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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

Biochem/physiol Actions

L-Citrulline, when orally administered is found to ameliorate the condition of sickle cell disease in humans. L-citrulline can be a replacement for L-arginine administration in case of defective NO synthetase. L-Citrulline supplementation is found to fulfill the purpose of NO-dependent signaling.

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.]

Bioavailability and Properties

L-citrulline is a natural precursor of L-arginine and is more bioavailable than L-arginine due to its ability to avoid hepatic first-pass metabolism and longer circulation time. It possesses antioxidant and vasodilation properties and is an integral part of the human nitric oxide system.

Enzymatic Regulation

The metabolism of L-citrulline involves key enzymes such as nitric oxide synthase (NOS), ornithine transcarbamylase (OTC), and argininosuccinate synthase (ASS), which are responsible for CIT synthesis and catabolism in mammals, respectively. These enzymes regulate CIT's involvement in various metabolic pathways.

Synthesis and Sources

Citrulline is synthesized from ornithine and carbamoyl phosphate in the urea cycle and is also produced from arginine as a by-product of the reaction catalyzed by NOS family enzymes. It is found primarily in watermelon, cucumbers, and other melons, with watermelon being the most naturally rich source.

Supplementation and Effects

L-citrulline is commonly supplemented in the form of citrulline malate, and its benefits may be attributed to the synergistic combination of L-citrulline and malate at the intramuscular metabolic level. Pharmacokinetic studies have shown that plasma citrulline reaches peak concentration between 40 and 60 minutes after ingestion, while plasma arginine peaks between 80 and 120 minutes, with elevated concentrations lasting up to 8 hours.

Metabolic Pathways

L-citrulline plays a crucial role in the urea cycle in the liver, responsible for ammonia elimination in the form of urea. During high-intensity exercise, citrulline supplementation may aid in ammonia detoxification, decrease lactate production, and enhance aerobic utilization of pyruvate, thereby improving muscle function and reducing fatigue.

Metabolic Characteristics

L-citrulline is an organic compound and a non-essential amino acid synthesized endogenously by the body. It is not involved in protein synthesis but is an important component of metabolic pathways such as arginine biosynthesis, the Arg-CIT-nitric oxide cycle, and the urea cycle.

Role in Sustainable Practices

Watermelon and its by-products, such as the rind, can be utilized for citrulline extraction, promoting sustainability in the fresh-cut watermelon industry and supporting a circular economy model.