Arginine Citrulline Ornithine and Proline Figure

Arginine is a nitrogen-rich amino acid because it contains three nitrogen atoms and is the precursor for nitric oxide (NO). The conversion to NO is catalyzed by the enzyme nitric oxide synthase (NOS), and results in coproduction of the amino acid citrulline. Depending on its site of release, NO exerts several functions including stimulation of the pituitary gland, vasodilation, neurotransmission, and immune modulation. Arginine is also a precursor for urea synthesis in the urea cycle, which has an important function in the detoxification of ammonia and excretion of waste nitrogen from the body. A full urea cycle is only present in the liver, but the arginase enzyme that converts argi-nine to urea and ornithine is to a limited extent also found in other tissues and cells, such as brain, kidney, small intestine, and red blood cells. Ornithine is utilized for the formation of proline, polyamines (putrescine, spermine, and spermidine), glutamic acid, and glutamine. Arginine is involved in collagen formation, tissue repair, and wound healing via proline, which is hydroxylated to form hydroxyproline. This role in wound healing may additionally be mediated by stimulation of collagen synthesis by NO, although this claim is still under investigation. It is currently thought that arginine availability is regulated by the balance between NOS and arginase enzyme activity, which subsequently determines substrate availability for NO and ornithine production. Proline also stimulates hepatocyte DNA and protein synthesis. Polyamines are potent inducers of cell differentiation.

In addition to synthesis of NO, urea, and ornithine, arginine is used for synthesis of creatine, which is an important constituent of skeletal muscle and neurons and acts as an energy source for these tissues. Furthermore, arginine may be catabolyzed to agmatine, which acts as a cell-signaling molecule. Arginine not only acts as an intermediate in the


(cell differentiation) Citrulline ■


(ammonia detoxification)


(hepatocyte DNA and protein synthesis)


(collagen synthesis)

Nitric oxide

(vasodilation, antimicrobial, neurotransmission)

Agmatine Creatin (cell signaling) (energy source skeletal muscle and neurons)

Figure 1 Specific functions of arginine metabolism.

synthesis of functional products, but also is a potent stimulus for the release of several hormones, such as insulin, glucagon, somatostatin, and growth hormone, illustrating its pharmacological characteristics.

Arginine can be synthesized by the body from citrulline. However, since virtually all arginine produced in the liver is trapped within the urea cycle, the kidney is the only arginine-synthesizing organ that significantly contributes to the total body pool of free arginine. Diminished renal arginine synthesis has been found in patients with renal failure and in highly catabolic conditions, like sepsis, burn injury, or trauma (which may be related to concomitant renal failure). In these situations arginine may be considered a conditionally essential amino acid and it has been suggested that arginine supplementation can become useful in these situations.

Citrulline is formed from glutamine, glutamic acid, and proline in the intestine. Plasma citrulline concentration reflects intestinal metabolic function and has recently been introduced as a potential marker for (reduced) enterocyte mass.

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