Transcriptional Regulation of N-Acetylglutamate Synthase

Heibel, Sandra Kirsch; López, Giselle Y.; Panglao, Maria; Sodha, Sonal; Mariño-Ramírez, Leonardo; Tuchman, Mendel; Caldovic, Ljubica

doi:10.1371/journal.pone.0029527

Cited by 28 publications

(46 citation statements)

References 93 publications

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“…NAG activates the first and rate-limiting enzyme of ureagenesis, carbamyl phosphate synthetase 1 (CPS1) (Fig. 1) (Heibel et al 2012). The enzyme that produces NAG from glutamate and Coenzyme A (CoA), NAG synthase (NAGS), is allosterically inhibited by arginine in microorganisms and plants but activated in mammals (Caldovic et al 2010).…”

Section: Metabolic Regulation Of Glutamate Utilizationmentioning

confidence: 99%

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Xie

Zhang

et al. 2014

Amino Acids

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The present review focuses on the physiological functions of glutamate-glutamine exchange involving placental amino acid transport and umbilical amino acid uptake in mammals (particularly in sows), with special emphasis on the associated regulating mechanisms. Glutamate plus glutamine are among the most abundant and the most utilized amino acids in fetus during late gestation. During pregnancy, amino acids, notably as precursors of macromolecules including proteins and nucleotides are involved in fetal development and growth. Amino acid concentrations in fetus are generally higher than in the mother. Among amino acids, the transport and metabolism of glutamate and glutamine during fetal development exhibit characteristics that clearly emphasize the importance of the interaction between the placenta and the fetal liver. Glutamate is quite remarkable among amino acids, which originate from the placenta, and is cleared from fetal plasma. In addition, the flux of glutamate through the placenta from the fetal plasma is highly correlated with the umbilical glutamate delivery rate. Glutamine plays a central role in fetal carbon and nitrogen metabolism and exhibits one of the highest fetal/maternal plasma ratio among all amino acids in human and other mammals. Glutamate is taken up by placenta from the fetal circulation and then converted to glutamine before being released back into the fetal circulation. Works are required on the glutamate-glutamine metabolism during late pregnancy in physiological and pathophysiological situations since such works may help to improve fetal growth and development both in humans and other mammals. Indeed, glutamine supplementation appears to ameliorate fetal growth retardation in sows and reduces preweaning mortality of piglets.

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Section: Metabolic Regulation Of Glutamate Utilizationmentioning

confidence: 99%

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Xie

Zhang

et al. 2014

Amino Acids

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“…The human NAGS gene is located on chromosome 17 within band 17q21.31 and spans approximately 8.5 kb. This includes seven exons that encode a 1605 bp open reading frame, six introns, a promoter, and an enhancer located about 3 kb upstream of the transcription start sites [45,47,[49][50][51]. The mouse Nags gene is located in the syntenic region on chromosome 11.…”

Section: Transcriptional Regulation Of Urea Cycle Genes 21 Transcripmentioning

confidence: 99%

“…The mouse Nags gene is located in the syntenic region on chromosome 11. Pairwise BLAST [52] was used for comparison of the regions upstream of the NAGS genes from seven mammals including human; this analysis revealed two conserved elements, one located immediately upstream of the first exon of the NAGS gene and a putative regulatory element located about 3 kb upstream of the NAGS translation initiation site [50]. The pattern of DNA sequence conservation within the conserved region immediately upstream of the first exon of the NAGS gene suggested that it might consist of a promoter and a proximal regulatory element, which is similar to the CPS1 regulatory region that will be described in the next section.…”

Section: Transcriptional Regulation Of Urea Cycle Genes 21 Transcripmentioning

confidence: 99%

Data Mining Approaches for Understanding of Regulation of Expression of the Urea Cycle Genes

Caldovic¹

2019

Gene Expression and Control

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Urea cycle converts ammonia, a waste product of protein catabolism and a neurotoxin, into non-toxic urea. Urea cycle disorders are a group of rare genetic diseases that have protein-restricted diet as a common treatment modality. Expression of urea cycle genes is regulated in concert by the dietary protein intake, but the mechanism of this regulation is not well understood. Data mining of databases such as ENCODE and Cistrome can be used to gain new information about regulatory elements, transcription factors, and epigenetic mechanisms that regulate expression of urea cycle genes. This can lead to better understanding of the common mechanism, which regulates urea cycle genes, and can generate testable hypotheses about regulation of gene expression and new treatments for urea cycle disorders.

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“…Correct sequence between AAV inverted repeats of the AAV2/8.TBG.mNAGS construct was verified by DNA sequencing. For the AAV2/8.NAGS.mNAGS construct the TBG promoter was replaced with the mouse Nags promoter [40]. Mouse genomic DNA was extracted following the standard protocol using DNeasy Blood and Tissue Kit, Qiagen (Valencia, CA).…”

Section: Plasmid Construction and Aav Vector Preparationmentioning

confidence: 99%

Impaired ureagenesis due to arginine-insensitive N-acetylglutamate synthase

Sonaimuthu

Senkevitch

Haskins

et al. 2018

Preprint

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The urea cycle protects the central nervous system from ammonia toxicity by converting ammonia to non-toxic urea. N-acetylglutamate synthase (NAGS) is an enzyme that catalyzes the formation of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1), the rate limiting enzyme of the urea cycle. Enzymatic activity of mammalian NAGS doubles in the presence of L-arginine but the physiological significance of NAGS activation by L-arginine is unknown. Previously, we have described the creation of a NAGS knockout (Nags -/-) mouse, which develops hyperammonemia without N-carbamylglutamate and L-citrulline supplementation (NCG+Cit). In order to investigate the effect of L-arginine on ureagenesis in vivo, we used adeno associated virus (AAV) mediated gene transfer to deliver either wild-type or E354A mutant mouse NAGS (mNAGS), which is not activated by L-arginine, to Nags -/mice. The ability of the E354A mNAGS mutant protein to rescue Nags -/mice was determined by measuring their activity on the voluntary wheel following NCG+Cit withdrawal. The Nags -/mice that received E354A mNAGS remained apparently healthy and active but had elevated plasma ammonia concentration despite similar expression levels of the E354A mNAGS and control wild-type NAGS proteins. The corresponding mutation in human NAGS (NP 694551.1:p.E360D) that abolishes binding and activation by L-arginine was also identified in a patient with hyperammonemia due to NAGS deficiency. Taken together, our results suggest that L-arginine binding to the NAGS enzyme is essential for normal ureagenesis.

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Transcriptional Regulation of N-Acetylglutamate Synthase

Cited by 28 publications

References 93 publications

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Data Mining Approaches for Understanding of Regulation of Expression of the Urea Cycle Genes

Impaired ureagenesis due to arginine-insensitive N-acetylglutamate synthase

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