Urea cycle metabolism with

A number of inherited disorders of urea cycle metabolism are known. Hy per-ammonemia I and II are associated with CPS I and ornithine transcarbamylase deficiencies, respectively. Citrullinemia, arginosuccinic aciduria, and argininemia are associated with low levels of arginosuccinic acid synthetase, arginosuccinase, and arginase, respectively. All such disorders are associated with mental retardation, convulsions, and failure to thrive if not treated. Treatment involves the feeding of low-protein diets or, experimentally, the administration of a-keto analogs of essential amino acids instead of protein. 

METABOLIC DISORDERS ARE ASSOCIATED WITH EACH REACTION OF THE UREA CYCLE... 

Hepatic urea synthesis takes place in part in the mitochondrial matrix and in part in the cytosol. Inborn errors of metabolism are associated with each reaction of the urea cycle. 

The urea cycle is essential for the detoxification of ammonia. The urea cycle (Fig. 40-5) converts ammonia to urea (10-20g/day in the healthy adult). A urea cycle enzymopathy, whether associated with cirrhosis or an inherited metabolic defect, often causes a hyperammone-mic encephalopathy and irreversible brain injury (see also Ch. 34). 

We begin this overview of manganese biochemistry with a brief account of its role in the detoxification of free radicals, before considering the function of a dinuclear Mn(II) active site in the important eukaryotic urea cycle enzyme arginase. We then pass in review a few microbial Mn-containing enzymes involved in intermediary metabolism, and conclude with the very exciting recent results on the structure and function of the catalytic manganese cluster involved in the photosynthetic oxidation of water. 

In the next 2 to 3 years further experiments, particularly by Eggleston, who had joined Krebs in January 1936, confirmed and extended the observations. Careful quantitative evaluation of the data indicated that citrate like fumarate (Szent-Gyorgi) and like ornithine in the urea cycle exerted a catalytic effect on muscle metabolism. If arsenite, which blocks 2-oxoglutarate oxidation, was added with citrate to a respiring pigeon-muscle preparation, 2-oxoglutarate accumulated. 

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. 

Metabolically, acetyl CoA that is generated is diverted to ketogenesis, and urea cycle activity is decreased, leading to hyperammonaemia associated with fasting hypoglycaemia, increased lactataemia associated with an increased lactate pyruvate ratio, and increased ketonaemia with ratio < 1. Data from a patient affected with a PC defect are presented in Table 1.4.12. 

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

FIGURE 18-14 Treatment for deficiencies in urea cycle enzymes. The aromatic acids benzoate and phenylbutyrate, administered in the diet, are metabolized and combine with glycine and glutamine, respectively. The products are excreted in the urine. Subsequent synthesis of glycine and glutamine to replenish the pool of these intermediates removes ammonia from the bloodstream. 

Cleavage of argininosuccinate Argininosuccinate is cleaved to yield arginine and fumarate. The arginine formed by this reaction serves as the immediate precursor of urea. Fumarate produced in the urea cycle is hydrated to malate, providing a link with sev eral metabolic pathways. For example, the malate can be trans ported into the mitochondria via the malate shuttle and reenter... 

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.

Figure 1. Interrelations of carbamyl-P, acetyl-P, and formyl-P metabolism with the urea cycle...

OTC deficiency is the most common urea cycle defect.As it is X linked, affected boys typically have severe disease with neonatal presentation as described in this chapter. The disease in women who carry an OTC mutation on one X chromosome ranges from severe early-onset disease to complete absence of symptoms. Furthermore, affected women may decompensate in the context of a metabolic stress such as an infection or following parturition. OTC-deficient patients have low plasma citrulline and high urine orotic acid. Confirmation of the diagnosis requires mutation analysis or a liver biopsy for enzymology. The carrier status of women is most accurately determined by mutation analysis. 

There are several theories behind the cause of hepatic encephalopathy. One of these is that the accumulation of toxins in the brain, particularly ammonia, is the cause. Ammonia is produced in the intestine and is usually metabolised in the liver to urea via the urea cycle. As a result of portosystemic shunting and reduced metabolism in the liver, ammonia serum levels rise as the transformation to urea is reduced. However, the validity of this theory is questionable as not all patients with signs of hepatic encephalopathy have raised serum ammonia levels. Another theory is that patients with hepatic encephalopathy have increased permeability of the blood-brain barrier, and hence the increased toxin levels permeate the brain more than usual, leading to altered neuropsychiatric function. There are also theories relating to increased levels of neurotransmitters, short-chain fatty acids, manganese and increased GABA-ergic transmission. 

The determination of ammonia in blood is carried out enzymatically, which is considered to be specific, precise and simple. (48) Serious mistakes can easily occur during the preanalytical phase of ammonia determination, making it imperative to comply with the standardized method of taking a blood sample, (s. p. 91) EDTA blood should be taken with the addition of sodium borate and L-serine. Furthermore, elevated serum y-GT activity and increased thrombocytes cause the ammonia level to rise, as does cigarette smoking prior to blood collection. Even minor haemolysis (e. g. in the event of prolonged transport) will spoil the blood for ammonia determination, since the ammonia concentration of erythrocytes is three times that found in plasma. Besides these interfering factors, ammonia concentration is influenced by (7.) the metabolic performance of the urea cycle, (2.) the extrahepatic formation and elimination of ammonia, and (5.) the acid-base status. 

With hepatic encephalopathy, there is often an increase in short-chain fatty acids such as propionate, butyrate, valerate and octa-noate in the serum and CSF. They are formed as a result of incomplete p-oxidation of long-chain fatty acids in the intestine. They are not - or only inadequately — metabolized in the damaged liver. The neuro toxic effect is based upon inhibition of various enzymes (including enzymes of the urea cycle) and competitive... 

Storage diseases Some of the genetic metabolic diseases require special dietary measures, e.g. (1.) disorders of the urea cycle are treated by means of a diet similar to that applied in encephalopathy (s. p. 594), (2.) Gierke s disease necessitates a high-carbohydrate diet (s. p. 595), (i.) Cori s disease is treated with formula diets and a starch diet (s. p. 596), (4.) galactosaemia requires a galactose-and lactose-free diet (s. p. 597), and (5.) in fructose intolerance, a fructose- and saccharose-free diet must be given, (s. p. 597)... 

The urea cycle is the most important process in biological ammonia detoxication, (s. pp 57, 266) (s. figs. 3.12, 3.13) It is directly linked with amino-acid metabolism and thus also with NH2 donors and precursors through specific amino acids and transamination processes. Here, the major transamination processes are those involving glutamate and oxalacetate as well as a-ketoglutarate and aspartate. 

Bachmann C, Colombo JP. Acid-base status and plasma glutamine in patients with hereditary urea cycle disorders. In Soeters PB, Wilson )HP, Meijer AJ, eds. Advances in ammonia metabolism and hepatic encephalopathy, 1st ed. Amsterdam Elsevier, 1988 72-8. 

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