| Structural highlights
5ojo is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| NonStd Res: | , , |
| Related: | 5ojn |
| Activity: | Carbamoyl-phosphate synthase (ammonia), with EC number 6.3.4.16 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
[SIR5_DANRE] NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo (By similarity). [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
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators.
Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features.,Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C Nat Commun. 2017 Nov 15;8(1):1513. doi: 10.1038/s41467-017-01701-2. PMID:29138502[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C. Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features. Nat Commun. 2017 Nov 15;8(1):1513. doi: 10.1038/s41467-017-01701-2. PMID:29138502 doi:http://dx.doi.org/10.1038/s41467-017-01701-2
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