Kidney urea cycle

If the effect of water stress is to alter regulation of the pathway such that the rate constant for reaction A G is increased or A CP is decreased (which would have an overall effect of conserving nitrogen), then the fractionation at G can be shown to be thereby increased. At present this is speculative, but in fact explanations for the water-stress effect using flow-models are rather constrained. For example, it is not possible to relate what might happen at the kidneys (e.g., resorption of urea) to the amino acid body pool, since the urea cycle is non-reversible. It should be possible to design experiments that test this suggestion. 

Nitrogen compounds commonly determined are creatinine, urea, and uric acid. Creatinine is an end product of the energy process occurring within the muscles, and is thus related to muscle mass. Creatinine in urine is commonly used as an indicator and correction factor of dilution in urine. Creatinine in serum is an indicator of the filtration capacity of the kidney. Urea is the end product of the nitrogen luea cycle, starting with carbon dioxide and ammonia, and is the bulk compoimd of urine. The production of uric acid is associated with the disease gout. In some cases, it appears that the excess of uric acid is a consequence of impaired renal excretion of this substance. 

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. 

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). 

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 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 ... 

It has been stated that the liver is the principal urea producer, yet several urea cycle intermediates are produced by other organs as well and must be moved to other organs to be processed. Thus, intestinal mucosal cells are able to convert ornithine to citrulline, but citrulline cannot be converted to arginine in that location. Citrulline must be transported to either the kidney or liver, where conversions to arginine and urea are possible. Kidney, on the other hand, cannot convert ornithine to citrulline. 

The final step of the urea cycle is the cleavage of arginine to release urea and regenerate ornithine. Ornithine then reenters the mitochondria via the ORNT-1 ornithine-citrulline antiporter. ARG-1 is a cytosolic homotrimeric enzyme of 35-kd monomers that is expressed in fiver and red blood cells. A second mitochondrial arginase (ARG-2) most likely plays a role in nitric oxide synthesis and is most abundant in brain, kidney, and prostate. ARG-1 deficiency is unique among the urea cycle deficiencies as patients do not present with hyperammonemia and encephalopathy but rather develop progressive spasticity of the lower limbs. Biochem-... 

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase, which catalyzes the reaction in which ammonia is condensed with 2-oxoglutarate to form glutamate (Sec. 15.1). Small amounts of ammonia are produced from important amine metabolites such as epinephrine, norepinephrine, and histamine via amine oxidase reactions. It is also produced in the degradation of purines and pyrimidines (Sec. 15.6) and in the small intestine from the hydrolysis of glutamine. The concentration of ammonia is regulated within narrow limits the upper limit of normal in the blood in humans is 70/tmol L-1. It is toxic to most cells at quite low concentrations hence there are specific chemical mechanisms for its removal. The reasons for ammonia toxicity are still not understood. The activity of the urea cycle in the liver maintains the concentration of ammonia in peripheral blood at 20/ molL. ... 

Most doctors use the plasma concentrations of creatinine, urea and electrolytes to determine renal function. These measures are adequate to determine whether a patient is suffering from kidney disease. Protein and amino acid catabolism results in the production of ammonia, which in turn is converted via the urea cycle into urea, which is then excreted via the kidneys. Creatinine is a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass). Creatinine is mainly filtered by the kidney, though a small amount is actively secreted. There is little to no tubular reabsorption of creatinine. If the filtering of the kidney is deficient, blood levels rise. 

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). 

A high amount of bicarbonate is constantly being produced in the body. Degradation of 100 g protein yields approximately 1 mol bicarbonate (= 61 g). Bicarbonate neutralization takes place via the urea cycle too, as the synthesis of 1 mol urea requires 2 mol bicarbonate. Besides the lungs and kidneys, the liver therefore also plays an important role in acid-base metabolism and is partly responsible for pH homoeostasis. 

FJGURE, 20 Eliminiitian of ammonium ions via the urea cycle or via direct excretion. With protein catabolism, the excretion of wafste nitrogen via the urea cycle results in net prod union of acid in the body however, excretion of ammonium ions by the kidney into the urine does not result in this production of acid in the body. 

Vidailhet et al. (VI) assayed all five enzymes involved in the urea cycle, and found no detectable activity of argininosuccinate synthetase, whereas the other enzymes were present in normal activity (Table 9). It is of interest that an appreciable synthetase activity was detectable in the kidney tissue in their patient, at a level of about 20% of that found in normal liver, despite its absence in the patient s liver (L4). This observation is similar to that of Colombo and Baumgartner (C8), who found argininosuccinate lyase in the kidney of their child with argininosuccinic aciduria, in spite of its absence from the liver. The question is again raised whether it is possible thus to account for the production of urea in these cases. However, since arginase is not present in the kidney, the arginine formed would have to be transported to the liver... 

Citrullinemia Urea Cycle Enzyme Levels in Liver and Kidney"... 

In eukaryotic cells, two separate pools of carbamoyl phosphate are synthesized by different enzymes located at different sites. Carbamoyl phosphate synthetase I (CPS I) is located in the inner membrane of mitochondria in the liver and, to lesser extent, in the kidneys and small intestine. It supplies carbamoyl phosphate for the urea cycle. CPS 1 is specific for ammonia as nitrogen donor and requires N-acetylglutamate as activator. Carbamoyl phosphate synthetase II (CPS II) is present in the cytosol. It supplies carbamoyl phosphate for pyrimidine nucleotide biosynthesis and uses the amido group of glutamine as nitrogen donor. The presence of physically separated CPSs in eukaryotes probably reflects the need for independent regulation of pyrimidine biosynthesis and urea formation, despite the fact that both pathways require carbamoyl phosphate. In prokaryotes, one CPS serves both pathways. 

The answer is e. (Murray, pp 30/-346. Sciivei, pp 1909-1964. Sack, pp 121—138. Wilson, pp 287-317.) In the liver, the urea cycle converts excess NH/ to a form amenable to excretion by the kidneys. Free NH/ condenses with CO2 to form carbamoyl phosphate in a reaction catalyzed by carbamoyl phosphate synthetase. This is an energy-expensive, essentially irreversible... 

WASTE REMOVAL All living cells produce waste products. For example, animal cells ultimately convert food molecules, such as sugars and amino acids, into COz, HzO, and NH3. These molecules, if not disposed of properly, can be toxic. Some substances are readily removed. In animals, for example, C02 diffuses out of cells and (after a brief and reversible conversion to bicarbonate by red blood cells) is quickly exhaled through the respiratory system. Excess HzO is excreted through the kidneys. Other molecules, however, are sufficiently toxic that elaborate mechanisms have been evolved to provide for their disposal. The urea cycle (described in Chapter 15), used in many animals to dispose of NH3, converts this extremely harmful substance into urea, a less toxic molecule. 

Persons who suffer from severe liver or kidney disease may be susceptible to ammonia intoxication, as it is chiefly by the actions of these organs that NH/ is biotransformed and excreted (Cordoba et al. 1998 Gilbert 1988 Jeffers et al 1988) individuals with hereditary urea cycle disorders are also at risk (Schubiger et al. 1991). In these individuals, the levels produced endogenously are sufficient to produce toxicity. Levels that are likely to be encountered in the environment, with the exception of those resulting from high-level accidental exposures, are insignificant, due to the low absorption rate, in comparison with levels produced within the body (WHO 1986). 

Urea cycle and arginine synthesis. The general aspect and control of the urea synthesis and the role of the intestine and kidney in arginine synthesis are shown above. 

Urea is synthesized almost exclusively in the liver and then transported to the kidneys for excretion. The process that generates urea is called the urea cycle and is depicted in Figure 20.13. Urea is synthesized almost exclusively in the liver and then transported to the kidneys for excretion. The enzyme arginase is responsible for the cyclic nature of the urea cycle and for production of urea, as follows ... 

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