Citrulline: Definition, Structure, Benefits, Sources and Uses

Citrulline is a non-essential amino acid generated from ornithine and carbamoyl phosphate in the urea cycle, or as a byproduct of arginine through nitric oxide synthase (NOS) catalysis. It exists in two forms: the naturally occurring isomer L-Citrulline and the less common but industrially applicable D-Citrulline. Citrulline is a non-protein amino acid capable of forming peptide bonds but does not participate in protein synthesis. Once thought to be an intermediate in the urea cycle, recent studies have shown that its derivatives have wide applications in medicine, food, and health, demonstrating significant pharmacological effects.

What is Citrulline?

Citrulline was first isolated from watermelon in 1914, but it wasn't until 1930 that it was truly identified. Maintaining proper levels of citrulline in the body promotes energy and ensures normal immune function. A deficiency in citrulline can lead to fatigue, negatively affecting work efficiency and quality of life. Moreover, research has shown that citrulline possesses strong antioxidant properties, capable of scavenging hydroxyl radicals and increasing arginine for nitric oxide synthesis, effectively protecting DNA and PMNs from oxidative damage. It can serve as an anti-aging and immune-boosting supplement, as well as a cosmetic ingredient for women's skincare products, offering benefits like wrinkle prevention and skin brightening. For instance, L-Citrulline malate is increasingly popular in the international market as an amino acid supplement, which can be made into conventional solid forms such as tablets, powders, granules, and capsules, or liquid formulations like water or oil suspensions, and syrups.

Citrulline Amino Acid

• L-Citrulline

Citrulline mainly exists in two forms: L-citrulline and D-citrulline. L-citrulline is a bioactive isomer involved in key metabolic processes. It is recognized for enhancing nitric oxide production, contributing to vasodilation and improving blood flow. This function makes L-citrulline a popular ingredient in pre-exercise supplements and sports drinks.

• D-Citrulline

On the other hand, D-citrulline is less common in biological systems, but has applications in certain industrial environments, including the synthesis of novel compounds and as a chiral structural unit in pharmaceutical preparations. Both forms of citrulline can be produced by various methods, including enzymatic conversion and chemical synthesis, making it a multifunctional component in various applications.

Citrulline Structure

The structural characteristics of citrulline play a crucial role in its function. The carbon skeleton of citrulline has a carboxyl group (-COOH), an amino group (-NH₂) and a side chain containing a secondary amine, which is its structural feature as an α-amino acid. The chemical properties of citrulline include the molecular formula of C₆H₁₃N₃O₃, the molar mass of 175.19 g/mol, the solubility in water is conducive to its absorption in biological systems and incorporation into various formulations, and it is relatively stable under physiological conditions, making it suitable for dietary supplements and other products that require long-term efficacy. These structural and chemical properties enable citrulline to effectively participate in biochemical reactions and contribute to its role in metabolism and cell signal transduction.

Fig. 1. L-citrulline structure.

Citrulline Benefits

Citrulline has demonstrated outstanding effects in improving cardiovascular health, enhancing exercise performance, and improving muscle function. At the same time, it may also possess some anti-inflammatory, antioxidant, and gastrointestinal barrier-improving properties.

• Promoting Cardiovascular Health: Research indicates that citrulline may be beneficial for cardiovascular health, including improving vascular function and lowering blood pressure. This is primarily related to an increase in nitric oxide availability.
• Enhancing Exercise Performance: Some studies suggest that citrulline supplementation may enhance exercise performance. For instance, a 2020 study indicated that citrulline supplementation could improve workout outcomes and recovery while reducing exercise-induced fatigue.
• Improving Muscle Growth and Function: Research has found that citrulline supplementation helps increase muscle mass and strength. For example, a 2015 study showed that citrulline supplementation was associated with lower mortality rates, higher lean body mass, and reduced fat mass in elderly rats.
• Anti-Inflammatory and Antioxidant Effects: Citrulline has shown anti-inflammatory and antioxidant properties, which may help alleviate certain inflammatory and oxidative stress conditions.
• Improving Gastrointestinal Barrier: Citrulline has demonstrated protective effects in reducing alcohol-induced gastric ulcers. Furthermore, citrulline supplementation combined with lactobacilli can enhance the integrity of intestinal epithelial cells, protecting the gut from pathogenic infections and improving the expression of tight junction proteins.

Citrulline Sources

From dietary sources rich in citrulline to the body's inherent capacity to synthesize this amino acid, the ways in which citrulline is obtained reflect its integral role in health and wellness. Additionally, advancements in industrial production techniques ensure that citrulline remains accessible for various applications, from supplements aimed at athletes to formulations in the pharmaceutical and cosmetic industries. By exploring these sources in depth, we can appreciate the multifaceted nature of citrulline and its significance in promoting optimal health and performance.

• Dietary Sources

Dietary sources of citrulline primarily include fruits and vegetables, with watermelon being the most notable. This refreshing fruit is not only delicious but also rich in citrulline, making it a popular choice among athletes and health-conscious individuals. In addition to watermelon, other sources include cucumbers and pumpkins, which also contribute to citrulline intake. Incorporating these foods into one's diet can help boost citrulline levels naturally, promoting its beneficial effects on performance and overall health.

• Biosynthesis

In terms of biosynthesis, citrulline is synthesized endogenously within the human body. This process predominantly occurs in the liver and kidneys, where arginine serves as a key precursor. Through the action of nitric oxide synthase, arginine is converted to citrulline as a byproduct of nitric oxide production. Furthermore, citrulline is generated during the breakdown of ornithine, another amino acid involved in the urea cycle. This pathway not only highlights the body's ability to produce citrulline but also underscores its role in detoxifying ammonia, showcasing its importance in metabolic health.

• Industrial Production

On the industrial front, citrulline is produced through various methods that facilitate its large-scale availability for dietary supplements and functional foods. Commercial production often involves fermentation processes that utilize specific bacterial strains capable of synthesizing citrulline efficiently. Chemical synthesis is another method employed, allowing for the creation of both L-citrulline and D-citrulline for different applications. This industrial capability meets the growing demand for citrulline in sports nutrition products, pharmaceuticals, and cosmetics, further establishing its relevance across multiple sectors.

What Does Citrulline Do?

Citrulline, particularly in its non-natural derivatives, has found diverse applications across various industrial fields, showcasing its versatility and functional properties. The unique characteristics of citrulline derivatives make them valuable components in industries such as sports nutrition, pharmaceuticals, cosmetics, and food manufacturing.

• Citrulline Supplement

In the sports nutrition industry, L-citrulline and its derivatives are widely used in supplements designed to enhance athletic performance and recovery. For example, citrulline malate—a compound formed by combining citrulline with malic acid—has gained popularity among athletes for its ability to improve endurance and reduce muscle soreness. This combination not only boosts nitric oxide production, facilitating increased blood flow during exercise but also aids in the removal of metabolic waste products. Products containing citrulline malate are commonly found in pre-workout formulations, highlighting its critical role in optimizing physical performance.

• Citrulline Drug

The pharmaceutical sector also leverages citrulline derivatives for therapeutic purposes. L-citrulline has been investigated for its potential to support cardiovascular health, particularly in the treatment of conditions related to impaired nitric oxide production. For instance, citrulline is being studied as a treatment option for erectile dysfunction, where increased blood flow is essential. Furthermore, citrulline derivatives are being explored in formulations aimed at managing hypertension, providing a natural alternative to traditional medications by promoting vasodilation and improving circulation.

• Citrulline in Cosmetics

In cosmetics, citrulline and its derivatives are utilized for their skin-rejuvenating properties. L-citrulline, with its hydrating and antioxidant effects, is often included in skincare formulations aimed at improving skin elasticity and moisture retention. Products containing citrulline can help enhance the overall appearance and health of the skin, making it a sought-after ingredient in moisturizers and anti-aging creams.

• Citrulline in Food

In the food manufacturing sector, citrulline is increasingly recognized for its functional benefits. It is used as a natural flavor enhancer in various health foods and beverages, capitalizing on its mild taste and potential health benefits. Additionally, citrulline is being explored as a functional ingredient in protein bars and sports drinks, providing not only nutritional value but also the benefits associated with enhanced blood flow and reduced muscle fatigue.

Arginine Vs Citrulline

Arginine and citrulline are two important amino acids that play vital roles in various physiological processes, particularly in the synthesis of nitric oxide, a key molecule involved in vascular health and muscle performance. While both amino acids contribute to enhancing blood flow and overall metabolic function, they differ in their chemical structure, sources, absorption rates, and specific health benefits. Understanding the distinctions between arginine and citrulline is crucial for determining their respective roles in supplementation and therapeutic applications.

In Conclusion

Citrulline is a multifaceted amino acid that plays a critical role in various biological processes, particularly in the production of nitric oxide, which enhances blood flow and vascular health. Its unique properties extend beyond mere metabolic functions, making it a valuable compound in multiple industries, including sports nutrition, pharmaceuticals, cosmetics, and food manufacturing. The ability of citrulline to improve athletic performance, support cardiovascular health, and promote skin rejuvenation underscores its significance in health and wellness formulations. Furthermore, the development of non-natural derivatives, such as citrulline malate, highlights the ongoing innovation surrounding this amino acid, catering to the growing demand for effective nutritional supplements. As research continues to unveil the full spectrum of citrulline's benefits, its role in both clinical and athletic settings will likely expand, reinforcing its status as an essential component in modern nutrition and biochemistry. With its diverse applications and proven efficacy, citrulline represents a promising avenue for enhancing overall health and performance across various domains.

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