Liver 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 result is that the amino groups can be dumped out as alanine (the transamination product of pyruvate). In the liver and kidney, alanine is transaminated to yield pyruvate and glutamate. As in the Cord cycle, the pyruvate is converted to glucose by the liver and is shipped out. The glutamate is fed into the urea cycle-nitrogen disposal system to get rid of the excess nitrogen. 

In 1930 Wada isolated citrulline from watermelon. It was an obvious candidate as an intermediate in the urea cycle. When tested by Krebs it was catalytic only at high concentrations. Citrulline is not normally detectable in liver. 

The reaction shown in Figure 8.6 is also important in the liver where glutamate dehydrogenase is involved in the catabolism of amino acids and the entry of nitrogen into the urea cycle, as explained in Chapter 6. 

In liver, aminotransferases ALT and AST can move the amino group from alanine arriving from muscle into aspartate, a direct donor of nitrogen into the urea cycle. 

Urea, which contains two nitrogens, is synthesized in the liver from aspartate and carbamoyl phosphate, which in turn is produced from ammonium ion and carbon dioxide by mitochondrial carbamoyl phosphate synthetase. The urea cycle and the carbamoyl phosphate synthetase reaction are shown in Figure 1-17-2. 

Arginine is converted to citrulline, which is released into the blood. This protects arginine from uptake and degradation in the urea cycle in the liver. Citrulline is released into the blood and transported to the kidney, where it is converted back to arginine (Chapter 8). 

Figure 10.1 Simple diagram of the sources of ammonia for the urea cycle. Sources are the Liver, bone marrow, immune cells, enterocytes, colonocytes and microorganisms. Numbers refer to list in text.

An increase in the protein content of the diet in rats increases the maximnm activities of all the enzymes of the cycle in the liver. It is assnmed that this represents increased amonnts of these enzymes in the liver (Table 10.4). Since a chronic increase in the protein in the diet in hnmans increases urea production over a long period and also a decrease in protein in the diet decreases urea production, it is assnmed that, as in the rat, this is due to changes in the concentrations and therefore activities of urea cycle enzymes. 

Table 10.4 Chronic effects of high and zero protein diets on maximum activities of urea cycle enzymes in the liver of the rat...

The toxicity of ammonia was dramatically demonstrated by experiments carried out as early as 1931 injection of the enzyme urease, which catalyses the conversion of urea to ammonia, into rabbits rapidly caused their death. The normal concentration of ammonia in blood is about 0.02 mmol/L toxicity becomes apparent at a concentration of abont 0.2 mmol/L or above (see Table 10.1). Ammonia toxicity in very young children is usually associated with vomiting and eventually coma. It is almost invariably due to the deficiency of an enzyme of the urea cycle (see below). In adults, ammonia accnmulation, and hence toxicity, usually results from damage to the liver caused by poisons, alcohol or viral infection. 

Two amino acids—asparagine and glutamine—contain acid-amide groups in the side chains, from which NH3 can be released by hydrolysis (hydrolytic deamination). In the blood, glutamine is the most important transport molecule for amino nitrogen. Hydrolytic deamination of glutamine in the liver also supplies the urea cycle with NH3. 

Urea is produced only in the liver, in a cyclic sequence of reactions (the urea cycle) that starts in the mitochondria and continues in the cytoplasm. The two nitrogen atoms are derived from NH4 " (the second has previously been incorporated into aspartate see below). The keto group comes from hydrogen carbonate (HC03 ), or CO2 that is in equilibrium with HC03. ... 

Liver disease due to alcohol abuse, chronic hepatitis, or hemochromatosis, leads to impairment of ammonia disposal by the urea cycle and is often the cause of this condition in adults. 

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. 

In ureotelic organisms, the ammonia deposited in the mitochondria of hepatocytes is converted to urea in the urea cycle. This pathway was discovered in 1932 by Hans Krebs (who later also discovered the citric acid cycle) and a medical student associate, Kurt Henseleit. Urea production occurs almost exclusively in the liver and is the fate of most of the ammonia channeled there. The urea passes into the bloodstream and thus to the kidneys and is excreted into the urine. The production of urea now becomes the focus of our discussion. 

The urea cycle begins inside liver mitochondria, but three of the subsequent steps take place in the cytosol the cycle thus spans two cellular compartments (Fig. 18-10). The first amino group to enter the urea cycle is derived from ammonia in the mitochondrial matrix—NHj arising by the pathways described above. 

These changes in demand for urea cycle activity are met over the long term by regulation of the rates of synthesis of the four urea cycle enzymes and carbamoyl phosphate synthetase I in the liver. All five enzymes are synthesized at higher rates in starving animals and in animals on veiy-high-protein diets than in well-fed animals eating primarily carbohydrates and fats. Animals on protein-free diets produce lower levels of urea cycle enzymes. 

Transamination and the Urea Cycle Aspartate aminotransferase has the highest activity of all the mammalian liver aminotransferases. Why ... 

Arginine is cleaved by arginase to produce ornithine. [Note This reaction occurs primarily in the liver as part of the urea cycle (9ee p. 253).] Ornithine is subsequently converted to a-ketoglutarate. 

Causes and symptoms When liver function is compromised, as a result of genetic defects in one of the urea cycle of hyperammonemia enzymes or to liver disease, hyperammonemia (ammonia intoxication) can occur. 

Some of the enzymes required are widely distributed, but ornithine curhamoylttwisferase occurs only in the liver and thus the complete urea cycle occurs only in that organ. 

The complete urea cycle as it occurs in the mammalian liver requires five enzymes Argininosuccinate synthase, arginase, and argininosuccinate lyase (which function in the cytosol), and ornithine transcarbamoylase, and carbamoyl phosphate synthase (which function in the mitochondria). Additional specific transport proteins are required for the mitochondrial uptake of L-ornithine, NH3, and HC03 and for the release of L-citrulline. 

The urea cycle is a unique function of the liver. Excess ammonia formed in other tissues must be carried in a nontoxic form to the liver. In many tissues glutamine serves as the carrier of excess nitrogen. The glutamine is formed in the tissues in a reaction, catalyzed by glutamine synthase, that combines NH3 with glutamate. 

Urea cycle. A metabolic pathway in the liver that leads to the synthesis of urea from amino groups and C02. The function of the pathway is to convert the ammonia resulting from catabolism to a nontoxic form, which is subsequently secreted. 

In the urea cycle ammonia is first combined with C02 to form carbamoyl phosphate. This then combines with ornithine to form citrulline. Citrulline then condenses with aspartate, the source of the second nitrogen atom in urea, to form argininosuccinate. This compound is in turn split to arginine and fumarate, and the arginine then splits to form urea and regenerate ornithine The first two reactions take place in the mitochondria of liver cells, the remaining three in the cytosol. 

The urea cycle Urea is synthesized in the liver by the urea cycle. It is then secreted into the bloodstream and taken up by the kidneys for excretion in the urine. The urea cycle was the first cyclic metabolic pathway to be discovered by Hans Krebs and Kurt Henseleit in 1932,5 years before Krebs discovered the citric acid cycle (see Topic LI). The overall reaction of the pathway is ... 

---