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N-acetylglutamate synthase

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
N Haskins, A Mumo, P H Brown, M Tuchman, H Morizono, L Caldovic
N-acetylglutamate synthase (NAGS; E.C. 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
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
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...
September 10, 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
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
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
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
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
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
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
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
Masaki Takayanagi
No abstract text is available yet for this article.
July 2015: Journal of Human Genetics
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
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
J Lazier, S M Lupichuk, I Sosova, A A Khan
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...
October 2014: Current Oncology
Giora van Straten, Frank G van Steenbeek, Guy C M Grinwis, Robert P Favier, Anne Kummeling, Ingrid H van Gils, Hille Fieten, Marian J A Groot Koerkamp, Frank C P Holstege, Jan Rothuizen, Bart Spee
The detoxification of ammonia occurs mainly through conversion of ammonia to urea in the liver via the urea cycle and glutamine synthesis. Congenital portosystemic shunts (CPSS) in dogs cause hyperammonemia eventually leading to hepatic encephalopathy. In this study, the gene expression of urea cycle enzymes (carbamoylphosphate synthetase (CPS1), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase (ARG1)), N-acetylglutamate synthase (NAGS), Glutamate dehydrogenase (GLUD1), and glutamate-ammonia ligase (GLUL) was evaluated in dogs with CPSS before and after surgical closure of the shunt...
2014: PloS One
Kazuyuki Inoue, Eri Suzuki, Toshiki Takahashi, Yoshiaki Yamamoto, Rei Yazawa, Yukitoshi Takahashi, Katsumi Imai, Kou Miyakawa, Yushi Inoue, Daiki Tsuji, Hideki Hayashi, Kunihiko Itoh
Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms in the genes encoding carbamoyl-phosphate synthase 1 (CPS1) and N-acetylglutamate synthase (NAGS) were recently reported to be risk factors for the development of hyperammonemia during valproic acid-based therapy. This study aimed to examine the influence of patient characteristics, including polymorphisms in CPS1 4217C>A and NAGS -3064C>A, on the development of hyperammonemia in Japanese pediatric epilepsy patients...
August 2014: Epilepsy Research
Ljubica Caldovic, Nantaporn Haskins, Amy Mumo, Himani Majumdar, Mary Pinter, Mendel Tuchman, Alison Krufka
The urea cycle converts ammonia, a waste product of protein catabolism, into urea. Because fish dispose ammonia directly into water, the role of the urea cycle in fish remains unknown. Six enzymes, N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase III, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase and arginase 1, and two membrane transporters, ornithine transporter and aralar, comprise the urea cycle. The genes for all six enzymes and both transporters are present in the zebrafish genome...
2014: PloS One
Kathrin Petri, Frederik Walter, Marcus Persicke, Christian Rückert, Jörn Kalinowski
BACKGROUND: Arginine biosynthesis in Corynebacterium glutamicum consists of eight enzymatic steps, starting with acetylation of glutamate, catalysed by N-acetylglutamate synthase (NAGS). There are different kinds of known NAGSs, for example, "classical" ArgA, bifunctional ArgJ, ArgO, and S-NAGS. However, since C. glutamicum possesses a monofunctional ArgJ, which catalyses only the fifth step of the arginine biosynthesis pathway, glutamate must be acetylated by an as of yet unknown NAGS gene...
2013: BMC Genomics
S Adam, M F Almeida, M Assoun, J Baruteau, S M Bernabei, S Bigot, H Champion, A Daly, M Dassy, S Dawson, M Dixon, K Dokoupil, S Dubois, C Dunlop, S Evans, F Eyskens, A Faria, E Favre, C Ferguson, C Goncalves, J Gribben, M Heddrich-Ellerbrok, C Jankowski, R Janssen-Regelink, C Jouault, C Laguerre, S Le Verge, R Link, S Lowry, K Luyten, A Macdonald, C Maritz, S McDowell, U Meyer, A Micciche, M Robert, L V Robertson, J C Rocha, C Rohde, I Saruggia, E Sjoqvist, J Stafford, A Terry, R Thom, K Vande Kerckhove, M van Rijn, A van Teeffelen-Heithoff, A van Wegberg, K van Wyk, C Vasconcelos, H Vestergaard, D Webster, F J White, J Wildgoose, H Zweers
BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported...
December 2013: Molecular Genetics and Metabolism
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