L(+)-Citrulline
[CAS# 372-75-8]

Identification

• Classification: Biochemical >> Common amino acids and protein drugs
• Name: L(+)-Citrulline
• Synonyms: L(+)-2-Amino-5-ureidovaleric acid; (S)-2-Amino-5-ureidopentanoic acid
• Molecular Formula: C₆H₁₃N₃O₃
• Molecular Weight: 175.19
• Protein Sequence: X
• CAS Registry Number: 372-75-8
• EC Number: 206-759-6
• SMILES: C(C[C@@H](C(=O)O)N)CNC(=O)N

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Melting point: 212 - 214 °C (Decomposes) (Expl.)
• Boiling point: 386.7±42.0 °C 760 mmHg (Calc.)^*
• Flash point: 187.7±27.9 °C (Calc.)^*
• Index of refraction: 1.531 (Calc.)^*
• alpha: 25.5 ° (c=8, 6N HCl)
• Water solubility: 200 g/L (20 °C)

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319
• Safety Statements: P264-P264+P265-P280-P302+P352-P305+P351+P338-P321-P332+P317-P337+P317-P362+P364

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovery and Applications

L(+)-Citrulline is a naturally occurring non-proteinogenic amino acid with the molecular formula C₆H₁₃N₃O₃. It plays a crucial role in the urea cycle, where it serves as an intermediate in the detoxification of ammonia in the liver. Structurally, L-citrulline is characterized by a central alpha-amino acid backbone substituted with a side chain terminating in a urea group, distinguishing it from standard proteinogenic amino acids.

Citrulline is biosynthesized in mammals as a byproduct of the enzymatic conversion of arginine into nitric oxide (NO) by nitric oxide synthase (NOS). In this pathway, one molecule of arginine yields one molecule of NO and one molecule of citrulline. The generated citrulline can then be recycled into arginine via the citrulline–NO cycle, which is especially active in vascular endothelial cells. This recycling is essential for sustained NO production, which plays a pivotal role in vasodilation and cardiovascular health.

In the urea cycle, citrulline is synthesized in the mitochondria of hepatocytes from ornithine and carbamoyl phosphate by the enzyme ornithine transcarbamylase. It is then transported to the cytosol, where it combines with aspartate to form argininosuccinate, catalyzed by argininosuccinate synthetase. This compound is subsequently cleaved by argininosuccinate lyase to yield arginine and fumarate. Arginine can then be hydrolyzed to produce urea and regenerate ornithine, thereby completing the cycle.

L(+)-Citrulline has gained significant interest in the fields of nutrition and medicine. Unlike arginine, which is subject to significant first-pass metabolism in the liver, oral L-citrulline is more effectively absorbed and converted into arginine in peripheral tissues. This makes citrulline supplementation a more efficient strategy for increasing systemic arginine levels and promoting nitric oxide synthesis. As such, it is commonly used in sports nutrition to improve blood flow, reduce muscle fatigue, and enhance exercise performance.

Furthermore, L-citrulline supplementation has been investigated for its potential therapeutic effects in conditions associated with endothelial dysfunction, such as hypertension, atherosclerosis, and erectile dysfunction. Clinical studies suggest that citrulline may help lower blood pressure and improve vascular function by enhancing NO availability.

In addition to its physiological and pharmacological importance, citrulline serves as a biomarker in clinical diagnostics. Elevated levels of citrulline in plasma can indicate inborn errors of metabolism such as citrullinemia, a rare urea cycle disorder resulting from a deficiency in argininosuccinate synthetase. Conversely, low levels may suggest intestinal mucosal damage or dysfunction, as enterocytes are a major site of citrulline production.

Citrulline is also of interest in immunology and autoimmune diseases. Modified citrullinated proteins are implicated in the pathogenesis of rheumatoid arthritis (RA), where they are recognized as neoantigens by the immune system. The presence of anti-citrullinated protein antibodies (ACPAs) is a highly specific diagnostic marker for RA.

In summary, L(+)-Citrulline is a versatile amino acid with key roles in nitrogen metabolism, nitric oxide production, and human health. Its physiological relevance spans hepatic function, cardiovascular health, athletic performance, and immunology, making it a valuable compound in both clinical and research settings.

References

1979. Effect of the Transition-State Analogue, delta-N-(Phosphonacetyl)-l-ornithine on Citrulline Synthesis in Isolated Rat-Liver Mitochondria and on Urea Synthesis in Isolated Rat Hepatocytes. European Journal of Biochemistry, 100(2).
DOI: 10.1111/j.1432-1033.1979.tb02062.x

1998. Assessment of Nitric Oxide Production by Measurement of [15N]Citrulline Enrichment in Human Plasma Using High-Performance Liquid Chromatography-Mass Spectrometry. Analytical Biochemistry, 257(2).
DOI: 10.1006/abio.1997.2515

1998. Reduction of serum citrulline levels in women at term toward the day of labor onset. Acta Obstetricia et Gynecologica Scandinavica, 77(2).
DOI: 10.1034/j.1600-0412.1998.770208.x