4217C>A polymorphism in carbamoyl-phosphate synthase 1 gene may not associate with hyperammonemia development during valproic acid-based therapy

2014 ◽  
Vol 108 (6) ◽  
pp. 1046-1051 ◽  
Author(s):  
Kazuyuki Inoue ◽  
Eri Suzuki ◽  
Toshiki Takahashi ◽  
Yoshiaki Yamamoto ◽  
Rei Yazawa ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Carbamoyl Phosphate ◽  
Phosphate Synthase

scholarly journals Structural requirements of the glucocorticoid-response unit of the carbamoyl-phosphate synthase gene

2004 ◽  
Vol 382 (2) ◽  
pp. 463-470 ◽  
Author(s):  
Onard J. L. M. SCHONEVELD ◽  
Ingrid C. GAEMERS ◽  
Atze T. DAS ◽  
Maarten HOOGENKAMP ◽  
Johan RENES ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Distal Enhancer ◽  
Carbamoyl Phosphate ◽  
Gene Encoding ◽  
Response Elements ◽  
Response Unit ◽  
Glucocorticoid Response ◽  
Protein Functions ◽  
Spatial Positioning ◽  
Phosphate Synthase

The GRU (glucocorticoid-response unit) within the distal enhancer of the gene encoding carbamoyl-phosphate synthase, which comprises REs (response elements) for the GR (glucocorticoid receptor) and the liver-enriched transcription factors FoxA (forkhead box A) and C/EBP (CCAAT/enhancer-binding protein), and a binding site for an unknown protein denoted P3, is one of the simplest GRUs described. In this study, we have established that the activity of this GRU depends strongly on the positioning and spacing of its REs. Mutation of the P3 site within the 25 bp FoxA–GR spacer eliminated GRU activity, but the requirement for P3 could be overcome by decreasing the length of this spacer to ≤12 bp, by optimizing the sequence of the REs in the GRU, and by replacing the P3 sequence with a C/EBPβ sequence. With spacers of ≤12 bp, the activity of the GRU depended on the helical orientation of the FoxA and GR REs, with highest activities observed at 2 and 12 bp respectively. Elimination of the 6 bp C/EBP–FoxA spacer also increased GRU activity 2-fold. Together, these results indicate that the spatial positioning of the transcription factors that bind to the GRU determines its activity and that the P3 complex, which binds to the DNA via a 75 kDa protein, functions to facilitate interaction between the FoxA and glucocorticoid response elements when the distance between these transcription factors means that they have difficulties contacting each other.

scholarly journals Nucleotide ligands protect the inter-domain regions of the multifunctional polypeptide CAD against limited proteolysis, and also stabilize the thermolabile part-reactions of the carbamoyl-phosphate synthase II domains within the CAD polypeptide

1986 ◽  
Vol 236 (2) ◽  
pp. 327-335 ◽  
Author(s):  
E A Carrey
Keyword(s):  
Conformational Stability ◽  
Limited Proteolysis ◽  
Nucleotide Binding ◽  
The Other ◽  
Aspartate Transcarbamoylase ◽  
Biosynthetic Enzymes ◽  
Carbamoyl Phosphate ◽  
Nitrogen Donor ◽  
Phosphate Synthase

Improved methodologies are described which allow the measurement of the part-reactions, with glutamine or ammonia as nitrogen donor, of mammalian carbamoyl-phosphate synthase II (EC 6.3.5.5) through the incorporation of [14C]bicarbonate into either carbamoyl phosphate or carbamoylaspartate. The enzyme is part of the multifunctional polypeptide (CAD) which also comprises the pyrimidine-biosynthetic enzymes aspartate transcarbamoylase (EC 2.1.3.2) and dihydro-orotase (EC 3.5.2.3). The conformational stability of the carbamoyl-phosphate synthase was investigated through the inactivation of the part-reactions which occurred during incubation at 37 degrees C. The domain involved in the removal of the amide N from glutamine was more thermolabile than the ammonia-dependent synthase moiety. The former activity was stabilized in the presence of sodium aspartate or MgATP, whereas the latter was stabilized by MgATP and MgUTP. Binding of MgUTP and MgATP to CAD restricted the initial proteolysis by trypsin and elastase of one or both regions linking the carbamoyl-phosphate synthase domain to the other major domains. A model is described to account for both aspects of nucleotide binding to CAD; these stabilizing effects may be important in the cell, where similar concentrations of nucleotides are found.

scholarly journals Increased Occurrence of Valproic Acid-Induced Hyperammonemia in Carriers of T1405N Polymorphism in Carbamoyl Phosphate Synthetase 1 Gene

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Piotr K. Janicki ◽  
Dmitri Bezinover ◽  
Marek Postula ◽  
Robert S. Thompson ◽  
Jayant Acharya ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Significant Risk ◽  
Epileptic Seizures ◽  
Normal Liver ◽  
Significant Risk Factor ◽  
Ammonia Level ◽  
Carrier Status ◽  
Carbamoyl Phosphate ◽  
Caucasian Patients ◽  
Patients With Epilepsy

Numerous cases of severe and life-threatening hyperammonemia (HA) related to the treatment of epileptic seizures with valproic acid (VPA) have been previously reported in the medical literature. The aim of this prospective, multicenter study was to verify the putative association between T1405 polymorphism and occurrence of VPA-induced HA in the cohort of 142 adult Caucasian patients with epilepsy treated with VPA for at least 1 year and with normal liver functions. The nonsynonymous T1405N polymorphism genotyping was performed by real-time TaqMan PCR genotyping. In addition to plasma ammonia level, concentrations of liver enzymes and total VPA were measured in plasma with standard laboratory methods. HA (defined as ammonia plasma level >65 μmol/L) was observed in total of 11 (7.7%) of patients treated with VPA, and the carrier status for the investigated polymorphism was significantly (P=0.009, odds ratio 5.4 with 95% confidence interval of 1.58–18.43) associated with the occurrence of HA. The results of this study support a notion that in the Caucasian patients with epilepsy undergoing VPA therapy, a T1405N (4217C > A, rs1047891) nonsynonymous variant was a significant risk factor for the occurrence of HA, even in patients with normal plasma levels of VPA.

Regulation of carbamoyl-phosphate synthase II

1986 ◽  
Vol 25 ◽  
pp. 65-83 ◽  
Author(s):  
George Weber ◽  
Melissa Reardon
Keyword(s):  
Carbamoyl Phosphate ◽  
Phosphate Synthase
Sign in / Sign up

Export Citation Format

Share Document