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n carbamyl glutamate

Dashuang Shi, Ljubica Caldovic, Mendel Tuchman
Carbamyl phosphate (CP) is well-known as an essential intermediate of pyrimidine and arginine/urea biosynthesis. Chemically, CP can be easily synthesized from dihydrogen phosphate and cyanate. Enzymatically, CP can be synthesized using three different classes of enzymes: (1) ATP-grasp fold protein based carbamyl phosphate synthetase (CPS); (2) Amino-acid kinase fold carbamate kinase (CK)-like CPS (anabolic CK or aCK); and (3) Catabolic transcarbamylase. The first class of CPS can be further divided into three different types of CPS as CPS I, CPS II, and CPS III depending on the usage of ammonium or glutamine as its nitrogen source, and whether N -acetyl-glutamate is its essential co-factor...
June 12, 2018: Biology
Dashuang Shi, Gengxiang Zhao, Nicholas Ah Mew, Mendel Tuchman
This study documents the disparate therapeutic effect of N-carbamyl-l-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme...
March 2017: Molecular Genetics and Metabolism
David Zimmerman, Joy J Goto, Viswanathan V Krishnan
Elevated incidences of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) is associated with β-methylamino-L-alanine (BMAA), a non-protein amino acid. In particular, the native Chamorro people living in the island of Guam were exposed to BMAA by consuming a diet based on the cycad seeds. Carbamylated forms of BMAA are glutamate analogues. The mechanism of neurotoxicity of the BMAA is not completely understood, and BMAA acting as a glutamate receptor agonist may lead to excitotoxicity that interferes with glutamate transport systems...
2016: PloS One
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 Millet, Pierre Bouzat, Thibaut Trouve-Buisson, Cécile Batandier, Karin Pernet-Gallay, Lucie Gaide-Chevronnay, Emmanuel L Barbier, Thierry Debillon, Eric Fontaine, Jean-François Payen
Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 μg/kg Cepo (TBI-Cepo)...
September 1, 2016: Journal of Neurotrauma
Carmen Díez-Fernández, José Gallego, Johannes Häberle, Javier Cervera, Vicente Rubio
Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is an inborn error of the urea cycle having autosomal (2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kDa C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS1, N-acetyl-L-glutamate (NAG), is bound or is not bound to it...
May 20, 2015: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Yuehong Wen, Tianlu Sheng, Zhenzhen Xue, Yong Wang, Chao Zhuo, Xiaoquan Zhu, Shengmin Hu, Xintao Wu
Utilizing the mixed-ligand strategy, a novel fourfold-interpenetrated 3D homochiral metal-organic framework (1) with rare pair quadruple-stranded helices was assembled from bpee (1,2-bis(4-pyridyl)ethylene) and NCG (N-carbamyl-l-glutamate). Changing the carbamyl substituent of NCG with benzoyl group (NBzG: N-benzoyl-l-glutamate), a non-interpenetrated 3D homochiral coordination polymer (2) composed of alternate right-handed and left-handed single helix was obtained. When p-tolylsulfonyl substituent was used instead, an interesting homochiral linear structure (3) was formed from mixed-ligand bpee and NTsG (N-p-tolylsulfonyl-l-glutamate), with all individual NTsG being lined up orderly...
April 20, 2015: Inorganic Chemistry
Nicholas Ah Mew, Robert McCarter, Yevgeny Daikhin, Uta Lichter-Konecki, Ilana Nissim, Marc Yudkoff, Mendel Tuchman
Identical studies using stable isotopes were performed before and after a 3-day trial of oral N-carbamyl-l-glutamate (NCG) in 5 subjects with late-onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in 1 subject.
August 2014: Journal of Pediatrics
Shengyun Tang, Yuanxing Wang, Pingwei Wen, Zhen Xin
A method was developed for the determination of N-carbamyl-L-glutamic acid (NCG) in feedstuff by high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The feedstuff samples were extracted with methanol, cleaned-up by a ProElut mixed-mode of strong anion exchange inverse column (PXA). Then the samples were separated with HPLC and detected with MS/MS in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI+). The fragment ions of m/z 148...
February 2014: Se Pu, Chinese Journal of Chromatography
Anouk Van Leynseele, Anna Jansen, Philippe Goyens, Geert Martens, Stefaan Peeters, An Jonckheere, Linda De Meirleir
Acute hyperammonemia has a variety of etiologies and clinical manifestations. If not treated early in neonates, it leads to irreversible brain damage or death. We present a 7-day-old female patient who was brought to the emergency department with drownsiness and vomiting. Metabolic work-up revealed a blood ammonia level of 290 μmol/L (normal <100 μmol/L in neonates) with a compensated respiratory alkalosis, normal glycaemia and lactate and absence of urinary ketones. Oral feeding was stopped, an infusion of 20 % glucose was started, and sodium benzoate and arginine hydrochloride were given...
December 2014: European Journal of Pediatrics
J S Pate, P Lindblad, C A Atkins
Freshly detached coralloid roots of several cycad species were found to bleed spontaneously from xylem, permitting identification of products of nitrogen transfer from symbiotic organ to host. Structural features relevant to the export of fixed N were described for Macrozamia riedlei (Fisch. ex Gaud.) Gardn. the principal species studied. Citrulline (Cit), glutamine (Gln) and glutamic acid (Glu), the latter usually in a lesser amount, were the principal translocated solutes in Macrozamia (5 spp.), Encephalartos (4 spp...
December 1988: Planta
Gengxiang Zhao, Zhongmin Jin, Norma M Allewell, Mendel Tuchman, Dashuang Shi
N-acetylglutamate synthase (NAGS) catalyzes the conversion of AcCoA and L-glutamate to CoA and N-acetyl-L-glutamate (NAG), an obligate cofactor for carbamyl phosphate synthetase I (CPSI) in the urea cycle. NAGS deficiency results in elevated levels of plasma ammonia which is neurotoxic. We report herein the first crystal structure of human NAGS, that of the catalytic N-acetyltransferase (hNAT) domain with N-acetyl-L-glutamate bound at 2.1 Å resolution. Functional studies indicate that the hNAT domain retains catalytic activity in the absence of the amino acid kinase (AAK) domain...
2013: PloS One
Nicolas Gauthier, Jiang Wei Wu, Shu Pei Wang, Pierre Allard, Orval A Mamer, Lawrence Sweetman, Ann B Moser, Lisa Kratz, Fernando Alvarez, Yves Robitaille, François Lépine, Grant A Mitchell
Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation...
2013: PloS One
Emilee Senkevitch, Juan Cabrera-Luque, Hiroki Morizono, Ljubica Caldovic, Mendel Tuchman
All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-l-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. Founder NAGS knockout heterozygous mice were obtained from the trans-NIH Knock-Out Mouse Project. Genotyping of the mice was performed by PCR and confirmed by Western blotting of liver and intestine...
June 2012: Molecular Genetics and Metabolism
Johannes Häberle
N-acetylglutamate synthase (NAGS) deficiency is a rare inborn error of metabolism affecting ammonia detoxification in the urea cycle. The product of NAGS is N-acetylglutamate which is the absolutely required allosteric activator of the first urea cycle enzyme carbamoylphosphate synthetase 1. In defects of NAGS, the urea cycle function can be severely affected resulting in fatal hyperammonemia in neonatal patients or at any later stage in life. NAGS deficiency can be treated with a structural analog of N-acetylglutamate, N-carbamyl-L-glutamate, which is available for enteral use as a licensed drug...
2011: Therapeutics and Clinical Risk Management
Sandra K Heibel, Nicholas Ah Mew, Ljubica Caldovic, Yevgeny Daikhin, Marc Yudkoff, Mendel Tuchman
N-acetylglutamate synthase (NAGS) catalyzes the conversion of glutamate and acetyl-CoA to NAG, the essential allosteric activator of carbamyl phosphate synthetase I, the first urea cycle enzyme in mammals. A 17-year-old female with recurrent hyperammonemia attacks, the cause of which remained undiagnosed for 8 years in spite of multiple molecular and biochemical investigations, showed markedly enhanced ureagenesis (measured by isotope incorporation) in response to N-carbamylglutamate (NCG). This led to sequencing of the regulatory regions of the NAGS gene and identification of a deleterious single-base substitution in the upstream enhancer...
October 2011: Human Mutation
Peter Gessler, Peter Buchal, Hans U Schwenk, Bendicht Wermuth
INTRODUCTION: N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment. CASE REPORT: We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction...
February 2010: European Journal of Pediatrics
Paul G Young, Clyde A Smith, Peter Metcalf, Edward N Baker
Folate derivatives are essential vitamins for cell growth and replication, primarily because of their central role in reactions of one-carbon metabolism. Folates require polyglutamation to be efficiently retained within the cell and folate-dependent enzymes have a higher affinity for the polyglutamylated forms of this cofactor. Polyglutamylation is dependent on the enzyme folylpolyglutamate synthetase (FPGS), which catalyzes the sequential addition of several glutamates to folate. FPGS is essential for the growth and survival of important bacterial species, including Mycobacterium tuberculosis, and is a potential drug target...
July 2008: Acta Crystallographica. Section D, Biological Crystallography
Virginie Levrat, Isabelle Forest, Alain Fouilhoux, Cécile Acquaviva, Christine Vianey-Saban, Nathalie Guffon
BACKGROUND: Hyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises. CASE PRESENTATION: We described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis...
2008: Orphanet Journal of Rare Diseases
P R McClure, G T Coker, K R Schubert
Detached roots and nodules of the N(2)-fixing species, Albus glutinosa (European black alder), actively assimilate CO(2). The maximum rates of dark CO(2) fixation observed for detached nodules and roots were 15 and 3 micromoles CO(2) fixed per gram dry weight per hour, respectively. The net incorporation of CO(2) in these tissues was catalyzed by phosphoenolpyruvate carboxylase which produces organic acids, some of which are used in the synthesis of the amino acids, aspartate, glutamate, and citrulline and by carbamyl phosphate synthetase...
March 1983: Plant Physiology
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