Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (8)

Search Parameters:
Keywords = N-acetylglutamate synthase

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
20 pages, 821 KiB  
Article
Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry
by Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo and Pilar Quijada-Fraileadd Show full author list remove Hide full author list
Nutrients 2025, 17(7), 1173; https://doi.org/10.3390/nu17071173 - 28 Mar 2025
Viewed by 1208
Abstract
Background/Objectives: The present study updates the Spanish registry of patients with urea cycle disorders (UCD), originally established in 2013, to provide comprehensive epidemiological data and evaluate the impact of therapeutic strategies and newborn screening (NBS) on clinical outcomes. Methods: This retrospective, [...] Read more.
Background/Objectives: The present study updates the Spanish registry of patients with urea cycle disorders (UCD), originally established in 2013, to provide comprehensive epidemiological data and evaluate the impact of therapeutic strategies and newborn screening (NBS) on clinical outcomes. Methods: This retrospective, multicenter study focuses on 255 Spanish UCD patients. It includes all living and deceased cases up to February 2024, analyzing demographic, clinical, and biochemical variables. Results: The incidence of UCD in Spain over the past decade was 1:36,063 births. The most common defects were ornithine transcarbamylase deficiency (OTCD) and argininosuccinate synthetase deficiency. Early-onset (EO) cases comprised 32.7%, and 10.6% were diagnosed through NBS. Global mortality was 14.9%, higher in carbamoylphosphate synthetase 1 deficiency (36.8%) and male OTCD patients (32.1%) compared to other defects (p = 0.013). EO cases presented a higher mortality rate (35.8%) than late-onset (LO) cases (7.1%) (p < 0.0001). The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410–1793) than in survivors at 294 µmol/L (IQR 71–494) (p < 0.0001). Diagnosis through NBS improved survival and reduced neurological impairment compared to symptomatic diagnosis. Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. Conclusions: This updated analysis highlights the positive impact of NBS and advanced treatments on mortality and neurologic outcomes. Persistent neurological challenges underscore the need for further therapeutic strategies. Full article
(This article belongs to the Special Issue Nutritional Treatment and Screening for Inherited Metabolic Diseases)
Show Figures

Figure 1

13 pages, 3015 KiB  
Article
Generation of a Yeast Cell Model Potentially Useful to Identify the Mammalian Mitochondrial N-Acetylglutamate Transporter
by Ruggiero Gorgoglione, Roberta Seccia, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Alessia Lodi, Federica Marra, Eleonora Paradies, Luigi Palmieri, Vincenzo Coppola, Vincenza Dolce and Giuseppe Fiermonte
Biomolecules 2023, 13(5), 808; https://doi.org/10.3390/biom13050808 - 10 May 2023
Cited by 3 | Viewed by 2905
Abstract
The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy [...] Read more.
The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy of this experimental approach is constrained to the commercial availability of the radiolabeled substrate to be used in the transport assays. A striking example is that of N-acetylglutamate (NAG), an essential regulator of the carbamoyl synthetase I activity and the entire urea cycle. Mammals cannot modulate mitochondrial NAG synthesis but can regulate the levels of NAG in the matrix by exporting it to the cytosol, where it is degraded. The mitochondrial NAG transporter is still unknown. Here, we report the generation of a yeast cell model suitable for identifying the putative mammalian mitochondrial NAG transporter. In yeast, the arginine biosynthesis starts in the mitochondria from NAG which is converted to ornithine that, once transported into cytosol, is metabolized to arginine. The deletion of ARG8 makes yeast cells unable to grow in the absence of arginine since they cannot synthetize ornithine but can still produce NAG. To make yeast cells dependent on a mitochondrial NAG exporter, we moved most of the yeast mitochondrial biosynthetic pathway to the cytosol by expressing four E. coli enzymes, argB-E, able to convert cytosolic NAG to ornithine. Although argB-E rescued the arginine auxotrophy of arg8∆ strain very poorly, the expression of the bacterial NAG synthase (argA), which would mimic the function of a putative NAG transporter increasing the cytosolic levels of NAG, fully rescued the growth defect of arg8∆ strain in the absence of arginine, demonstrating the potential suitability of the model generated. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
Show Figures

Figure 1

13 pages, 4601 KiB  
Article
Construction of an Escherichia coli Strain Capable of Utilizing Steamed Rice as the Sole Carbon and Energy Source by Extracellular Expression of Amylase and Its Use for the Production of Putrescine
by Hideyuki Suzuki, Nana Iwamoto and Manami Nishimura
Appl. Microbiol. 2023, 3(2), 375-387; https://doi.org/10.3390/applmicrobiol3020026 - 24 Apr 2023
Cited by 1 | Viewed by 6140
Abstract
The amyE gene encoding α-amylase from Bacillus subtilis 168 was fused to several genes, the products of which are membrane proteins to express AmyE extracellularly. Genes of CapA, a subunit of the capsular poly-γ-glutamate synthetase of Bacillus subtilis subsp. natto; YiaTR232 [...] Read more.
The amyE gene encoding α-amylase from Bacillus subtilis 168 was fused to several genes, the products of which are membrane proteins to express AmyE extracellularly. Genes of CapA, a subunit of the capsular poly-γ-glutamate synthetase of Bacillus subtilis subsp. natto; YiaTR232, the first 232 residues of YiaT, an outer membrane protein of Escherichia coli K-12; and PgsA, cytidine 5′-diphosphate-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase of B. subtilis subsp. natto, were used. The Escherichia coli strain harboring the plasmid carrying the pgsA-amyE fusion expressed a very high level of amylase not only on the extracellular surface of the cells but also in the medium and the intracellular space and solubilized steamed rice in two days. The N-terminal amino acid sequence of the amylase purified from the culture medium (Ser-Ala-Glu-Thr-Ala) indicated that it was cleaved at the signal peptide cleavage site of AmyE. The strain SH2204, transformed with pKN11 carrying speA (arginine decarboxylase gene), speB (agmatinase gene) and argAATG Y19C (N-acetylglutamate synthase gene) and pMAN63 carrying pgsA-amyE produced 1.2 mM putrescine from 5 mM arginine by adding 0.5 mM IPTG in eight days. Discarding steamed rice is not only a food loss, but also a waste of renewable, biogenerated resources due to the burning of it with petroleum, increasing carbon dioxide in the atmosphere. The E. coli strain developed in this study can help solve this problem because it can produce an important chemical using steamed rice as the sole carbon and energy source. Full article
Show Figures

Figure 1

26 pages, 4629 KiB  
Article
NAGS, CPS1, and SLC25A13 (Citrin) at the Crossroads of Arginine and Pyrimidines Metabolism in Tumor Cells
by Melissa Owusu-Ansah, Nikita Guptan, Dylon Alindogan, Michio Morizono and Ljubica Caldovic
Int. J. Mol. Sci. 2023, 24(7), 6754; https://doi.org/10.3390/ijms24076754 - 4 Apr 2023
Cited by 9 | Viewed by 4003
Abstract
Urea cycle enzymes and transporters collectively convert ammonia into urea in the liver. Aberrant overexpression of carbamylphosphate synthetase 1 (CPS1) and SLC25A13 (citrin) genes has been associated with faster proliferation of tumor cells due to metabolic reprogramming that increases the activity [...] Read more.
Urea cycle enzymes and transporters collectively convert ammonia into urea in the liver. Aberrant overexpression of carbamylphosphate synthetase 1 (CPS1) and SLC25A13 (citrin) genes has been associated with faster proliferation of tumor cells due to metabolic reprogramming that increases the activity of the CAD complex and pyrimidine biosynthesis. N-acetylglutamate (NAG), produced by NAG synthase (NAGS), is an essential activator of CPS1. Although NAGS is expressed in lung cancer derived cell lines, expression of the NAGS gene and its product was not evaluated in tumors with aberrant expression of CPS1 and citrin. We used data mining approaches to identify tumor types that exhibit aberrant overexpression of NAGS, CPS1, and citrin genes, and evaluated factors that may contribute to increased expression of the three genes and their products in tumors. Median expression of NAGS, CPS1, and citrin mRNA was higher in glioblastoma multiforme (GBM), glioma, and stomach adenocarcinoma (STAD) samples compared to the matched normal tissue. Median expression of CPS1 and citrin mRNA was higher in the lung adenocarcinoma (LUAD) sample while expression of NAGS mRNA did not differ. High NAGS expression was associated with an unfavorable outcome in patients with glioblastoma and GBM. Low NAGS expression was associated with an unfavorable outcome in patients with LUAD. Patterns of DNase hypersensitive sites and histone modifications in the upstream regulatory regions of NAGS, CPS1, and citrin genes were similar in liver tissue, lung tissue, and A549 lung adenocarcinoma cells despite different expression levels of the three genes in the liver and lung. Citrin gene copy numbers correlated with its mRNA expression in glioblastoma, GBM, LUAD, and STAD samples. There was little overlap between NAGS, CPS1, and citrin sequence variants found in patients with respective deficiencies, tumor samples, and individuals without known rare genetic diseases. The correlation between NAGS, CPS1, and citrin mRNA expression in the individual glioblastoma, GBM, LUAD, and STAD samples was very weak. These results suggest that the increased cytoplasmic supply of either carbamylphosphate, produced by CPS1, or aspartate may be sufficient to promote tumorigenesis, as well as the need for an alternative explanation of CPS1 activity in the absence of NAGS expression and NAG. Full article
(This article belongs to the Section Biochemistry)
Show Figures

Figure 1

11 pages, 1243 KiB  
Article
Optimization of L-Citrulline Operon in Corynebacterium glutamicum for L-Citrulline Production
by Zaiwei Man, Jin Li, Huihui Cui, Zhiqiang Cai and Jing Guo
Processes 2022, 10(10), 2153; https://doi.org/10.3390/pr10102153 - 21 Oct 2022
Cited by 1 | Viewed by 2996
Abstract
L-citrulline plays important roles in many physiological processes, and its application range is expanding rapidly. Corynebacterium glutamicum strains have the potential to be efficient L-citrulline producers. In this study, we performed optimization of L-citrulline biosynthesis operon in C. glutamicum ATCC13032 for L-citrulline production. [...] Read more.
L-citrulline plays important roles in many physiological processes, and its application range is expanding rapidly. Corynebacterium glutamicum strains have the potential to be efficient L-citrulline producers. In this study, we performed optimization of L-citrulline biosynthesis operon in C. glutamicum ATCC13032 for L-citrulline production. Chromosomal integration of the integral argBEc gene from Escherichia coli (encoding natively insensitive N-acetylglutamate kinase), the deletion of the argR gene (encoding repressor ArgR), and the deletion of the argG gene (encoding argininosuccinate synthase) were achieved simultaneously by one-step genome modification and by obtaining the L-citrulline-producing strain. Then, plasmid-based overexpression of the optimized L-citrulline operon was carried out and the L-citrulline production was further improved. In fed-batch fermentation, the L-citrulline production and yield from glucose of the final strain reached 26.7 g/L and 0.18 g/g, respectively. These results indicate that optimization of L-citrulline operon in C. glutamicum is effective to construct the L-citrulline over-producing strain. Full article
Show Figures

Figure 1

9 pages, 1756 KiB  
Case Report
Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature
by Catia Cavicchi, Chiara Chilleri, Antonella Fioravanti, Lorenzo Ferri, Francesco Ripandelli, Cinzia Costa, Paolo Calabresi, Paolo Prontera, Francesca Pochiero, Elisabetta Pasquini, Silvia Funghini, Giancarlo La Marca, Maria Alice Donati and Amelia Morrone
Int. J. Mol. Sci. 2018, 19(2), 345; https://doi.org/10.3390/ijms19020345 - 24 Jan 2018
Cited by 10 | Viewed by 6156
Abstract
N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent [...] Read more.
N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent headaches who experienced an acute onset of NAGSD. As very few papers focus on headaches in UCDs, we also report a literature review of types and pathophysiologic mechanisms of UCD-related headaches. In our case, headaches had been present since puberty (3–4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. Identification of the new homozygous c.344C>T (p.Ala115Val) NAGS variant allowed the definite diagnosis of NAGSD. Bioinformatic analysis suggested that an order/disorder alteration of the mutated form could affect the arginine-binding site, resulting in poor enzyme activation and late-onset presentation. After optimized treatment for NAGSD, ammonia and amino acid levels were constantly normal and prevented other headache bouts. The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Show Figures

Graphical abstract

19 pages, 4322 KiB  
Article
The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms
by Dashuang Shi, Norma M. Allewell and Mendel Tuchman
Int. J. Mol. Sci. 2015, 16(6), 13004-13022; https://doi.org/10.3390/ijms160613004 - 9 Jun 2015
Cited by 28 | Viewed by 11276
Abstract
N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and l-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase [...] Read more.
N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and l-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle. Recent work has shown that several different genes encode enzymes that can catalyze NAG formation. A bifunctional enzyme was identified in certain bacteria, which catalyzes both NAGS and N-acetylglutamate kinase (NAGK) activities, the first two steps of the arginine biosynthetic pathway. Interestingly, these bifunctional enzymes have higher sequence similarity to vertebrate NAGS than those of the classical (mono-functional) bacterial NAGS. Solving the structures for both classical bacterial NAGS and bifunctional vertebrate-like NAGS/K has advanced our insight into the regulation and catalytic mechanisms of NAGS, and the evolutionary relationship between the two NAGS groups. Full article
(This article belongs to the Special Issue Protein Crystallography in Molecular Biology 2015)
Show Figures

Graphical abstract

4 pages, 1383 KiB  
Case Report
Hyperammonemic Encephalopathy in An Adenocarcinoma Patient Managed with Carglumic Acid
by J. Lazier, S.M. Lupichuk, I. Sosova and A.A. Khan
Curr. Oncol. 2014, 21(5), 736-739; https://doi.org/10.3747/co.21.2076 - 1 Oct 2014
Cited by 13 | Viewed by 890
Abstract
Hyperammonemic encephalopathy (HE) is a rare complication of malignancy and chemotherapy. Although the cause of HE is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could [...] Read more.
Hyperammonemic encephalopathy (HE) is a rare complication of malignancy and chemotherapy. Although the cause of HE is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could lead to inhibition of N-acetylglutamate synthase (NAGS), a urea cycle enzyme, resulting in hyperammonemia. We present a case of chemotherapy-induced HE in a patient with no underlying primary urea cycle disorder. The patient had a successful trial of carglumic acid (a synthetic analog of the product of NAGS), which suggests that, at least in some cases, HE can be treated by overcoming proximal inhibition of the urea cycle. Further, our case is the first in the literature to exclude genetic defects and disorders of the proximal urea cycle, suggesting that hyperammonemia in these patients is probably secondary to chemotherapy. Full article
Back to TopTop