Nitrogen metabolism urea cycle

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

The nitrogen contained in the amino acids is usually disposed of through the urea cycle. One of the early, if not the first, steps in amino acid catabolism involves a transamination using oxaloacetate or a-ketoglutarate as the amino-group acceptor. This converts the amino acid into a 2-keto acid, which can then be metabolized further. 

The urea cycle is essential for the detoxification of ammonia 678 Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant 679 Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle 680 Successful management of urea cycle defects involves a low-protein diet to minimize ammonia production as well as medications that enable the excretion of ammonia nitrogen in forms other than urea 680... 

Cheung, C.W., Cohen, N.G., Raijman, L. (1989). Channeling of urea cycle intermediates in situ in permeabilized hepatocytes. J. Biol. Chem. 264,4038-4044. Cohen, P.P. (1954). Nitrogen metabolism of amino acids. In Chemical Pathways in Metabolism (Greenberg, D.M., Ed.), Vol. 2, pp. 1-46. Academic Press, New York. Fisher, R.B. (1954). Protein Metabolism. Methuen, London. 

Urea is a colorless, odorless crystalline substance discovered by Hilaire Marin Rouelle (1718—1779) in 1773, who obtained urea by boiling urine. Urea is an important biochemical compound and also has numerous industrial applications. It is the primary nitrogen product of protein (nitrogen) metabolism in humans and other mammals. The breakdown of amino acids results in ammonia, NH3, which is extremely toxic to mammals. To remove ammonia from the body, ammonia is converted to urea in the liver in a process called the urea cycle. The urea in the blood moves to the kidney where it is concentrated and excreted with urine. 

Metabolism of nitrogen in a patient with a deficiency in the urea cycle enzyme carbamoyl phosphate synthetase I. Treatment with phenylbutyrate converts nitrogenous waste to a form that can be excreted. 

Figure 24-11 Integration of the urea cycle with mitochondrial metabolism. Green lines trace the flow of nitrogen into urea upon deamination of amino acids or upon removal of nitrogen from the side chain of glutamine.

Urea cycle This pathway converts ammonia, a toxic nitrogen-containing waste product of protein metabolism, into another, less toxic molecule called urea, which can be eliminated from the body as urine. 

While the expression and regulation of the urea cycle are widely appreciated (Campbell, 1991, 1995 Walsh and Mommsen, 2000), a few general functional properties of this pathway of nitrogen metabolism need to be mentioned here. 

One of the major products of amino acid metabolism is ammonia (NLI3), a molecule known to be highly toxic to higher organisms. In the liver, ammonia and carbon dioxide are used to produce a water-soluble form of nitrogen, urea, via the urea cycle. The liver passes this urea to the blood, which carries it to the kidneys to be filtered out and excreted in the urine. Since one function of the kidney is to collect and excrete urea, increases in the concentration of this compound in the blood are an indicator of poor kidney function. Since urea is formed in the liver, low blood urea nitrogen is often the consequence of impaired liver function due to disease or as the result of infection (hepatitis). 

Protein metabolism - nitrogen metabolism and the urea cycle... 

In terrestrial vertebrates, urea is synthesized by the urea cycle (Figure 23.16). The urea cycle, proposed by Hans Krebs and Kurt Henseleit in 1932, was the first cyclic metabolic pathway to be discovered. One of the nitrogen atoms of the urea is transferred from an amino acid, aspartate. The other nitrogen atom is derived directly from free NH4 +, and the carbon atom comes from HCO3 (derived by hydration of CO2 see Section 9.2). 

In mammals, hepatic arginase is the terminal enzyme of the urea cycle, which represents the major end-product of nitrogen metabolism — the average adult human excretes some 10 kg of urea per year. The enzyme is not restricted to the liver, since ornithine is a precursor of the nonessential amino acid proUne, and a biosynthetic precursor of polyamines, required for rapidly dividing tissues. Arginine is also the precursor of the important messenger in many vertebrate signal-transduction pathways nitric oxide, NO (Scheme 16.1), of which more shortly. 

The fact that relatively large amounts of urea can be produced by subjects in whom an enzyme defect of the urea cycle has been proved has perplexed many investigators. Despite the fact that the activity of the rate-limiting enzyme has been reduced even to zero as measured by a sophisticated method, urea production still continues. It must therefore be concluded that, in all these cases, urea production is only impaired, not abolished. In all normal circumstances, all but a small fraction of the nitrogen in excess of tissue protein requirements is still excreted as urea and/or as the amino acid whose further metabolism is blocked. The impairment shows itself in the elevated levels of blood ammonia and consequently of glutamine, which vary according to the stress placed upon the urea cycle by varying the rates of protein intake. 

Figure 23.18 Metabolic integration of nitrogen metabolism. The urea cycle, gluconeogenesis, and the transamination of oxaloacetate are linked by fumarate and aspartate.

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. 

If any of the urea cycle enzymes is missing, ammonia (the nitrogen-containing substrate of the cycle) cannot be metabolized. If any of the enzymes is defective (i.e., it does not catalyze its reaction at an appropriate rate), ammonia is metabolized slowly. Under both circumstances the body s ammonia concentration is excessively high. 

See also Urea Cycle Reactions, Urea, Uric Acid, The Nitrogen Cycle, Utilization of Ammonia, Metabolic Nitrogen Balance, Amino Acid Degradation, Ammonia Transport in the Body, Citric Acid Cycle, ATP as Free Energy Currency (from Chapter 12)... 

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