Role of the Hinge Loop Linking the N- and C-Terminal Domains of the Amidotransferase Subunit of Carbamoyl Phosphate Synthetase

2000 ◽  
Vol 380 (1) ◽  
pp. 174-180 ◽  
Author(s):  
Xinyi Huang ◽  
Frank M. Raushel
Keyword(s):  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Terminal Domains

scholarly journals Adaptative increase of ornithine production and decrease of ammonia metabolism in rat colonocytes after hyperproteic diet ingestion

2004 ◽  
Vol 287 (2) ◽  
pp. G344-G351 ◽  
Author(s):  
Béatrice Mouillé ◽  
Véronique Robert ◽  
François Blachier
Keyword(s):  
Cell Metabolism ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Ammonia Metabolism ◽  
Ornithine Carbamoyl Transferase ◽  
Urea Production ◽  
Colonic Lumen ◽  
Isocaloric Diets ◽  
The One

Chronic high-protein consumption leads to increased concentrations of NH4+/NH3 in the colon lumen. We asked whether this increase has consequences on colonic epithelial cell metabolism. Rats were fed isocaloric diets containing 20 (P20) or 58% (P58) casein as the protein source for 7 days. NH4+/NH3 concentration in the colonic lumen and in the colonic vein blood as well as ammonia metabolism by isolated surface colonic epithelial cells was determined. After 2 days of consumption of the P58 diet, marked increases of luminal and colonic vein blood NH4+/NH3 concentrations were recorded when compared with the values obtained in the P20 group. Colonocytes recovered from the P58 group were characterized at that time and thereafter by an increased capacity for l-ornithine and urea production through arginase ( P < 0.05). l-Ornithine was mostly used in the presence of NH4Cl for the synthesis of the metabolic end product l-citrulline. After 7 days of the P58 diet consumption, however, the ammonia metabolism into l-citrulline was found lower ( P < 0.01) when compared with the values measured in the colonocytes recovered from the P20 group despite any decrease in the related enzymatic activities (i.e., carbamoyl-phosphate synthetase I and ornithine carbamoyl transferase). This decrease was found to coincide with a return of blood NH4+/NH3 concentration in colonic portal blood to values close to the one recorded in the P20 group. In response to increased NH4+/NH3 concentration in the colon, the increased capacity of the colonocytes to synthesize l-ornithine is likely to correspond to an elevated l-ornithine requirement for the elimination of excessive blood ammonia in the liver urea cycle. Moreover, in the presence of NH4Cl, colonocytes diminished their synthesis capacity of l-citrulline from l-ornithine, allowing a lower cellular utilization of this latter amino acid. These results are discussed in relationship with an adaptative process that would be related to both interorgan metabolism and to the role of the colonic epithelium as a first line of defense toward luminal NH4+/NH3 concentrations.

scholarly journals Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 744
Author(s):  
Dirk Andreas Ridder ◽  
Mario Schindeldecker ◽  
Arndt Weinmann ◽  
Kristina Berndt ◽  
Lana Urbansky ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cox Regression ◽  
Distant Metastases ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Independent Prognostic Marker ◽  
Pyrimidine Synthesis ◽  
Short Overall Survival

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.

scholarly journals Inhibition of ureagenesis by valproate in rat hepatocytes. Role of N-acetylglutamate and acetyl-CoA

1983 ◽  
Vol 216 (1) ◽  
pp. 233-236 ◽  
Author(s):  
F X Coude ◽  
G Grimber ◽  
P Parvy ◽  
D Rabier ◽  
F Petit
Keyword(s):  
Rat Hepatocytes ◽  
Urea Synthesis ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Acetyl Coa ◽  
Isolated Rat Hepatocytes ◽  
Cellular Concentration ◽  
Acetylglutamate Synthase ◽  
Ornithine Transcarbamoylase

Valproate (0.5-5 mM) strongly inhibited urea synthesis in isolated rat hepatocytes incubated with 10 mM-alanine and 3 mM-ornithine. Valproate at the same concentrations markedly decreased concentrations of N-acetylglutamate, an essential activator of carbamoyl-phosphate synthetase I (EC 6.3.4.16), in parallel with the inhibition of urea synthesis by valproate. This compound also lowered the cellular concentration of acetyl-CoA, a substrate of N-acetylglutamate synthase (EC 2.3.1.1); glutamate, aspartate and citrulline were similarly decreased. Valproate in a dose up to 2 mM did not significantly affect the cellular concentration of ATP and had no direct effect on N-acetylglutamate synthesis, carbamoyl-phosphate synthetase I and ornithine transcarbamoylase (EC 2.1.3.3) activities.

scholarly journals Role of dexamethasone and insulin on the development of the five urea-cycle enzymes in cultured rat foetal hepatocytes

1985 ◽  
Vol 225 (1) ◽  
pp. 271-274 ◽  
Author(s):  
A Husson ◽  
M Bouazza ◽  
C Buquet ◽  
R Vaillant
Keyword(s):  
Urea Cycle ◽  
Carbamoyl Phosphate Synthetase ◽  
Argininosuccinate Synthetase ◽  
Carbamoyl Phosphate ◽  
Urea Cycle Enzymes

The activity changes of the urea-cycle enzymes were monitored in cultured foetal hepatocytes after dexamethasone and insulin treatments. Addition of dexamethasone induced the development of carbamoyl-phosphate synthetase, argininosuccinate synthetase, argininosuccinase and arginase activities as soon as day 16.5 of gestation. When insulin was added together with dexamethasone, it markedly inhibited the steroid-induced increase in carbamoyl-phosphate synthetase, argininosuccinate synthetase and argininosuccinase activities.

Role of Conserved Residues within the Carboxy Phosphate Domain of Carbamoyl Phosphate Synthetase†

Biochemistry ◽  
1996 ◽  
Vol 35 (45) ◽  
pp. 14352-14361 ◽  
Author(s):  
Michelle A. Stapleton ◽  
Farah Javid-Majd ◽  
Marilyn F. Harmon ◽  
Brent A. Hanks ◽  
Jennifer L. Grahmann ◽  
...  
Keyword(s):  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Conserved Residues

Role of the four conserved histidine residues in the amidotransferase domain of carbamoyl phosphate synthetase

Biochemistry ◽  
1991 ◽  
Vol 30 (32) ◽  
pp. 7901-7907 ◽  
Author(s):  
Sophie Gaillard Miran ◽  
Sun Hee Chang ◽  
Frank M. Raushel
Keyword(s):  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Histidine Residues

scholarly journals Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential

2021 ◽  
Vol 22 (19) ◽  
pp. 10253
Author(s):  
Guanya Li ◽  
Dunhui Li ◽  
Tao Wang ◽  
Shanping He
Keyword(s):  
Metabolic Diseases ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Nucleotide Synthesis ◽  
Multifunctional Protein ◽  
The Past ◽  
Pyrimidine Nucleotide ◽  
Diagnostic Potential ◽  
Active Intermediates

CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.

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