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N-acetylglutamate synthase

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https://www.readbyqxmd.com/read/29364180/late-onset-n-acetylglutamate-synthase-deficiency-report-of-a-paradigmatic-adult-case-presenting-with-headaches-and-review-of-the-literature
#1
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, Amelia Morrone
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...
January 24, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29094226/aminoacidopathies-prevalence-etiology-screening-and-treatment-options
#2
REVIEW
Muhammad Wasim, Fazli Rabbi Awan, Haq Nawaz Khan, Abdul Tawab, Mazhar Iqbal, Hina Ayesha
Inborn errors of metabolism (IEMs) are a group of inherited metabolic disorders which are caused by mutations in the specific genes that lead to impaired proteins or enzymes production. Different metabolic pathways are perturbed due to the deficiency or lack of enzymes. To date, more than 500 IEMs have been reported with most of them being untreatable. However, fortunately 91 such disorders are potentially treatable, if diagnosed at an earlier stage of life. IEMs have been classified into different categories and one class of IEMs, characterized by the physiological disturbances of amino acids is called as aminoacidopathies...
November 1, 2017: Biochemical Genetics
https://www.readbyqxmd.com/read/29071700/-treatment-of-encephalopathy-by-means-of-valproic-acid-with-carglumic-acid-two-case-reports-and-a-review-of-the-literature
#3
J J Nava-Mateos, P Roiz-Rey, J Diaz Alvarez-Mediavilla, D Cebrian-Novella, V Gomez-Del Olmo, L Ceberio-Hualde
INTRODUCTION: Valproic acid (VPA) is a drug mainly used to treat epilepsy. Hyperammonaemic encephalopathy due to VPA is a rare but serious complication. The mechanism by which VPA influences the increase in ammonia consists in blocking the urea cycle, thereby inhibiting N-acetylglutamate synthase and diminishing acetyl coenzyme A. Generally, the treatment employed has been to withdraw VPA and to administer arginine, carnitine, antibiotics, glucose and protein restriction. Previous experience with carglumic acid is limited to reports of isolated cases of paediatric patients...
November 1, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/29055942/interaction-of-excitatory-amino-acid-transporters-1-3-eaat1-eaat2-eaat3-with-n-carbamoylglutamate-and-n-acetylglutamate
#4
Birgitta C Burckhardt, Gerhard Burckhardt
BACKGROUND/AIMS: Inborn deficiency of the N-acetylglutamate synthase (NAGS) impairs the urea cycle and causes neurotoxic hyperammonemia. Oral administration of N-carbamoylglutamate (NCG), a synthetic analog of N-acetylglutamate (NAG), successfully decreases plasma ammonia levels in the affected children. Due to structural similarities to glutamate, NCG may be absorbed in the intestine and taken up into the liver by excitatory amino acid transporters (EAATs). METHODS: Using Xenopus laevis oocytes expressing either human EAAT1, 2, or 3, or human sodium-dependent dicarboxylate transporter 3 (NaDC3), transport-associated currents of NAG, NCG, and related dicarboxylates were assayed...
October 20, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28943401/crystal-structure-of-l-glutamate-n-acetyltransferase-arga-from-mycobacterium-tuberculosis
#5
Xiuna Yang, Lijie Wu, Yajun Ran, Ao Xu, Bing Zhang, Xiaolin Yang, Rongguang Zhang, Zihe Rao, Jun Li
l-arginine is used as a source of both carbon and nitrogen in Mycobacterium tuberculosis (Mtb) and its biosynthesis is essential for the pathogen's survival. MtbArgA (Rv2747) catalyzes the initial step in l-arginine biosynthesis by transferring an acetyl group from acetyl coenzyme A (AcCoA) to l-glutamate. MtbArgA is a class III N-acetylglutamate synthase (NAGS) with no structural information. Here, we solved the crystal structure of MtbArgA complexed with AcCoA and l-glutamate. The overall structure adopts a classic fold of the GCN5-related N-acetyltransferase (GNAT) family, characterized by a "V"-shaped cleft and β-bulge, but uses distinct residues for the binding and reaction of AcCoA...
September 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28888854/quantitation-of-phenylbutyrate-metabolites-by-uplc-ms-ms-demonstrates-inverse-correlation-of-phenylacetate-phenylacetylglutamine-ratio-with-plasma-glutamine-levels
#6
Yi Jiang, Mohammed Almannai, V Reid Sutton, Qin Sun, Sarah H Elsea
Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels...
August 31, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28281899/targeting-cps1-in-the-treatment-of-carbamoyl-phosphate-synthetase-1-cps1-deficiency-a-urea-cycle-disorder
#7
REVIEW
Carmen Diez-Fernandez, Johannes Häberle
Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches...
April 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/27934952/effect-of-arginine-on-oligomerization-and-stability-of-n-acetylglutamate-synthase
#8
N Haskins, A Mumo, P H Brown, M Tuchman, H Morizono, L Caldovic
N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals...
December 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27771289/a-novel-uplc-ms-ms-based-method-to-determine-the-activity-of-n-acetylglutamate-synthase-in-liver-tissue
#9
Marli Dercksen, Marinus Duran, Lodewijk IJlst, Wim Kulik, Jos P N Ruiter, Arno van Cruchten, Mendel Tuchman, Ronald J A Wanders
BACKGROUND: N-acetylglutamate synthase (NAGS) plays a key role in the removal of ammonia via the urea cycle by catalyzing the synthesis of N-acetylglutamate (NAG), the obligatory cofactor in the carbamyl phosphate synthetase 1 reaction. Enzymatic analysis of NAGS in liver homogenates has remained insensitive and inaccurate, which prompted the development of a novel method. METHODS: UPLC-MS/MS was used in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d5 acid) dilution for the quantitative detection of NAG produced by the NAGS enzyme...
December 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27613354/citrulline-for-urea-cycle-disorders-in-japan
#10
Kenichi Tanaka, Kimitoshi Nakamura, Shirou Matsumoto, Jun Kido, Hiroshi Mitsubuchi, Toshihiro Ohura, Fumio Endo
BACKGROUND: The amino acid l-citrulline is used as a therapeutic agent for urea cycle disorders (UCD) including ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase I deficiency (CPSD), and N-acetylglutamate synthase deficiency. There are few reports, however, on the use of l-citrulline in Japan and little consensus regarding the effects of l-citrulline. METHODS: We conducted a questionnaire survey of patients undergoing l-citrulline treatment for a UCD to evaluate the current status of this therapy...
April 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/27570737/n-acetylglutamate-synthase-deficiency-novel-mutation-associated-with-neonatal-presentation-and-literature-review-of-molecular-and-phenotypic-spectra
#11
Eiman H Al Kaabi, Ayman W El-Hattab
The urea cycle is the main pathway for the disposal of excess nitrogen. Carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG), and thus N-acetylglutamate synthase (NAGS) is an essential part of the urea cycle. Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. Here we report an infant with NAGS deficiency who presented with neonatal hyperammonemia...
September 2016: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/27215558/improving-long-term-outcomes-in-urea-cycle-disorders-report-from-the-urea-cycle-disorders-consortium
#12
Susan E Waisbren, Andrea L Gropman, Mark L Batshaw
The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN])...
July 2016: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/27147233/hyperammonemia-due-to-adult-onset-n-acetylglutamate-synthase-deficiency
#13
Anne-Els van de Logt, Leo A J Kluijtmans, Marleen C D G Huigen, Mirian C H Janssen
A 59-year-old woman, with a medical history of intellectual disability after perinatal asphyxia, was admitted because of coma due to hyperammonemia after she was treated for a fracture of the pelvis. The ammonia level was 280 μM. Acquired disorders as explanation for the hyperammonemia were excluded. Metabolic investigations showed an elevated glutamine and alanine and low citrulline, suspect for a urea cycle defect (UCD). Orotic acid could not be demonstrated in urine. DNA investigations were negative for mutations or deletions in the OTC and CPS1 gene, but revealed a homozygous c...
2017: JIMD Reports
https://www.readbyqxmd.com/read/27030250/carglumic-acid-enhances-rapid-ammonia-detoxification-in-classical-organic-acidurias-with-a-favourable-risk-benefit-profile-a-retrospective-observational-study
#14
MULTICENTER STUDY
Vassili Valayannopoulos, Julien Baruteau, Maria Bueno Delgado, Aline Cano, Maria L Couce, Mireia Del Toro, Maria Alice Donati, Angeles Garcia-Cazorla, David Gil-Ortega, Pedro Gomez-de Quero, Nathalie Guffon, Floris C Hofstede, Sema Kalkan-Ucar, Mahmut Coker, Rosa Lama-More, Mercedes Martinez-Pardo Casanova, Agustin Molina, Samia Pichard, Francesco Papadia, Patricia Rosello, Celine Plisson, Jeannie Le Mouhaer, Anupam Chakrapani
BACKGROUND: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation...
March 31, 2016: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/26521658/controlling-the-transcription-levels-of-arggh-redistributed-l-arginine-metabolic-flux-in-n-acetylglutamate-kinase-and-argr-deregulated-corynebacterium-crenatum
#15
Qinqin Zhao, Yuchang Luo, Wenfang Dou, Xian Zhang, Xiaomei Zhang, Weiwei Zhang, Meijuan Xu, Yan Geng, Zhiming Rao, Zhenghong Xu
Corynebacterium crenatum SYPA5-5, an L-arginine high-producer obtained through multiple mutation-screening steps, had been deregulated by the repression of ArgR that inhibits L-arginine biosynthesis at genetic level. Further study indicated that feedback inhibition of SYPA5-5 N-acetylglutamate kinase (CcNAGK) by L-arginine, as another rate-limiting step, could be deregulated by introducing point mutations. Here, we introduced two of the positive mutations (H268N or R209A) of CcNAGK into the chromosome of SYPA5-5, however, resulting in accumulation of large amounts of the intermediates (L-citrulline and L-ornithine) and decreased production of L-arginine...
January 2016: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/26188117/acute-and-sub-acute-oral-toxicological-evaluations-and-mutagenicity-of-n-carbamylglutamate-ncg
#16
Xin Wu, Dan Wan, Chunyan Xie, Tiejun Li, Ruilin Huang, Xugang Shu, Zheng Ruan, Zeyuan Deng, Yulong Yin
N-carbamylglutamate (NCG) is a metabolically stable analog of N-acetylglutamate that activates carbamyl phosphate synthase-1, a key arginine synthesis enzyme in enterocytes. It is a promising feed additive in swine in China. In this study, we assessed the acute and sub-acute toxicity of NCG in Sprague-Dawley (SD) rats. All rats survived until they were killed at a scheduled time point. No adverse effects or mortality was observed following acute oral administration of 5000 mg/kg NCG to SD rats. No biologically significant or test substance-related differences were observed in body weights, feed consumption, clinical signs, a functional observational battery, organ weights, histopathology, ophthalmology, hematology, coagulation, and clinical chemistry parameters in any of the treatment groups in sub-acute doses of NCG at target concentrations corresponding to 500, 2000, and 3000 mg/kg/day for 28 days neither...
October 2015: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/26068232/the-n-acetylglutamate-synthase-family-structures-function-and-mechanisms
#17
REVIEW
Dashuang Shi, Norma M Allewell, Mendel Tuchman
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...
2015: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/25994872/a-commentary-on-short-term-efficacy-of-n-carbamylglutamate-in-a-patient-with-n-acetylglutamate-synthase-deficiency
#18
Masaki Takayanagi
No abstract text is available yet for this article.
July 2015: Journal of Human Genetics
https://www.readbyqxmd.com/read/25787344/short-term-efficacy-of-n-carbamylglutamate-in-a-patient-with-n-acetylglutamate-synthase-deficiency
#19
Ja Hye Kim, Yoo-Mi Kim, Beom Hee Lee, Ja Hyang Cho, Gu-Hwan Kim, Jin-Ho Choi, Han-Wook Yoo
N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error regarding the urea cycle, however, its diagnosis is important as it can be effectively treated by N-carbamylglutamate. We evaluated a patient with NAGS deficiency who harbored two novel NAGS mutations and who showed excellent responsiveness during 1 year of N-carbamylglutamate treatment.
July 2015: Journal of Human Genetics
https://www.readbyqxmd.com/read/25354943/transporters-involved-in-renal-excretion-of-n-carbamoylglutamate-an-orphan-drug-to-treat-inborn-n-acetylglutamate-synthase-deficiency
#20
Elisabeth Schwob, Yohannes Hagos, Gerhard Burckhardt, Birgitta C Burckhardt
Inborn defects in N-acetylglutamate (NAG) synthase (NAGS) cause a reduction of NAG, an essential cofactor for the initiation of the urea cycle. As a consequence, blood ammonium concentrations are elevated, leading to severe neurological disorders. The orphan drug N-carbamoylglutamate (NCG; Carbaglu), efficiently overcomes NAGS deficiency. However, not much is known about the transporters involved in the uptake, distribution, and elimination of the divalent organic anion NCG. Organic anion-transporting polypeptides (OATPs) as well as organic anion transporters (OATs) working in cooperation with sodium dicarboxylate cotransporter 3 (NaDC3) accept a wide variety of structurally unrelated drugs...
December 15, 2014: American Journal of Physiology. Renal Physiology
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