Abstract
N-acetylglutamate (NAG) is an endogenous essential cofactor for conversion of ammonia to urea in the liver. Deficiency of NAG causes hyperammonemia and occurs because of inherited deficiency of its producing enzyme, NAG synthase (NAGS), or interference with its function by short fatty acid derivatives. N-carbamylglutamate (NCG) can ameliorate hyperammonemia from NAGS deficiency and propionic and methylmalonic acidemia. We developed a stable isotope 13C tracer method to measure ureagenesis and to evaluate the effect of NCG in humans. Seventeen healthy adults were investigated for the incorporation of 13C label into urea. [13C]urea appeared in the blood within minutes, reaching maximum by 100 min, whereas breath 13CO2 reached a maximum by 60 min. A patient with NAGS deficiency showed very little urea labeling before treatment with NCG and normal labeling thereafter. Correspondingly, plasma levels of ammonia and glutamine decreased markedly and urea tripled after NCG treatment. Similarly, in a patient with propionic acidemia, NCG treatment resulted in a marked increase in urea labeling and decrease in glutamine, alanine, and glycine. These results provide a reliable method for measuring the effect of NCG on nitrogen metabolism and strongly suggest that NCG could be an effective treatment for inherited and secondary NAGS deficiency.
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Abbreviations
- CPS1:
-
Carbamyl phosphate synthetase 1
- NAG:
-
N-acetylglutamate
- NAGS:
-
N-acetylglutamate synthase
- NCG:
-
N-carbamylglutamate
References
Hall LM, Metzenberg RL, Cohen PP 1958 Isolation and characterization of a naturally occurring cofactor of carbamyl phosphate biosynthesis. J Biol Chem 230: 1013–1021
Shigesada K, Aoyagi K, Tatibana M 1978 Role of acteylglutamate in ureotelism variations in acetylglutamate level and its possible significance in control of urea synthesis in mammalian liver. Eur J Biochem 85: 385–391
Felipo V, Minana MD, Grisolia S 1988 Long-term ingestion of ammonium increases acetylglutamate and urea levels without affecting the amount of carbamoly-phosphate synthase. Eur J Biochem 176: 567–571
Meijer AJ, Lof C, Ramos IC, Verhoeven AJ 1985 Control of ureogenesis. Eur J Biochem 148: 189–196
Bachmann C, Colombo JP, Jaggi K 1982 N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol 153: 39–45
Schubiger G, Bachmann C, Barben P, Colombo J, Tonz O, Schupbach D 1991 N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr 150: 353–356
Caldovic L, Morizono M, Panglao M, Cheng SF, Packman S, Tuchman M 2003 Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 112: 364–368
Caldovic L, Morizono H, Panglao MG, Lopez G, Shi S, Summar ML, Tuchman M 2005 Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat 25: 293–298
Rubio V, Grisolia S 1981 Treating urea cycle defects. Nature 292: 496
Guffon N, Vianey-Saban C, Bourgeois J, Rabier D, Colombo JP, Guibaud P 1995 A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis 18: 61–65
Hinnie J, Colombo JP, Wermuth B, Dryburgh FJ 1997 N-Acetylglutamate synthetase deficiency responding to carbamylglutamate. J Inherit Metab Dis 20: 839–840
Morris AA, Richmond SW, Oddie SJ, Pourfarzam M, Worthington V, Leonard JV 1998 N-acetylglutamate synthetase deficiency: favourable experience with carbamylglutamate. J Inherit Metab Dis 21: 867–868
Gebhardt B, Vlaho S, Fischer D, Sewell A, Bohles H 2003 N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria. Mol Genet Metab 79: 303–304
Gebhardt B, Dittrich S, Parbel S, Vlaho S, Matsika O, Bohles H 2005 N-carbamylglutamate protects patients with decompensated propionic aciduria from hyperammonaemia. J Inherit Metab Dis 28: 241–244
Forget PP, van Oosterhout M, Bakker JA, Wermuth B, Vles JS, Spaapen LJ 1999 Partial N-acetyl-glutamate synthetase deficiency masquerading as a valproic acid-induced Reye-like syndrome. Acta Paediatr 88: 1409–1411
Castillo L, Beaumier L, Ajami AM, Young VR 1996 Whole body nitric oxide synthesis in healthy men determined from [15N]arginine-to-[15N]citrulline labeling. Proc Natl Acad Sci USA 93: 11460–11465
Jahoor F, Wolfe RR 1987 Reassessment of primed constant-infusion tracer method to measure urea kinetics. Am J Physiol 252: E557–E564
Matthews DE, Downey RS 1984 Measurement of urea kinetics in humans: a validation of stable isotope tracer methods. Am J Physiol 246: E519–E527
Cheema-Dhadli S, Leznoff CC, Halperin ML 1975 Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria. Pediatr Res 9: 905–908
Brock M, Buckel W 2004 On the mechanism of action of the antifungal agent propionate. Eur J Biochem 271: 3227–3241
Kalhan SC 1996 Stable isotopic tracers for studies of glucose metabolism. J Nutr 126: 362S–369S
Meer K, Roef MJ, Kulik W, Jakobs C 1999 In vivo research with stable isotopes in biochemistry, nutrition and clinical medicine: an overview. Isotopes Environ Health Stud 35: 19–37
Yudkoff M, Daikhin Y, Nissim I, Jawad A, Wilson J, Batshaw M 1996 In vivo nitrogen metabolism in ornithine transcarbamylase deficiency. J Clin Invest 98: 2167–2173
Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M 2004 Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr 145: 552–554
Brown R, Manning R, Delp M, Grisolia S 1958 Treatment of hepatocerebral intoxication. Lancet 1: 591–592
Elsas LJ, Danner DJ 1982 The role of thiamin in maple syrup urine disease. Ann N Y Acad Sci 378: 404–421
Matalon R, Koch R, Michals-Matalon K, Moseley K, Surendran S, Tyring S, Erlandsen H, Gamez A, Stevens RC, Romstad A, Moller LB, Guttler F 2004 Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 6: 27–32
Coude FX, Sweetman L, Nyhan WL 1979 Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria: a possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest 64: 1544–1551
Coude FX, Rabier D, Cathelineau L, Grimber G, Parvy P, Kamoun P 1982 A mechanism for valproate-induced hyperammonemia. Adv Exp Med Biol 153: 153–161
Coude FX, Grimber G, Parvy P, Rabier D, Petit F 1983 Inhibition of ureagenesis by valproate in rat hepatocytes. Role of N-acetylglutamate and acetyl-CoA. Biochem J 216: 233–236
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This work was supported in part by public health service grants R01DK47870, R01DK064913, and R01DK53761 from the National Institute of Diabetes and Digestive and Kidney Diseases, grant U54RR019453 from the Rare Disease Centers Program of the Office for Rare Disorders and the National Center for Research Resources, and the Mental Retardation and Developmental Disabilities Research Centers P30HD40677 and P30HD2697 from the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.
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Tuchman, M., Caldovic, L., Daikhin, Y. et al. N-carbamylglutamate Markedly Enhances Ureagenesis in N-acetylglutamate Deficiency and Propionic Acidemia as Measured by Isotopic Incorporation and Blood Biomarkers. Pediatr Res 64, 213–217 (2008). https://doi.org/10.1203/PDR.0b013e318179454b
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DOI: https://doi.org/10.1203/PDR.0b013e318179454b
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