Urea cycle function

N=1 Follow-up age 3-5 years Older children 0.7-1.1 g/kg requirements 1,350-1,660 kcal effect of reintroduction of L-arginine on nutrition, growth, and urea cycle function... 

Nagasaka H et al. Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamy-lase deficiency. Eur J Pediatr. 2006 165(9) 618-24. 

Colostrum produced by the milk glands in the first few days after parturition is rich in protein and minerals. The protein content is particularly rich in immunoglobulins providing anti-infective agents, tryptophan needed for regulating nitrogen synthesis, and arginine which stimulates urea cycle function. 

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. 

Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed by mitochondrial carbamoyl phosphate synthase I (reaction 1, Figure 29-9). A cytosolic form of this enzyme, carbamoyl phosphate synthase II, uses glutamine rather than ammonia as the nitrogen donor and functions in pyrimidine biosynthesis (see Chapter 34). Carbamoyl phosphate synthase I, the rate-hmiting enzyme of the urea cycle, is active only in the presence of its allosteric activator JV-acetylglutamate, which enhances the affinity of the synthase for ATP. Formation of carbamoyl phosphate requires 2 mol of ATP, one of which serves as a phosphate donor. Conversion of the second ATP to AMP and pyrophosphate, coupled to the hydrolysis of pyrophosphate to orthophosphate, provides the driving... 

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. 

FIGURE 3-8 Uncommon amino acids, (a) Some uncommon amino acids found in proteins. All are derived from common amino acids. Extra functional groups added by modification reactions are shown in red. Desmosine is formed from four Lys residues (the four carbon backbones are shaded in yellow). Note the use of either numbers or Creek letters to identify the carbon atoms in these structures, (b) Ornithine and citrulline, which are not found in proteins, are intermediates in the biosynthesis of arginine and in the urea cycle. 

The carbamoyl phosphate, which functions as an activated carbamoyl group donor, now enters the urea cycle. The cycle has four enzymatic steps. First, carbamoyl phosphate donates its carbamoyl group to ornithine to form citrulline, with the release of Pj (Fig. 18-10, step ). Ornithine plays a role resembling that of oxaloacetate in the citric acid cycle, accepting material at each turn of the cycle. The reaction is catalyzed by ornithine transcarbamoylase, and the citrulline passes from the mitochondrion to the cytosol. 

Integrates the latest on regulation of reactions throughout the chapter, with new material on genetic defects in urea cycle enzymes, and updated information on the regulatory function of N-acetylglutamate synthase. 

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. 

Although the primary function of the urea cycle is usually regarded as the removal of NH4+ from the body, it also removes HC03 in equal amounts (Eq. 24-24). This is essential for maintenance of neutral pH,... 

The urea cycle is a mechanism for removing unwanted nitrogen. Sources of nitrogens involved in urea formation are shown in red. Five enzymes are used in the urea cycle. Three of these function in the cytosol, and two, as shown, function in the mitochondrial matrix. 

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. 

Hyperammonemia is an increase in the levels of ammonia in the blood caused by a defect in an enzyme of the urea cycle. The excess ammonia is channeled into glutamate and glutamine with a deleterious effect on brain function. 

While the expression and regulation of the urea cycle are widely appreciated (Campbell, 1991, 1995 Walsh and Mommsen, 2000), a few general functional properties of this pathway of nitrogen metabolism need to be mentioned here. 

The most abundant amino add in the human organism does not occur in proteins and does not have a carboxyl group. Its addic residue is the sulfonate group, and its name is taurine (N+H3-CH2-CH2-S03 ). It occurs in the free state (exact function often unknown) and in bile salts, in which it plays an important role in fat digestion and absorption (see Chapters 9 and 19). Other amino acids that do not occur in proteins are ornithine and citrulline. They are important intermediates in the urea cycle described in Chapter 20. 

Ornithine is required to maintain the urea cycle. Conversion of glutamate to ornithine via glutamate semialdehyde is therefore an anaplerotic reaction. Melatonin is a compound synthesized from serotonin. It has a function in the circadian rhythm activity and has nothing to do with intracellular protein degradation. 

Urea is synthesized via the urea cycle (Fig. 18-1). In 1932, Krebs and Henseleit pubEshed data demonstrating that ornithine stimulates the synthesis of urea without stoichiometric consumption of this intermediate. This apparent catalytic function was determined to be the result of the cycEc nature of the pathway. This was a revolutionary idea since metabolic pathways were conceptualized as purely linear prior to the pubEcation of these observations. In the foUowing sections, we discuss the biochemical processes involved in urea formation. 

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). 

Two of the molecules that were assayed for in pig serum are often used to assess overall liver function. Name these two molecules. Using your knowledge of the gluconeogenesis pathway and the urea cycle, explain how increased or decreased levels of these two molecules could be used to assess the overall function of the liver. 

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. 

Hyperammonemia occurs in biotin deficiency and the functional deficiency associated with lack of holocarboxylase synthetase (Section 11.2.2.1) and bio-tinidase (Section 11.2.3.1). In deficient rats, the activity of ornithine carbamyl-transferase is two - thirds of that in control animals, as a result of decreased gene expression, although the activities of other urea cycle enzymes are unaffected (Maeda etal., 1996). 

Bleeding is a welldmown complication of uraemia that is attributed to the suppression of platelet function by the disease process. Interestingly, L-arginine and some ofoer platelet-inhibitory metabolites of the urea cycle are accumulated in uraemia (Horowitz et al 1970) and this is associated witii an increase in TNF levels (Noris et al 1993). It has been shown that platelets obtained from luaemic patients generate more NO than controls so tiiat increased expression and/or activity of NOS may play a role in platelet dysfunction observed in uraemia (Noris et al 1993). 

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