men’s health.

Increases athletic efficiency

Citrulline supplements helps guys in various sports by modulating blood flow and basal metabolism. Through an increase of nitric oxide, L-citrulline increases the blood flow. This is essential to deliver nutrients to your muscles throughout intense exercise.

Beyond circulatory modifications, L-citrulline also regulates glycogen breakdown and the conversion of glucose into energy. Studies reveal that citrulline malate increases the effectiveness of ATP inside the muscle. This ATP is the energy particle that triggers muscle movement.

Furthermore, L-citrulline is understood to reduce ammonia accumulation in the muscles as an action to extreme exercise. By doing so, muscle tiredness lowers, and physical performance increases.

Prevents high blood pressure

Individuals with high blood pressure and pre-hypertension can benefit commonly from L-citrulline supplements. According to studies, this amino acid has a blood pressure-lowering result in these patients.

On the other hand, healthy individuals won’t decrease blood pressure however lower pulse wave speed. All of this is due to increased nitric oxide levels.

L citrulline benefits blood circulation by promoting nitric oxide synthesis. This substance unwinds capillary and enhances blood circulation. That’s why clients with citrulline supplements experience fewer blood pressure spikes and defense from lung hypertension.

Counters impotence

Nitric oxide is related to blood pressure levels, as kept in mind above, but also favors erectile function. Therefore, citrulline supplements is likewise an alternative way to increase penile blood circulation in erectile dysfunction.

It is considered as a pro-erectile representative due to the fact that it is a precursor of L arginine, which produces nitric oxide. In turn, nitric oxide induces cGMP, using the exact same pathway as Viagra and other PDE5 inhibitors.

L-citrulline is not equally powerful as Viagra, and it may not work in the short-term. But research studies show that taking this supplement daily for one month enhanced erectile function in half of the patients, who were extremely satisfied with their treatment.

Counters anemia and tiredness

L citrulline malate improves exercise capability, exercise performance, and blood flow. Naturally, this means that people might anticipate a reduction in tiredness levels. This is more noticeable when you have an extended workout. So, in the beginning, you may not experience any difference, however after a while, you could increase the variety of repeatings by approximately 52%.

There’s an additional application in clients with sickle cell anemia. These patients can get L-citrulline supplements integrated with medical treatment to experience faster recovery rates. They decrease fatigue levels and report improvements in total health.

Improves insulin secretion

Besides improving blood flow and improving cardiovascular health, citrulline supplements might also increase insulin secretion. At a physiological serum concentration, citrulline stimulates beta cells in the pancreas. These cells release more insulin in reaction to glucose, which is excellent news for type 2 diabetes patients.

Remarkably, the supplement modulates insulin levels instead of producing an indiscriminate boost. For example, throughout and after workout, there is a burst in insulin production. However taking a supplement 3 hours prior to workout lowers insulin spikes in action to activity.

Modulates protein synthesis rate

Citrulline supplements have an additional impact on muscle tissue. Some studies recommend that it increases muscle protein synthesis. After food limitation, there is a decrease in protein synthesis and muscular function.

Citrulline helps restore this physiologic procedure, which may also prefer muscle growth. It improves nitrogen balance, which prefers protein synthesis and is essential to grow larger muscles.

Enhances growth hormonal agent concentrations

Growth hormone is an important hormonal agent in males. It increases muscle mass and favors bone health. Citrulline malate increases growth hormone levels, according to research studies, particularly when integrated with exercise. Professional athletes are anticipated to have 66% higher serum development hormonal agent levels after exercise.

As such, citrulline supplements can be utilized in sports nutrition to accelerate the outcomes of training prior to a sporting occasion.

Minimizes arterial tightness

As we age, our capillary alter their setup and flexible properties. Fat plaques form in the arterial walls, and we go through arterial stiffness. As a precursor of arginine, citrulline increases nitric oxide and improves arterial stiffness in human beings. Research studies show that this effect is independent of a decrease in high blood pressure.

Reducing arterial tightness enhances the response of arteries to the heartbeat. It promotes blood circulation and circulation, decreasing the risk of heart disease.

Aids with muscle pain issues after intense workout

L citrulline advantages exercise efficiency while lowering muscle pain after workout. According to a research study, professional athletes receiving citrulline supplementation reported a 39% and 41% reduction in muscle soreness 24 and 48 hours after weight lifting.

This effect is related to nitric oxide and its effect on the blood vessels. The blood flow boosts, preferring muscle pump and cleaning lactic acid faster from the muscle tissue.

Stimulates your heart to remain strong

Besides the cardiovascular benefits noted above, citrulline malate may also assist clients with heart failure.

According to research studies, L citrulline supplements can increase right ventricular ejection fraction. It preserves the capacity of the heart to pump blood and the capability of the blood vessels to transfer nutrients.

Surprisingly, L citrulline benefits heart health at a lower dosage than arginine. These clients may have a better workout performance and tolerance than previously and lower their fatigue symptoms. [9]

Citrullinemia type 1

Synonyms of citrullinemia type 1

  • Argininosuccinate synthetase deficiency
  • Argininosuccinic acid synthetase shortage
  • Ass shortage
  • Citrullinemia, timeless
  • Ctln1

General discussion

Citrullinemia type I (CTLN1) is a rare autosomal recessive congenital disease that consists of a neonatal acute (timeless) form, a milder late-onset kind, a type that starts during or after pregnancy, and an asymptomatic form.

CTLN1 is caused by shortage or lack of the enzyme argininosuccinate synthetase (ASS). ASS is one of six enzymes that play a role in the elimination of nitrogen from the body, a procedure called the urea cycle. The absence of this enzyme leads to excessive build-up of nitrogen, in the form of ammonia (hyperammonemia), in the blood and all body fluids.

Infants with the traditional kind might experience throwing up, refusal to eat, progressive lethargy, and program signs of increased intracranial pressure. Trigger treatment can prolong survival, however neurologic deficits are usually present. The course of the late-onset form is sometimes milder but episodes of hyperammonemia resemble the classic form.

Symptoms and signs

The intensity of CTLN1 differs from client to client. The timeless form, defined by extensive lack of ASS enzyme activity, displays symptoms quickly after birth (neonatal duration). A milder type of the disorder, which is defined by partial lack of the ASS enzyme, impacts some babies later throughout infancy or childhood.

The signs of CTLN1 are caused by the accumulation of ammonia in the blood and cerebrospinal fluid (CSF). The traditional kind occurs within 24-72 hours after birth, normally following a protein feeding and is initially identified by rejection to eat, lethargy, lack of cravings, throwing up, and irritation. Affected infants might also experience seizures, decreased muscle tone (hypotonia), breathing distress, build-up of fluid in the brain (cerebral edema), and liver failure.

If neglected, CTLN1 may progress to coma due to high levels of ammonia in the CSF (hyperammonemic coma). Neurological irregularities consisting of developmental delays, intellectual disability, and spastic paralysis might take place and are more serious in babies who remain in hyperammonemic coma for more than 3 days. Increased intracranial pressure can lead to increased muscle tone, spasticity, irregular reflex motions of the foot (ankle clonus), and seizures. If left untreated, the condition will result in life-threatening complications.

In some clients, consisting of those with partial enzyme deficiency, start of the disorder may not occur until later on during infancy or youth. Symptoms might consist of failure to grow and put on weight at the expected rate (failure to flourish), avoidance of high-protein foods from the diet, inability to coordinate voluntary movements (ataxia), progressive sleepiness, and vomiting. Babies with the moderate form may alternate between durations of health and hyperammonemia. Babies and kids with this kind of CTLN1 may also establish hyperammonemic coma and life-threatening complications.

Another form of CTLN1 occurs during and after pregnancy. Affected ladies may experience duplicated episodes of throwing up, sleepiness, seizures, confusion, hallucinations, and potentially coma. Behavioral changes might likewise happen consisting of manic episodes and psychosis. Affected ladies might likewise have accumulation of fluid in the brain (cerebral edema).

Some individuals with CTLN1 do not experience symptoms or hyperammonemia. The basis for these milder variations is not developed. [10]


Anomalies in the ASS1 and SLC25A13 genes trigger citrullinemia. The proteins produced from these genes play roles in the urea cycle. The urea cycle is a series of chemical reactions that occurs in liver cells. These reactions procedure excess nitrogen that is produced when protein is used by the body. The excess nitrogen is utilized to make a compound called urea, which is excreted in urine.

Anomalies in the ASS1 gene cause type I citrullinemia. This gene provides guidelines for making an enzyme, argininosuccinate synthase 1, that is accountable for one step of the urea cycle. Mutations in the ASS1 gene decrease the activity of the enzyme, which interrupts the urea cycle and prevents the body from processing nitrogen successfully. Excess nitrogen (in the form of ammonia) and other byproducts of the urea cycle build up in the blood stream. Ammonia is particularly toxic to the nervous system, which assists explain the neurologic symptoms (such as sleepiness, seizures, and ataxia) that are often seen in type I citrullinemia.

Mutations in the SLC25A13 gene are accountable for adult-onset type II citrullinemia, NICCD, and FTTDCD. This gene supplies directions for making a protein called citrin. Within cells, citrin helps transport particles utilized in the production and breakdown of simple sugars, the production of proteins, and the urea cycle. Particles transferred by citrin are likewise involved in making nucleotides, which are the building blocks of DNA and its chemical cousin, RNA. Anomalies in the SLC25A13 gene generally avoid cells from making any functional citrin, which prevents the urea cycle and interferes with the production of proteins and nucleotides. The resulting buildup of ammonia and other hazardous compounds causes the signs and symptoms of adult-onset type II citrullinemia. An absence of citrin also leads to the functions of NICCD and FTTDCD, although ammonia does not build up in the blood stream of people with these conditions.

Due to the fact that citrullinemia is caused by problems with the urea cycle, it belongs to a class of genetic diseases called urea cycle disorders. [11]

Possible adverse effects

Citrulline has actually been used as an oral (by mouth) supplement for many years, without reports of severe security concern. Although adverse effects of citrulline are uncommon, there have been some reports of mild signs such as queasiness, indigestion, and diarrhea. [12]

How to take?

To supplement L-citrulline for circulatory health or to reduce erectile dysfunction, take 2,000 mg of citrulline, three times a day with meals, for a total day-to-day dosage of 6,000 mg. L-citrulline does not need to be taken with meals, nevertheless.

To supplement for circulatory health with a citrulline malate supplement, take 1.76 g of citrulline malate for each 1 gram of citrulline you would usually take.

To supplement L-citrulline to enhance sports performance, take 6,000– 8,000 mg of citrulline malate about an hour before workout. On days that you do not work out, it can be separated into smaller sized doses. [13]


Medications for male sexual dysfunction (Phosphodiesterase-5 Inhibitors) Interaction Score: Significant Do not take this combination. L-citrulline might reduce blood pressure. Some medications for male sexual dysfunction can likewise reduce blood pressure. Taking L-citrulline along with medications for male sexual dysfunction might cause your blood pressure to go too low.

Some medications for male sexual dysfunction consist of sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).

Medications that increase blood flow to the heart (Nitrates) Interaction Score: Major Do not take this combination. L-citrulline might reduce blood pressure and boost blood circulation. Taking L-citrulline with other medications that increase blood circulation to the heart may increase the opportunity of lightheadedness and lightheadedness.

A few of these medications that increase blood circulation to the heart consist of nitroglycerin (Nitro-Bid, Nitro-Dur, Nitrostat) and isosorbide (Imdur, Isordil, Sorbitrate).

Medications for hypertension (Antihypertensive drugs) Interaction Rating: Moderate Be cautious with this mix. Talk with your health company.

L-citrulline might decrease high blood pressure. Taking L-citrulline in addition to medications for hypertension might trigger your blood pressure to go too low.

Some medications for hypertension include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), Amlodipine (Norvasc), hydrochlorothiazide (HydroDIURIL), furosemide (Lasix), and lots of others. [14]

Pregnancy and breastfeeding

L-arginine is utilized in pregnancy under particular scenarios, including preeclampsia.

L-arginine supplementation during pregnancy is generally recommended and monitored by a doctor for a specific factor, such as preeclampsia or the threat of preeclampsia and intrauterine development limitation (IUGR).

There’s some proof that L-arginine supplements may enhance pregnancy results, as well as fetal and maternal health in women from both high- and low-resource areas.

This is because during pregnancy, the body’s need for L-arginine grows due to fetal development and placental development. This increased need may not be fulfilled through diet, especially in women living in low-resource settings without access to protein-rich foods.

Additionally, although the increased demand for arginine during pregnancy can be supplied through diet, protein or individual amino acid supplements might be necessary under particular situations.

This might consist of ladies who follow limiting diet plans or are experiencing extreme queasiness and throwing up during pregnancy, rendering them not able to meet demands through dietary intake.

Nevertheless, supplements during pregnancy must constantly be authorized and monitored by a healthcare provider. If you are pregnant and interested in taking additional L-arginine, consult your healthcare provider for guidance.

L-arginine supplements have not been looked into in breastfeeding ladies. For this reason, it is necessary to ask your doctor whether taking L-arginine supplements is safe and needed for your individual needs during breastfeeding. [15]


l-citrulline through the production of nitric oxide activates the vasodilatation procedure which prefers the passage of nutrients between the muscles and the blood, hence improving athletic performance and decreasing muscle discomfort. Scientific studies suggest that taking together l-arginine and l-citrulline allows to increase the bioavailability of l-arginine and for that reason the production of nitric oxide. [16]


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