Urea cycle pathways

Figure 24-2 The urea cycle pathway. CPS I, Carbamyl phosphate synthetase I N-acetyigiutamate as positive allosteric effector OTC, ornithine transcarbamyiase MS, argininosuccinate synthetase Ai, argininosuccinate iyase AR, arginase ADP, adenosine diphosphate, ATf adenosine triphosphate, P, inorganic phosphate.

Fig. 5. Diagrammatio representation of intracellular localization of urea cycle pathway showing diffusion pattern. CPS, carbamyl phosphate synthetase ASL, argininosuccinate lyase ASA, argininosucoinate.

Thus the pathway for the synthesis of ornithine from glutamine, along with part of the urea cycle pathway, can together be considered as a de novo pathway for the synthesis of arginine. Arginine can in turn be used for the synthesis of urea, or it can serve instead as one of the amino acids used for polypeptide synthesis. 

In 1937 Krebs found that citrate could be formed in muscle suspensions if oxaloacetate and either pyruvate or acetate were added. He saw that he now had a cycle, not a simple pathway, and that addition of any of the intermediates could generate all of the others. The existence of a cycle, together with the entry of pyruvate into the cycle in the synthesis of citrate, provided a clear explanation for the accelerating properties of succinate, fumarate, and malate. If all these intermediates led to oxaloacetate, which combined with pyruvate from glycolysis, they could stimulate the oxidation of many substances besides themselves. (Kreb s conceptual leap to a cycle was not his first. Together with medical student Kurt Henseleit, he had already elucidated the details of the urea cycle in 1932.) The complete tricarboxylic acid (Krebs) cycle, as it is now understood, is shown in Figure 20.4. 

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. 

Introduction of photoelectric cells led to the replacement of the Duboscq colorimeter and so to quantitative spectrophotometric methods of analysis which met biochemical requirements. This introduction of spectrophotometry as a routine procedure was one of the earliest technological advances underpinning the elucidation of biochemical pathways between 1930-1960. Micromanometric methods also became available about the same time, and offered a means to measure cell respiration. Manometry was developed in Warburg s laboratory in Berlin and was one of the main techniques used by H.A. Krebs in his studies on the citric acid and urea cycles (Chapters 5 and 6). 

Cheung, C.W., Cohen, N.G., Raijman, L. (1989). Channeling of urea cycle intermediates in situ in permeabilized hepatocytes. J. Biol. Chem. 264,4038-4044. Cohen, P.P. (1954). Nitrogen metabolism of amino acids. In Chemical Pathways in Metabolism (Greenberg, D.M., Ed.), Vol. 2, pp. 1-46. Academic Press, New York. Fisher, R.B. (1954). Protein Metabolism. Methuen, London. 

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. 

T) Pentose phosphate pathway Gluconeogenesis Glycolysis P-Oxidation (5) Fatty acid biosynthesis Tricarboxylic acid cycle (7) Urea cycle... 

Inherited absence or mutations in enzymes involved in critical metabolic pathways—eg, the urea cycle or glycogen metabolism—are referred to as inborn errors of metabolism. If not detected soon after birth, these conditions can lead to serious metabolic derangements in infants and even death. 

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 begins inside liver mitochondria, but three of the subsequent steps take place in the cytosol the cycle thus spans two cellular compartments (Fig. 18-10). The first amino group to enter the urea cycle is derived from ammonia in the mitochondrial matrix—NHj arising by the pathways described above. 

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. 

The interconnected cycles have been called the "Krebs bicycle." The pathways linking the citric acid and urea cycles are called the aspartate-argininosuccinate shunt these effectively link the fates of the amino groups and the carbon skeletons of amino acids. The interconnections are even more elaborate than the arrows suggest. For... 

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). 

Urea cycle shown as part of the essential reactions of energy metabolism. (See Figure 8.2, p. 90, for a more detailed view of the metabolic pathway.)... 

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... 

Pathway involved Urea cycle Pyrimidine synthesis... 

Allantoin is the excretory product in most mammals other than primates. Most fish hydrolyze allantoin to allantoic acid, and some excrete that compound as an end product. However, most continue the hydrolysis to form urea and glyoxylate using peroxisomal enzymes.336 In some invertebrates the urea may be hydrolyzed further to ammonia. In organisms that hydrolyze uric acid to urea or ammonia, this pathway is used only for degradation of purines from nucleotides. Excess nitrogen from catabolism of amino acids either is excreted directly as ammonia or is converted to urea by the urea cycle (Fig. 24-10). 

Synthesis of arginine by the salvage pathway found in vertebrates and by the de novo pathway found in plants and bacteria. The final steps from ornithine to arginine are also part of the urea cycle (see fig. 22.7). 

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. 

Urea cycle This pathway converts ammonia, a toxic nitrogen-containing waste product of protein metabolism, into another, less toxic molecule called urea, which can be eliminated from the body as urine. 

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 ... 

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