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6uel

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Revision as of 07:27, 8 April 2020

CPS1 bound to allosteric inhibitor H3B-193

Structural highlights

6uel is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	CPS1 (HUMAN)
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

[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

Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.

Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.,Yao S, Nguyen TV, Rolfe A, Agrawal AA, Ke J, Peng S, Colombo F, Yu S, Bouchard P, Wu J, Huang KC, Bao X, Omoto K, Selvaraj A, Yu L, Ioannidis S, Vaillancourt FH, Zhu P, Larsen NA, Bolduc DM Cell Chem Biol. 2020 Jan 28. pii: S2451-9456(20)30034-9. doi:, 10.1016/j.chembiol.2020.01.009. PMID:32017919^[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
↑ Yao S, Nguyen TV, Rolfe A, Agrawal AA, Ke J, Peng S, Colombo F, Yu S, Bouchard P, Wu J, Huang KC, Bao X, Omoto K, Selvaraj A, Yu L, Ioannidis S, Vaillancourt FH, Zhu P, Larsen NA, Bolduc DM. Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket. Cell Chem Biol. 2020 Jan 28. pii: S2451-9456(20)30034-9. doi:, 10.1016/j.chembiol.2020.01.009. PMID:32017919 doi:http://dx.doi.org/10.1016/j.chembiol.2020.01.009

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6uel"

@@ Line 3: / Line 3: @@
 <StructureSection load='6uel' size='340' side='right'caption='[[6uel]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6uel]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UEL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UEL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6uel]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UEL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UEL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q5A:N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide'>Q5A</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q5A:N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide'>Q5A</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CPS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamoyl-phosphate_synthase_(ammonia) Carbamoyl-phosphate synthase (ammonia)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.16 6.3.4.16] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6uel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uel OCA], [http://pdbe.org/6uel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uel RCSB], [http://www.ebi.ac.uk/pdbsum/6uel PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uel ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uel OCA], [http://pdbe.org/6uel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uel RCSB], [http://www.ebi.ac.uk/pdbsum/6uel PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uel ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Larsen, N A]]

6uel

From Proteopedia

Revision as of 07:27, 8 April 2020

CPS1 bound to allosteric inhibitor H3B-193

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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