Citrulline synthesis metabolism

For descriptive information on the principles of the phosphor imaging process, see Klein and Clark (1993) and Clark and Klein (1996) and literature available from the companies named above. An example of a commercial instrument is shown in Figure 13.5. The method was applied to studies of drug metabolism (Nagatsuka et al., 1993 Ueda et al., 1993), iodothyronine deiodinase activity (Koopdonk-Kool et al., 1993), and citrulline synthesis by nitric oxide synthase activity (Vyas et al., 1996). The synthesis of cholesterol in rat liver was studied using a combination of bioimaging and liquid scintillation counting (Okuyama et al., 1995). 

Wu, G., N.E. Flynn, W. Yan and D.G. Barstow, Jr., 1995. Glutamine metabolism in chick enterocytes absence of pyrroline-5-carhoxylase synthase and citrulline synthesis. Biochem. J. 306, 717-721. 

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. 

There are small but significant alterations in the plasma levels of two of the amino acids involved in the urea cycle. Both citrulline and arginine levels are low, about one-third to one-half the normal levels (Lll) sometimes even lower (Table 6). These changes would be expected since these acids are in the metabolic pathway beyond the block. What appears surprising is that the level of ornithine, the amino acid whose further metabolism is blocked, which would be expected to rise, is actually usually within normal limits. There are two possible explanations for this. The biosynthesis of urea forms a cycle in which each intermediate is re-formed in the process. The block in the synthesis of citrulline from ornithine results in a decreased formation of arginine which in turn will... 

R4. Ratner, S., Urea synthesis and metabolism of arginine and citrulline. Advan. Enzymol. Relat. Subj. Biochem. 16, 319-387 (1954). 

Several standard and nonstandard amino acids act as metabolic intermediates. For example, arginine, citrulline, and ornithine (Figure 5.6) are components of the urea cycle (Chapter 15). The synthesis of urea, a molecule formed in vertebrate livers, is the principal mechanism for the disposal of nitrogenous waste. 

Some nonstandard amino acids are not found in proteins. Examples include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part of amino acid catabolism (see below). A rare exception to the dominance of a-amino acids in biology is the P-amino acid beta alanine (3-aminopropanoic acid), which is used in plants and microorganisms in the synthesis of pantothenic acid (vitamin B5), a component of coenzyme A. 

Citrulline, a non-protein amino acid, was identified independently by Mitsimori Wada in watermelon juice (Wada, 1930) and by Dankwart Ackermann as a product of the degradation of arginine (Ackermann, 1931). Soon afterwards, Hans Krebs and Kurt Henseleit (Krebs and Henseleit, 1932) proposed the first metabolic cycle ever described, in which citrulline was an intermediary in the synthesis of urea. A few years later, the role of aspartate as the donor of the second nitrogen for urea synthesis was established by Sarah Ratner (Ratner and Pappas, 1949). 

The enzymes of the urea cycle, however, are not only expressed in the liver, but also in other tissues and cell types. In fact, it is believed that the urea cycle evolved from the arginine metabolic pathway present in lower organisms (Takiguchi et al, 1989). This difference in function between urea and arginine synthesis is reflected by the different tissue localization, function and regulation of the enzymes of the urea cycle and other enzymes involved in the metabolism of the urea cycle intermediates, arginine, citrulline and ornithine. 

Numerous reviews dealing with different aspect of the metabolism of arginine and citrulline have been published over the last years (Morris, 2006,2007 Curis et al, 2007 Crenn, 2008 Wu et al, 2009). A renewed interest in arginine metabolism has been sparked due to the functional role of this amino acid in many processes, such as nitric oxide synthesis (Luiking etal, 2005), lipid metabolism (Fu et al, 2005 Hayashi et al, 2005) and diabetes (Kohh et al, 2004). 

Marini JC, I. Cajo, L. Castillo and B. Lee, 2010. Glutamine precursor or nitrogen donor for the synthesis of citrulline In Crovetto, G.M. (ed.) Energy and protein metabolism and nutrition. Wageningen Academic Publishers, Wageningen, the Netherlands, p. 123-124. 

---