Liver ammonia converted

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

Liver plays a major role, since it can oxidize all amino acids except leucine, isoleucine, and valine (see Chapter 22). It also produces the nonessential amino acids from the appropriate carbon precursors. Ammonia formed in the gastrointestinal tract or from various deaminations in the liver is converted to urea and excreted in urine (discussed later). 

The activity of ornithine transcarbamoylase, the next enzyme in the urea cycle, appears to be extremely high. In the case of excess ammonia, almost all of the ornithine present in the liver is converted to citrulline, indicating a sufficient activity of carbamoyl phosphate... 

Before the carbon skeletons of amino acids are oxidized, the nitrogen must be removed. Amino acid nitrogen forms ammonia, which is toxic to the body. In the liver, ammonia and the amino groups from amino acids are converted to urea, which is nontoxic, water-soluble, and readily excreted in the urine. The process by which urea is produced is known as the urea cycle. The liver is the organ responsible for producing urea. Branched-chain amino acids can be oxidized in many tissues, but the nitrogen must always travel to the liver for disposal. 

Fig. 38.11. Synthesis of glutamine in peripheral tissues and its transport to the liver. Within the liver, glutaminase converts glutamine to glutamate. Note how a-ketoglutarate can accept two molecules of ammonia to form glutamine. GDH = glutamate dehydrogenase.

To some extent, humans excrete urea into the gut and saliva. Intestinal bacteria convert urea to ammonia. This ammonia, as well as ammonia produced by other bacterial reactions in the gut, is absorbed into the hepatic portal vein. It is normally extracted by the liver and converted to urea. Approximately one fourth of the total urea released by the liver each day is recycled by bacteria. 

The ammonia in rumen liquor is the key intermediate in microbial degradation and synthesis of protein. If the diet is deficient in protein, or if the protein resists degradation, then the concentration of rumen ammonia will be low (about 50 mg/1) and the growth of rumen organisms will be slow in consequence, the breakdown of carbohydrates will be retarded. On the other hand, if protein degradation proceeds more rapidly than synthesis, then ammonia will accumulate in rumen liquor and the optimum concentration will be exceeded. When this happens, ammonia is absorbed into the blood, carried to the liver and converted to urea (see Fig. 8.8). Some of this urea may be returned to the rumen via the saliva and also directly through the rumen wall, but the greater part is excreted in the urine and thus wasted. 

Ammonia is produced in proximal and distal segments of the tubules. It is formed by the deamination of glutamine and other amino acid substrates in the liver, intestinal mucosa and the kidney. Any ammonia in the blood is taken up by the liver and converted to urea, the liver being the only organ in which urea is formed. Unlike blood, the urine contains appreciable quantities of ammonia. The enzyme glutaminase, located in the mitochondria of the renal tubule cells, catalyses the production of ammonia the reaction is shown in section A.2. Glutaminase is present in large amounts in the kidney and Its concentration there is raised in acidosis. 

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. 

Liver s main job is to keep up the levels of blood glucose. To do this, it breaks down glycogen and turns on gluconeogenesis. The liver takes lactate and alanine from the circulation and through gluconeogenesis converts it into glucose. The ammonia from the alanine is pushed... 

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 ... 

The aspartate and glutamate produced by these reactions, plus those taken up from the lumen, are metabolised to oxaloacetate and oxoglutarate, respectively, as discussed above. The a-NH2 group in these amino acids is transferred to pyruvate to form alanine, which is released and then taken up by the liver, where the NH2 group is converted to ammonia and then to urea. 

Figure 8.30 Different roles of periportal and perivenous cells in the liver in respect of glutamine metabolism. Glutamine is converted to glucose in periportal cells via gluconeogenesis in perivenous cells, ammonia is taken up, to form glutamine, which is released into the blood. This emphasises the importance of the liver in removing ammonia from the blood, i.e. if possesses two process to ensure that all the ammonia is removed.

C. Ammonia is converted to a nontoxic form, mainly glutamine, for transport to the liver for further processing. 

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 man, BH4 is degraded either nonenzymatically by side-chain cleavage to pterin or is enzymatically metabolized in the gastrointestinal tract to become a lumazine [2]. Pterin and dihydropterin are converted by xanthine dehydrogenase to isoxanthopterin and xanthopterin, respectively [3,4]. It is assumed, however, that most of the ingested BH4 is used as a cofactor (mainly for PAH in the liver) and is catabolized to nonfluorescing compounds it may even be degraded to C02 and ammonia. 

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. 

Amino acids are used to synthesize liver and plasma proteins, or their carbon skeletons are converted to glucose and glycogen by gluconeogenesis the ammonia formed by deamination is converted to urea. 

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. 

It is clear, however, that the quantitative difference described by McDermott (M5) is proportional to the amount of destruction and repair present in a particular liver, rather than to a nebulous farrago of complex biochemical changes. We are still dealing with ammonia intoxication in the cases reported. This is not to deny the very real and as yet minimally understood relation of the liver to brain metabolism (vide infra), but it is essential to the development of a lucid picture of disease as a biochemical phenomenon that we do not convert variations of the same process into a multiplicity of syndromes. 

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