Carbamyl-phosphate synthetase

Diagnosis of CPS or OTC deficiency may not be apparent from the blood aminogram. Ornithine levels typically are normal. The presence of hyperammonemia, hyperglu-taminemia, hyperalaninemia and orotic aciduria in a critically ill infant affords presumptive evidence for OTC deficiency. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. 

Carbamyl phosphate synthetase deficiency. Carbamyl phosphate synthetase deficiency is rare. Neonates quickly develop lethargy, hypothermia, vomiting and irritability. The hyperammonemia typically is severe, even exceeding 1 mmol/1. Occasional patients with a partial enzyme deficiency have had a relapsing syndrome of lethargy and irritability upon exposure to protein. Brain damage can occur in both neonatal and late-onset groups. 

CPS carbamyl phosphate synthetase FSH follicle-stimulating hormone... 

Carbamyl phosphate synthetase catalyzes the synthesis of carbamyl-P from HCO3-, glutamine, and 2 moles of ATP. The enzyme also catalyzes the HC03 -dependent hydrolysis of ATP. Raushel and Villafranca (5) followed the exchange of from the bridge to the nonbridge position of [y- 0]ATP after Incubation with enzyme and bicarbonate. The exchange rate was O.A times the rate of ADP formation. These results support the formation of carboxy phosphate as the first Intermediate In the catalytic sequence. 

The positional Isotope exchange has also been measured with 31p-nmr In the reverse reaction of carbamyl phosphate synthetase ... 

Production of urea by cestodes suggests the existence of the urea (Krebs-Henseleit) cycle, which is shown in Fig. 6.11. One of the key enzymes, arginase, has been widely reported in cestodes (796, 185-187). However, some of the other enzymes, notably carbamyl phosphate synthetase and ornithine transcarbamyl, are either absent or present in only low amounts (39) and it is doubtful if a complete cycle operates in cestodes. It is likely that the urea excreted by tapeworms comes from the activity of arginase alone. The uric acid produced and excreted by cestodes probably arises from the breakdown of purines (39). 

Fig. 6.11. The (Krebs-Henseleit) ornithine cycle. Numbers refer to enzymes as follows. (1) Carbamyl phosphate synthetase (E.C.2.7.2.a). (2) Ornithine transcarbamylase (E.C.2.1.3.3). (3) Arginino-succinate synthetase (E.C.6.3.4.5). (4) Arginino-succinate lyase (E.C.4.3.2.1). (5) Arginase (E.C.3.5.3.1). (After Smyth, 1969.)...

Guy, H. I., and Evans, D. R. (1996). Function of the major synthetase subdomains of carbamyl-phosphate synthetase. / Biol. Chern., 271, 13762-13769. 

Animal and bacterial enzymes that utilize or synthesize carbamyl phosphate have activity with acetyl phosphate. Acyl phosphatase hydrolyzes both substrates, and maybe involved in the specific dynamic action of proteins. Ornithine and aspartic transcarbamylases also synthesize acetylornithine and acetyl aspartate. Finally, bacterial carbamate kinase and animal carbamyl phosphate synthetase utilize acetyl phosphate as well as carbamyl phosphate in the synthesis of adenosine triphosphate. The synthesis of acetyl phosphate and of formyl phosphate by carbamyl phosphate synthetases is described. The mechanism of carbon dioxide activation by animal carbamyl phosphate synthetase is reviewed on the basis of the findings concerning acetate and formate activation. 

Schooler, Fahien, and Cohen (40) have reported that 2-acetoxyglu-tarate is an activator of carbamyl phosphate synthetase. One of the structures proposed by Jones and Spector for the carboxylated derivative of acetyl glutamate is thus ruled out. 

Propionyl CoA inhibits A(-acetylglutamate synthetase competitively with respect to acetyl CoA, forming A(-propionylglutamate and reducing the synthesis of A(-acetylglutamate. This is an obligatory activator of carbamyl phosphate synthetase, the first enzyme of urea synthesis. Vitamin B12 deficiency may result in some degree of protein intolerance and hyperammonemia. 

The role of ATP in the carboxylation of biotin is unclear. It is possible that biotin is O-phosphorylated during the carboxylation reaction. However, evidence suggests that the immediate reactive species that carboxylates biotin is carboxyphosphate, as in the (biotin-independent) reaction of carbamyl phosphate synthetase in urea and pyrimidine synthesis. 

Cohen, S., and Raijman, L. (i960). The apparent K of ATPMg for carbamyl phosphate synthetase (ammonia) in sRn. /. Biot. Chem. 255,3352-3357. 

Citrulline is an endogenous amino acid involved in the urea cycle. Clinically, it can be used as an arginine substitute in the treatment of inborn errors of urea synthesis, including carbamyl phosphate synthetase and ornithine transcarbamylase. It is also a diuretic. 

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.

Call G, Seay AR, Sherry R, Qureshi lA. Clinical features of carbamyl phosphate synthetase-I deficiency in an adult. Ann Neurol 1984 16 90-3. 

Haraguchi Y, Uchino T, Takiguchi M, Endo F, Mori M, Matsuda I. Cloning and sequence of a cDNA encoding human carbamyl phosphate synthetase I molecular analysis of hyperammonemia. Gene 1991 107 335-40. 

Hoshide R, Matsuura T, Haraguchi Y, Endo F, Yoshinaga M, Matsuda I. Carbamyl phosphate synthetase I deficiency-one base substitution in an exon of the CPSI gene causes a 9-basepair deletion due to aberrant splicing. J Clin Invest 1993 91 1884-7. 

Lo WD, Sloan HR, Sotos JF, Klinger RJ. Late clinical presentation of partial carbamyl phosphate synthetase I deficiency Am J Dis Child 1993 147 267-9. 

Sassaman EA, Zartler AS, Mulick JA. Cognitive functioning in two sisters with carbamyl phosphate synthetase I deficiency, f Ped Psychol 1981 6 171-5. 

Summar ML, Dasouki MJ, Schofield PJ, Krishnamani MRS, Vnencak-Jones C, Tuchman M, et al. Physical and linkage mapping of human carbamyl phosphate synthetase I (CPSI) and reassignment from 2p to 2q35. Cytogenet Cell Genet 1995 71 266-7. 

Kuo AN, WiUis AS, et al. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene 2003 311 51-7. 

Tuchman M, Mauer SM, Holzknecht RA, Summar ML, Vnencak-Jones CL. Prospective versus clinical diagnosis and therapy of acute neonatal hyperam-monaemia in two sisters with carbamyl phosphate synthetase deficiency. J Inher Metab Dis 1992 15 269-77. 

Zimmer KP, Naim HY, Koch HG, Golombo JP, Rossi R, Schmid KW, et al. Survival after early treatment for carbamyl phosphate synthetase (CPS) I deficiency associated with increase of intramitochondrial CPS I. Lancet 1995 346 1530-1. 

Figure 47-SO The major metabolic pathways for the use of ammonia by the hepatocyte. Solid bars indicate the sites of primary enzyme defects in various metabolic disorders associated with hyperammonemia /) carbamyl phosphate synthetase I, (2) ornithine transcarbamylase, (3) argininosuccinate synthetase, (4) argininosuccinate lyase, (5) arginase, (6) mitochondrial ornithine transport, (7) propionyi CoA carboxylase, (fi) methylmalonyl CoA mutase, (9) L-lysine dehydrogenase, and (10) N-acetyl glutamine synthetase. Dotted lines indicate the site of pathway activation (+) or inhibition ( ). (From Flannery OB, Hsia YE, Wolf 6. Current status of /lyperommofiemjo syndromes. Hepatology 1982 2 495-506,)...

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