Carbamoylphosphate synthetases

Eukaryotic organisms contain a multifunctional enzyme with carbamoylphosphate synthetase, aspartate transcarbamoylase, and dihydroorotase activities. Two mechanisms control this enzyme. First, control at the level of enzyme synthesis exists the transcription of the gene for the enzyme is reduced if an excess of pyrimidines is present. Secondly, control exists at the level of feedback inhibition by pyrimidine nucleotides. This enzyme is also an example of the phenomenon of metabolic channeling aspartate, ammonia, and carbon dioxide enter the enzyme and come out as orotic acid. 

Souciet, J. L., Nagy, M., Le Gouar, M., Lacroute, F., and Potier, S. (1989). Organization of the yeast URA2 gene identification of a defective dihydroorotase-like domain in the multifunctional carbamoylphosphate synthetase-aspartate transcarbamylase complex. Gene, 79, 59—70. 

Hyperammonemia I Unclear Urea cycle Carbamoylphosphate synthetase... 

F.S. Lawson, R.L. Charlebois, and J.A. Dillon. 1996. Phylogenetic analysis of carbamoylphosphate synthetase genes Complex evolutionary history includes an internal duplication within a gene which can root the tree of life Mol. Biol. Evol. 13 970-977. (PubMed)... 

C.R. McCudden and S.G. Powers-Lee. 1996. Required allosteric effector site forJV-acetylglutamate on carbamoylphosphate synthetase I Biol. Chem. 271 18285-18294. (PubMed)... 

As a congenital disorder, an enzyme deficiency in the urea cycle relates to carbamoylphosphate synthetase or N-ace-tyl-glutamate synthetase (= hyperammonaemia type I) and ornithine carbamoyltransferase (= hyperammonaemia type II) (D.B. Flannery et al., 1982). (27) (s. p. 594) This condition mainly affects the channelling of ammonium into the mitochondria and the conversion of ornithine into citrulline. (s. fig. 3.12) Similar acquired enzymopathies can be expected in Reye s syndrome and in cases of zinc deficiency. Such a hyperammonaemia syndrome can also produce the clinical picture of HE. 

Branched-chain amino acids apparently stimulate the urea cycle. Carbamoylphosphate synthetase, which channels ammonia into the urea cycle, is induced by ornithine and N-acetylglutamate as a cofactor of urea synthesis. Here, BCAA follow two modes of action (i.) they stimulate the synthesis of N-acetylglutamate via synthetase formed from glutamate and acetyl CoA, and (2.) they inhibit omithine-keto acid transferase, which is the enzyme responsible for ornithine degradation, leading to an increase in ornithine concentration. Ammonia detoxication is thus stimuiated by two regu-iatory mechanisms, (s. fig. 40.2)... 

Horiuchi M, Imamura Y, Nakamura N, Maruyama I, Saheki T. Carbamoylphosphate synthetase deficiency in an adult deterioration due to administration of valproic acid. J Inher Metab Dis 1993 16 39-45. 

Rapp B, Haberle J, Linnebank M, Wermuth B, Marquardt T, Harms E, et al. Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts. Eur J Pediatr 2001 160 283-7. 

Wong LJ, Craigen W), O Brien WE. Postpartum coma and death due to carbamoylphosphate synthetase I deficiency. Ann Intern Med 1994 120 216-7. 

This raises some unresolved questions about whether there is a functioning urea cyde in avian liver. Arginase is detedable in avian liver extrads (Table 5.1), albeit in small amounts, and its activity in vivo may be much lower than in intro. Another important enzyme necessary for a functioning urea cyde is carbamoylphosphate synthetase 1 ... 

Valproate may contribute to hyperammonemia by inhibiting carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Phenobarbital may potentiate the toxic effect of valproate. The electroencephalogram in severe hyperammonemic encephalopathy exhibits continuous generalized slowing, a predominance of theta and delta waves, bursts of frontal intermittent rhythmic delta activity, and triphasic waves (Segura-Bruna et al., 2006). 

Rate liver carbamoylphosphate synthetase I and ornithine transcarbamoyiase UDP-galactopyranose mutase... 

Guthohrlein, G., and Knappe, J., 1968, Stmcture and function of carbamoylphosphate synthetase. On the mechanism of bicarbonate activation, Eur. ]. Biochem. 7 119. 

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