Citrulline metabolism

Speranza, A. and Bagni, N., Products of L-[14C]carbamoyl citrulline metabolism in Helianthus tuberosus activated tissues, Z. Pflanzenphysiol., 88, 163-168, 1978. 

T3. Tedesco, T. A., and Mellman, W. J., Argininosuccinate synthetase activities and citrulline metabolism in cells cultured from a citrullinaemic subject. Proc. Nat. Acad. Sci. U.8. 67, 829-834 (1967). 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

L-Ornithine transcarbamoylase catalyzes transfer of the carbamoyl group of carbamoyl phosphate to ornithine, forming citrulline and orthophosphate (reaction 2, Figure 29-9). While the reaction occurs in the mitochondrial matrix, both the formation of ornithine and the subsequent metabolism of citmlline take place in the cytosol. Entry of ornithine into mitochondria... 

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some covalent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. 

CFS patients and is related to autonomic dysfunction. In a separate rat study, Giannesini et al. used citrulline malate (CM) to treat asthenia and found that the supplementation prevented the basal PCr/ATP ratio reduction and normalized the pHi time-course during muscular activ-ity. They conclude that CM supplementation corrects the impaired control of oxidative function and has protective effect on basal energy metabolism. The data from either human or animal studies provide a potential approach to therapy. 

In 1987, Hibbs published a landmark paper in the nitric oxide field (Hibbs et al., 1987a), by demonstrating that the L-arginine that is required for CAM cytostatic activity is metabolized to L-citrulline (similar to L-arginine but less one nitrogen atom from the guanidinium group) and nitrite plus nitrate. In addition,... 

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

Briand, J., Blehaut, H., Calvayrac, R., Laval-Martin, D. Use of a microbial model for the determination of drug effects on cell metabolism and energetics study of citrulline-malate. Biopharm. Drug Dispos. 1992,13 1-22. 

OTC deficiency is the most common urea cycle defect.As it is X linked, affected boys typically have severe disease with neonatal presentation as described in this chapter. The disease in women who carry an OTC mutation on one X chromosome ranges from severe early-onset disease to complete absence of symptoms. Furthermore, affected women may decompensate in the context of a metabolic stress such as an infection or following parturition. OTC-deficient patients have low plasma citrulline and high urine orotic acid. Confirmation of the diagnosis requires mutation analysis or a liver biopsy for enzymology. The carrier status of women is most accurately determined by mutation analysis. 

Citrulline takes its name from the watermelon genus (Citrullus) in which it was first found in 1930. It was also discovered the same year as a bacterial degradation product of arginine. Krebs, who elucidated the form of the urea cycle, demonstrated that citrulline was the intermediate between ornithine and arginine. The urea cycle was the first metabolic cycle to be discovered. In Krebs words, it revealed a new pattern of the organization of metabolic processes. ... 

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