Regulation of the urea cycle

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. 

Q-28. How the regulation of the Urea Cycle takes place in the body ... 

K2. Katunuma, N., Okada, M., and Nishi, Y., Regulation of the urea cycle and TCA cycle by ammonia. Advan. Enzyme Regul. 4, 317-335 (1966). 

The activity of the urea cycle is regulated at the level of enzyme synthesis and by allosteric regulation of the enzyme that catalyzes the formation of carbamoyl phosphate. 

Morris, S.M. (2002) Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 22, 87-105. 

The oxidative phosphorylation system contains over 80 polypeptides. Only 13 of them are encoded by mtDNA, which is contained within mitochondria, and all the other proteins that reside in the mitochondrion are nuclear gene products. Mitochondria depend on nuclear genes for the synthesis and assembly of the enzymes for mtDNA replication, transcription, translation, and repair (Tl). The proteins involved in heme synthesis, substrate oxidation by TCA cycle, degradation of fatty acids by /i-oxidalion, part of the urea cycle, and regulation of apoptosis that occurs in mitochondria are all made by the genes in nuclear DNA. 

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. ... 

Regulation of Levels of the Intermediate Metabolites of the Urea Cycle in the Liver... 

The determination of plasma ammonia is of great importance both for the diagnosis and for the treatment of hereditary metabolic disorders of the urea cycle. The level is always raised in these conditions since the other mechanisms for regulating blood ammonia mentioned above are not able by themselves to keep the ammonia level within normal limits. 

Two other types of regulation control the urea cycle allosteric activation of CPSI by 7V-acetylglutamate (NAG) and induction/repression of the synthesis of urea cycle enzymes. NAG is formed specifically to activate CPSI it has no other known function in mammals. The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine (Fig. 38.15). Thus, as arginine levels increase within the liver, two important reactions are stimulated. The first is the synthesis of NAG, which will increase the rate at which carbamoyl phosphate is produced. The second is to produce more ornithine (via the arginase reaction), such that the cycle can operate more rapidly. 

The major regulated step of the urea cycle is which of the following ... 

Gene expression of the urea cycle enzymes in liver is down regulated to 10% by lipopolysaccharides Frozen material cannot be used for ornithine incorporation assay... 

The enzymes of the urea cycle, however, are not only expressed in the liver, but also in other tissues and cell types. In fact, it is believed that the urea cycle evolved from the arginine metabolic pathway present in lower organisms (Takiguchi et al, 1989). This difference in function between urea and arginine synthesis is reflected by the different tissue localization, function and regulation of the enzymes of the urea cycle and other enzymes involved in the metabolism of the urea cycle intermediates, arginine, citrulline and ornithine. 

Regulation of the activity of the hepatic and extrahepatic enzymes of the urea cycle... 

Two different arginase (ARG) isoforms, with different biochemical characteristics and tissue distribution, have been identified (Reddi etal, 1975). These enzymes were shown to be the product of two different, but related genes (see Cederbaum et al, 2004). ARG I (liver type) is cytosolic and the last step of the urea cycle which regenerates ornithine and releases urea. In contrast, ARG II (kidney type) is present in the mitochondria and is involved in providing ornithine for poly amine and prohne synthesis (Cederbaum et al, 2004) and in regulating arginine availability for nitric oxide synthesis (Topal et al, 2006). ARG II is present in enterocytes and thus has the potential to generate ornithine... 

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