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Citrulline OTC

Ornithine OAT

Glutamate y-Semialdehyde

P5C SYNTHAS E M- Glutamate

FIGURE 4 Extrahepatic arginine synthesis. ASL, argininosuccinate lyase, ASS, argininosuccinate synthetase, CPS 1, carbamoyl phosphate synthetase 1, OTC, ornithine transcarbomylase, OAT, ornithine aminotransferase, P5C, pyrroline 5-carboxylate.

but the very high arginase activity of the liver means that both dietary arginine and arginine synthesized within the liver are rapidly hydrolyzed and not available to the body. Thus the arginine required for the synthesis of protein, nitric oxide, polyamines, etc. is made in extra-hepatic tissues (Figure 4). The mucosa of the small intestine expresses both carbamoyl phosphate synthe-tase I and ornithine transcarbamoylase, and together with pyrroline 5-carboxylate synthase and ornithine aminotransferase, this allows the synthesis of citrulline from glutamate and ammonia. This citrulline is released into the circulation to be taken up by the kidney, which expresses both argininosuccinate synthase and argini-nosuccinate lyase, and used for arginine synthesis. Thus by restricting expression of four enzymes of the ornithine cycle to these two extra-hepatic tissues the body is able to obtain sufficient arginine. Strict carnivores, such as cats and ferrets, lack the intestinal part of this pathway and therefore arginine must be provided in the diet. This is not usually a problem but if, experimentally, they are fed an arginine-free diet, they are unable to generate sufficient ornithine in the liver to allow increased flux through the cycle. This results in hyperammonenia and is one of the very few known cases of acute toxicity arising from a nutritional deficiency.

Inborn Errors of the Ornithine Cycle

As detailed above, the ornithine cycle is not required in utero and thus the genes encoding the cycle enzymes are not expressed until very late in gestation. Therefore it is possible to develop to full term with a misfunctional ornithine cycle gene (inborn errors may arise from a complete lack of a protein, changes in Vmax or KM, or the ability to bind cofactors or regulators). Inborn errors for all five cycle enzymes, plus some of the ancillary proteins such as N-acetyl glutamate synthetase and the ORN 1 transporter, have been described. All are characterized by hyperammonemia that is usually accompanied by very high levels of the non-essential amino acids alanine and glutamine. Other intermediates of the cycle accumulate according to the specific enzyme defect. The severity is usually more pronounced with deficiencies of the first two enzymes, carbamoyl phosphate synthetase 1 and ornithine transcarbamoylase, especially if there is a complete lack of activity. The gene encoding ornithine transcarbamoylase is located on the X chromosome and thus boys are most severely affected, however due to Lyonization different alleles are expressed in different cells and some female carriers of a defective gene will present with very low ornithine transcarbamoylase activity. This was traditionally believed to be benign since these women often exhibit protein intolerance and simply self limit their protein intake. It is now recognized however, that times of increased endogenous proteol-ysis, such as occurs in hypercatabolic states or even pregnancy, can represent a risk for hyperammonemia in such individuals. In classic cases of ornithine transcar-bamoylase deficiency, some of the excess carbamoyl phosphate in the mitochondria escapes to the cytosol where it enters the pyrimidine synthesis pathway. This causes production of relatively large amounts of orotic acid which is lost in the urine and the presence of significant orotate excretion is considered definitive evidence for ornithine transcarbamoylase deficiency.

A defect in argininosuccinate synthase results in citrullinemia and excretion of citrulline in the urine. To a limited extent, this lessens the need for urea synthesis and threrefore the ammonemia is not as severe as seen with defects in the first two enzymes. Similarly, with defects of argininosuccinate lyase and argininase, there is excretion of argininosuccinate and arginine, again lowering the need for urea synthesis and the severity of the condition.

The treatment for all inborn errors of the ornithine cycle begins with a limited protein diet to lower the need for urea synthesis. However, depending on the severity of the condition, patients will still encounter periods of hyperammonemia, and additional treatments have been developed. Most commonly, oral benzoic acid or nh3+ hco3

phenylacetate (or phenylbutyrate) are given since these are detoxified in the liver by conjugation with glycine or glutamine respectively. The amino acid conjugates are excreted which effectively removes nitrogen from the body, again lessening the need for urea synthesis. Recently a number of liver transplants have been carried out and gene therapy trials have been initiated. With inborn errors of the ornithine cycle, except arginase deficiency, arginine becomes an essential amino acid. In cases of argininosuccinate synthase and lyase deficiences, very large amounts of dietary arginine are required to replace the arginine equivalents lost as citrulline and argininosuccinate in the urine. Similarly, while liver transplantion or liver-specific gene therapy will correct the defect in urea synthesis, they do not change the defect in the extra-hepatic arginine synthesis pathway and thus, arginine remains an essential amino acid after such treatments.

See Also the Following Articles

Amino Acid Metabolism • Gluconeogenesis • Urea Cycle, Inborn Defects of

Glossary ammonia In this context to the sum of NH3 plus NH4. In the cell, at physiological pH, > 99% is present as NH4. equilibrium An enzyme-catalyzed reaction in which there is little change in Gibbs free energy between the substrates and products. In practice, this means that the reaction is freely reversible and both the direction and magnitude of net flux is determined by the rate of substrate supply and/or product removal. gluconeogenesis The formation of glucose from non-carbohydrate prescursors such as lactate, glycerol, and amino acids. hypercatabolic states Conditions in which the body is undergoing extensive catabolism (degradation) of tissues, particularly skeletal muscle, to provide amino acids for acute phase protein synthesis, gluconeogenesis, and tissue repair, after severe injury or infection. transaminases Enzymes that catalyze the transfer of amino (NH2) groups between a-amino acids and a-keto acids. Also known as aminotransferases usually glutamate and a-ketoglutarate act as the amino donor or acceptor respectively.

Further Reading

Grisolia, S., Baguena, R., and Mayor, F. (eds.) (1976). The Urea Cycle.

Wiley-Interscience, New York. Jungas, R. L., Halperin, M. L., and Brosnan, J. T. (1992). Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol. Rev. 72, 419-448. Krebs, H. A. (1982). The discovery of the ornithine cycle of urea synthesis. Trends Biochem. Sci. 7, 76-78. Lee, B., and Gross, J. (2001). Long term correction of urea cycle disorders. J. Pediatr. 138, S62-S71. Meijer, A. J. (1995). Urea synthesis in mammals. In Nitrogen Metabolism and Excretion (P. Walsh and P. Wright, eds.) pp. 193-204. CRC Press, Boca Raton, FL. Morris, S. M. Jr (2002). Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 22, 87-105. Stipanuk, M. H., and Watford, M. (2000). Amino acid metabolism. In Biochemical and Physiological Aspects of Human Nutrition (M. H. Stipanuk, ed.) pp. 233-286, Saunders, Philadelphia, PA. Watford, M. (1991). The urea cycle: A two-compartment system.

Essays Biochem. 26, 49-58. Watford, M (2003). The urea cycle. Biochem. Mole. Biol. Education 31, 289-297.

Wu, G., and Morris, S. M. Jr (1998). Arginine metabolism; nitric oxide and beyond. Biochem. J. 336, 1-17.


Malcolm Watford obtained his D.Phil. from the Metabolic Research Laboratory, Oxford, and did postdoctoral work at the University of Montreal and Case Western Reserve University. He is currently on the faculty of the Department of Nutritional Sciences, Rutgers University where he teaches metabolic regulation and carries out research on glutamine metabolism and gluconeogenesis.

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