Carbamoylphosphate

Paschos, A, Class, R. S. and Bock, A. (2001) Carbamoylphosphate requirement for synthesis of the active center of [NiFe]-hydrogenases. FEBS Lett., 488, 9-12. 

A different, simpler , pathway is involved in the synthesis of pyrimidine nucleotides. A pyrimidine base (orotate), is synthesised first. Then the ribose is added from 5-phosphoribosyl 1-pyrophosphate. The two precursors for the formation of orotate are carbamoylphosphate and aspartate, which form carbamoyl aspartate, catalysed by aspartate carbamoyltransferase. 

Figure 7-20 (A) Subunit assembly of two C3 catalytic trimers (green) and three R2 regulatory dimers around the periphery in aspartate carbamoyltransferase. After Krause et a/.109 Courtesy of William N. Lipscomb. The aspartate-and carbamoylphosphate-binding domains of the catalytic subunits are labeled Asp and CP, respectivley, while the zinc and allosteric domains of the regulatory subunits are labeled Alio and Zn, respectively. (B) Ribbon drawing of a single pair of regulatory (left) and catalytic (right) subunits with the structural domains labeled. MolScript drawing from Thomas et al.no...

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. 

The second reaction in the urea cycle is the condensation of carbamoylphosphate with ornithine, a basic amino acid not found in proteins but readily formed from glutamate (see later). The product is another basic amino acid called... 

Hyperammonemia I Unclear Urea cycle Carbamoylphosphate synthetase... 

Type I Carbamoylphosphate Within 24-72 hours after birth the infant... 

Carbamoylphosphate carbamylates the ornithine So we get a kind of steady state generating citrulline ... 

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. 

Formation of urea in hepatocytes. NAGS = N-acetylglutamate synthase CPSI = carbamoylphosphate synthase I OCT = ornithine carbamoyltransferase C-OT = citrulline-omithine translocase AS = argininosuccinate synthase AL = argininosuccinate lyase A = arginase. — -> indicates the absolute requirement of N-acetylglutamate for CPSI activity. 

---