Urea, biosynthesis

Urea biosynthesis occurs in four stages (1) transamination, (2) oxidative deamination of glutamate, (3) ammonia transport, and (4) reactions of the urea cycle (Figure 29-2). 

Carbamoyl Phosphate Synthase I Initiates Urea Biosynthesis... 

Figure 29-9. Reactions and intermediates of urea biosynthesis. The nitrogen-containing groups that contribute to the formation of urea are shaded. Reactions and occur in the matrix of iiver mitochondria and reactions , , and in iiver cytosoi. COj (as bicarbonate), ammonium ion, ornithine, and cit-ruiiine enter the mitochondriai matrix via specific carriers (see heavy dots) present in the inner membrane of iiver mitochondria.

Metabolic disorders of urea biosynthesis, while extremely rare, illustrate four important principles (1) Defects in any of several enzymes of a metabolic pathway enzyme can result in similar clinical signs and symptoms. (2) The identification of intermediates and of ancillary products that accumulate prior to a metabolic block provides insight into the reaction that is impaired. (3) Precise diagnosis requires quantitative assay of the activity of the enzyme thought to be defective. (4) Rational therapy must be based on an understanding of the underlying biochemical reactions in normal and impaired individuals. 

Changes in enzyme levels and allosteric regulation of carbamoyl phosphate synthase by A -acetylglutamate regulate urea biosynthesis. 

The experiments described above indicated amino acids were oxidatively deaminated in liver and their a-amino groups converted to urea. A start on investigations of the mechanism of urea biosynthesis was made by Schultzen and Nenki (1869) who concluded that amino acids gave rise to cyanate which might combine with ammonia from proteins to produce urea. Von Knieren (1873) demonstrated that when he drank an ammonium chloride solution, or gave it to a dog, there was an increase in the formation of urea, without any rise in urinary ammonia. His results were consistent with the cyanate theory but did not eliminate the possibility that urea arose from ammonium carbonate which could be dehydrated to urea ... 

Most instructive is what happens to the same processes in 02-limited turtle liver cells. Under conditions of total anoxia, the ATP demand of protein turnover drops to less than 10% of normoxic rates urea biosynthesis drops to essentially zero, as does the biosynthesis of glucose (not unexpectedly, because a major role of the liver under anoxic conditions is to supply glucose for the rest of the body). Although the ATP requirements of the Na+-K+-ATPase are also drastically reduced, the suppression in percentage terms is less than for overall ATP turnover. As a result, under anoxic conditions, the Na+ pump becomes the cell s dominant energy sink, accounting for up to 75% of the ATP demand of the cell (Buck and Hochachka, 1993). In turtle brain these adjustments occur along with a measurable decrease in Na+-K+-... 

MIO. Mora, J.,. Martuscelli, J., Ortig-Pineda, J-, and Soberson, G., The regulation of urea-biosynthesis enzymes in vertebrates. Biochem. J. 96, 28-35 (1965). 

Raushel FM Texas A M University System Mechanism and control of urea biosynthesis National Institute of Diabetes and Digestive and Kidney Diseases... 

Fig. 38.10. The glucose/alanine cycle. Within the muscle, amino acid degradation leads to the transfer of nitrogens to a-ketoglutarate and pym-vate. The alanine formed travels to the liver, where the carbons of alanine are used for gluconeogenesis and the alanine nitrogen is used for urea biosynthesis. This could occur during exercise, when the muscle uses blood-borne glucose (see Chapter 47).

Which would you expect to have a greater effect on the rate of urea biosynthesis, a defect in fumarase activity or a defect in alanine aminotransferase ... 

Bipalium kewense 51) suggests that urea biosynthesis arose very early in metazoan evolution. 

Ammonia Metabolism and Urea Biosynthesis (Volume 1, Chapter 4)... 

In addition to being a small neutral molecule, urea has a considerable advantage over uric acid as a terminal product of nitrogen metabolism in that it is much more soluble. As has been the case for many other pathways in intermediary metabolism, the understanding of ureas biosynthesis began with the availability of isotopic nitrogen and carbon. The administration of [ NJammonium salt and " C-labeled bicarbonate salt demonstrated that urea nitrogen derives from ammonia and urea carbon from respiratory CO2. 

A basic amino acid found in many proteins. It is also involved in urea biosynthesis. In the inborn error, cystinuria, it is excreted in the urine in large amounts, along with other basic amino acids. 

The role of transamination in oxidative deamination, urea biosynthesis, etc., will be discussed in the Section VII. 

Aspartate Urea biosynthesis glucogenic precursor pyrimidine precursor... 

Urea is produced as a non-toxic soluble vehicle for the elimination of nitrogen originating from the catabolism of amino acids. Urea is synthesized by a cyclic pathway discovered, in outline, by Krebs and Henseleit in 1932. A major function of the liver is urea biosynthesis but enzymes of the pathway also occur in kidney, skin, brain plus some other cells where their primary purpose is to synthesize arginine. 

Figure 16.S illustrates the reactions and the com-partmentalization of the enzymes of the urea cycle. The first reaction in urea biosynthesis is the mitochondrial formation of carbamoyl phosphate, the substrate of the urea cycle. The reaction utilizes an ammonium (NH4 ) ion, delivered into the mitochondrion as glutamate by the action of both the glutamate-aspartate (Section 11.3) and the glutamate-hydroxyl ion antiport carriers. Oxidative deamination of glutamate by glutamate dehydrogenase releases an NH4 ion.

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