| Structural highlights
Disease
[CPSM_HUMAN] Defects in CPS1 are the cause of carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300]. CPS1D is an autosomal recessive disorder of the urea cycle causing hyperammonemia. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Note=Genetic variations in CPS1 influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406.[13]
Function
[CPSM_HUMAN] Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
Publication Abstract from PubMed
Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 A-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations.
Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis.,de Cima S, Polo LM, Diez-Fernandez C, Martinez AI, Cervera J, Fita I, Rubio V Sci Rep. 2015 Nov 23;5:16950. doi: 10.1038/srep16950. PMID:26592762[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Finckh U, Kohlschutter A, Schafer H, Sperhake K, Colombo JP, Gal A. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat. 1998;12(3):206-11. PMID:9711878 doi:<206::AID-HUMU8>3.0.CO;2-E 10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E
- ↑ Funghini S, Donati MA, Pasquini E, Zammarchi E, Morrone A. Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat. 2003 Oct;22(4):340-1. PMID:12955727 doi:http://dx.doi.org/10.1002/humu.9184
- ↑ Haberle J, Schmidt E, Pauli S, Rapp B, Christensen E, Wermuth B, Koch HG. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Hum Mutat. 2003 Apr;21(4):444. PMID:12655559 doi:10.1002/humu.9118
- ↑ Rapp B, Haberle J, Linnebank M, Wermuth B, Marquardt T, Harms E, Koch HG. Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts. Eur J Pediatr. 2001 May;160(5):283-7. PMID:11388595
- ↑ Aoshima T, Kajita M, Sekido Y, Kikuchi S, Yasuda I, Saheki T, Watanabe K, Shimokata K, Niwa T. Novel mutations (H337R and 238-362del) in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. Hum Hered. 2001;52(2):99-101. PMID:11474210 doi:53360
- ↑ Wakutani Y, Nakayasu H, Takeshima T, Adachi M, Kawataki M, Kihira K, Sawada H, Bonno M, Yamamoto H, Nakashima K. Mutational analysis of carbamoylphosphate synthetase I deficiency in three Japanese patients. J Inherit Metab Dis. 2004;27(6):787-8. PMID:15617192
- ↑ Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. 2004 May;24(5):378-83. PMID:15164414 doi:10.1002/pd.884
- ↑ Eeds AM, Hall LD, Yadav M, Willis A, Summar S, Putnam A, Barr F, Summar ML. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Mol Genet Metab. 2006 Sep-Oct;89(1-2):80-6. Epub 2006 Jun 5. PMID:16737834 doi:10.1016/j.ymgme.2006.04.006
- ↑ Kurokawa K, Yorifuji T, Kawai M, Momoi T, Nagasaka H, Takayanagi M, Kobayashi K, Yoshino M, Kosho T, Adachi M, Otsuka H, Yamamoto S, Murata T, Suenaga A, Ishii T, Terada K, Shimura N, Kiwaki K, Shintaku H, Yamakawa M, Nakabayashi H, Wakutani Y, Nakahata T. Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency. J Hum Genet. 2007;52(4):349-54. Epub 2007 Feb 20. PMID:17310273 doi:10.1007/s10038-007-0122-9
- ↑ Pekkala S, Martinez AI, Barcelona B, Yefimenko I, Finckh U, Rubio V, Cervera J. Understanding carbamoyl-phosphate synthetase I (CPS1) deficiency by using expression studies and structure-based analysis. Hum Mutat. 2010 Jul;31(7):801-8. doi: 10.1002/humu.21272. PMID:20578160 doi:10.1002/humu.21272
- ↑ Moonen RM, Reyes I, Cavallaro G, Gonzalez-Luis G, Bakker JA, Villamor E. The T1405N carbamoyl phosphate synthetase polymorphism does not affect plasma arginine concentrations in preterm infants. PLoS One. 2010 May 25;5(5):e10792. doi: 10.1371/journal.pone.0010792. PMID:20520828 doi:10.1371/journal.pone.0010792
- ↑ Haberle J, Shchelochkov OA, Wang J, Katsonis P, Hall L, Reiss S, Eeds A, Willis A, Yadav M, Summar S, Lichtarge O, Rubio V, Wong LJ, Summar M. Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Hum Mutat. 2011 Jun;32(6):579-89. doi: 10.1002/humu.21406. Epub 2011 May 5. PMID:21120950 doi:10.1002/humu.21406
- ↑ Moonen RM, Reyes I, Cavallaro G, Gonzalez-Luis G, Bakker JA, Villamor E. The T1405N carbamoyl phosphate synthetase polymorphism does not affect plasma arginine concentrations in preterm infants. PLoS One. 2010 May 25;5(5):e10792. doi: 10.1371/journal.pone.0010792. PMID:20520828 doi:10.1371/journal.pone.0010792
- ↑ de Cima S, Polo LM, Diez-Fernandez C, Martinez AI, Cervera J, Fita I, Rubio V. Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. Sci Rep. 2015 Nov 23;5:16950. doi: 10.1038/srep16950. PMID:26592762 doi:http://dx.doi.org/10.1038/srep16950
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