Ornithine urea cycle

E2. Efron, M. L., Disorders of ornithine-urea cycle. In Amino Acid Metabolism and Genetic Variation (W. L. Nyhan, ed.), pp. 219-234. McGraw-Hill, New York, 1967. 

The Ornithine Urea Cycle Biosynthesis and Regulation of Carbamyl Phosphate Synthetase I and Ornithine Transcar-... 

Many fish produce urea as the major end product of protein metabolism and some synthesize this compound via the well-known ornithine-urea cycle. Other species, however, convert amino acids first to uric acid, and this purine is then converted to urea by the processes described above (38). 

A common basic amino acid is the lower homologue of lysine, L-ornithine (L-2,5-diaminovaleric acid, 2-41), which is an intermediate in the biosynthesis of arginine and an important amino acid of the ornithine (urea) cycle, which has the function of converting toxic ammonia into less toxic urea in mammals. Ornithine formed in dough through the action of yeast Sac-charomyces cerevisiae) is the main precursor of the typical aroma of bread crust, for which 2-acetyl-l-pyrroline together with 6-acetyl-l,2,3,4-tetrahydropyridine and its isomer 6-acetyl-2,3,4,5-tetrahydropyridine are responsible (see Section 8.2.12.4.1). 

Ornithine transcarbamylase deficiency. This is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. If inactivation affects primarily the X chromosome bearing the mutant OTC gene, then a more favorable outcome can be anticipated. Conversely, the unfavorably lyonized female has a more active disease. 

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. 

The two conditions can be distinguished by an increase in orotic add and uracil, which occurs in ornithine transcarbamoylase deficiency, but not in the defldency of carbamoyl phosphate synthetase. Orotic acid and uracil are intermediates in pyrimidine synthrais (see Chapter 18). This pathway is stimulated by the accumulation of carbamoyl phosphate, the substrate for ornithine transcarbamoylase in the urea cycle and for aspartate transcarbamoylase in pyrimidine synthesis. 

Answer E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase. 

Ammonia is generated mainly from the metabolism of amino acids and from the catabolism of purine and pyrimidine bases, which are produced from nucleic acids. Since it is toxic, it must be converted to a non-toxic compound for excretion from the body. This is achieved via the ornithine cycle, more usually known as the urea cycle. 

Only a few important representatives of the non-proteinogenic amino acids are mentioned here. The basic amino acid ornithine is an analogue of lysine with a shortened side chain. Transfer of a carbamoyl residue to ornithine yields citrulline. Both of these amino acids are intermediates in the urea cycle (see p.l82). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in the biosynthesis of catecholamines (see p.352) and of melanin. It is in clinical use in the treatment of Parkinson s disease. Selenocys-teine, a cysteine analogue, occurs as a component of a few proteins—e.g., in the enzyme glutathione peroxidase (see p.284). 

Urea cycle disorders (UCDs) Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCDs, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Precautions). 

Ornithine is a metabolically quite active amino acid, and the important precursor of pyrrolidine nucleus, which is found in pyrrolizidine alkaloids. Ornithine itself is a non-protein amino acid formed mainly from L-glumate in plants, and synthesized from the urea cycle in animals as a result of the reaction catalyzed by enzymes in arginine. 

In the urea cycle, two molecules of ammonia combine with a molecule of carbon dioxide to produce a molecule of urea and water. The overall cycle involves a series of biochemical reactions dependent on enzymes and carrier molecules. During the urea cycle the amino acid ornithine (C5H12N202) is produced, so the urea cycle is also called the ornithine cycle. A number of urea cycle disorders exist. These are genetic disorders that result in deficiencies in enzymes needed in one of the steps in the urea cycle. When a urea cycle deficiency occurs, ammonia cannot be eliminated from the body and death ensues. 

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. 

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. 

Ammonia is highly toxic to animal tissues. In the urea cycle, ornithine combines with ammonia, in the form of carbamoyl phosphate, to form citrulline. A second amino group is transferred to citrulline from aspartate to form arginine—the immediate precursor of urea. Arginase catalyzes hydrolysis of arginine to urea and ornithine thus ornithine is regenerated in each turn of the cycle. 

Many important neurotransmitters are primary or secondary amines, derived from amino acids in simple pathways. In addition, some polyamines that form complexes with DNA are derived from the amino acid ornithine, a component of the urea cycle. A common denominator of many of these pathways is amino acid decarboxylation, another PLP-requiring reaction (see Fig. 18-6). 

Formation of citrulline Ornithine and citrulline are basic amino acids that participate in the urea cycle. [Note They are not incorporated into cellular proteins, because there are no codons for these amino acids (see p. 429).] Ornithine is regenerated with each turn of the urea cycle, much in the same way that oxaloacetate is regenerated by the reactions of the citric acid cycle (see p 109). The release of the high-energy phosphateof carbamoyl phosphate as inorganic phosphate drives the reaction in the forward direction. The reaction product, citrulline, is trans ported to the cytosol. 

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. 

Correct answer = D. Methionine is the precursor of cysteine. An increase in gluconeogenesis releases increased ammonia and results in increased urea production. The essential amino acids leucine and lysine are ketogenic. Ornithine and citrulline are amino acids that are intermediates in the urea cycle, but are not found in tissue proteins. 

The 5-carbon skeleton of glutamic acid gives rise directly to those of proline, ornithine, and arginine. The reactions are outlined in Fig. 24-9. Arginine, in turn, is involved in the urea cycle, which is shown in detail in Fig. 24-10. Arginine is also a biosynthetic precursor of the polyamines. Another important biosynthetic product of glutamate metabolism is 8-aminolevulinate, a precursor to porphyrins (Eq. 24-44) in some organisms.139... 

---