Glutamine and glutamate—their central role in cell metabolism and function

Newsholme, Philip; Procópio, Joaquim; Lima, Manuela Maria Ramos; Pithon-Curi, Tânia Cristina; Curi, Rui

doi:10.1002/cbf.1003

Cited by 538 publications

(440 citation statements)

References 63 publications

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“…Thus, in order to enhance anabolism, supplementation of essential amino acids enriched with BCAA along with sufficient calories to patients with a UCD during acute decompensation and hyperammonaemia would seem prudent. Moreover, in view of the contribution of the splanchnic system to protein retention and metabolism (Newsholme et al 2003), it would be advantageous to treat patients who present with metabolic decompensation through enteral supplementation, as previously suggested (Leonard 2001;Summar 2001), rather than intravenously.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation

Rodney

Boneh

2012

JIMD Reports

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Urea cycle disorders (UCDs) result from inherited defects in the ammonia detoxification pathway, leading to episodes of hyperammonaemia and encephalopathy. The purpose of this study was to answer the question, "what is the likely plasma amino acid profile of a patient known to have a UCD presenting with hyperammonaemia during acute metabolic decompensation", in order to support informed decisions regarding management.We analysed the results of plasma ammonia levels and amino acid profiles taken simultaneously or within 30 min of each other during acute admissions of all patients with a UCD at the Royal Children's Hospital, Melbourne, over 28 years. Samples from 96 admissions (79, 9 and 8 admissions for OTC, CPS and ASS deficiencies, respectively) from 14 patients fulfilled these criteria. Amino acid levels were measured by ion exchange chromatography with post-column ninhydrin derivatisation and interpreted in relation to age-related reference ranges.Plasma concentrations of all measured essential amino acids were low or low-normal in almost all samples. There was a strong positive correlation between low plasma branched-chain amino acids and other essential amino acids, and a negative correlation between ammonia and phenylalanine to tyrosine (Phe:Tyr) ratio in patients with OTC deficiency, and between glutamine and Phe:Tyr ratio in all patients, indicating protein deficiency.Conclusion: At admission, protein deficiency is common in patients with a UCD with hyperammonaemia. These results challenge the current guideline of stopping protein intake during acute decompensation in UCDs. Supplementation with essential amino acids (particularly branched-chain amino acids) at these times should be considered.

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Section: Discussionmentioning

confidence: 99%

Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation

Rodney

Boneh

2012

JIMD Reports

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“…Foi possível verificar que após 5 dias do aparecimento das primeiras lesões, as aves dos tratamentos com Gln/Glu não apresentavam mais lesões indicando rápida recuperação da mucosa intestinal, o que pode estar associado ao fato da glutamina e ácido glutâmi-co contribuírem com o fornecimento de energia necessário para células que proliferam rapidamente, como as células do intestino, além de serem considerados como precursores para síntese de outros aminoácidos e nucleotídeos importantes na síntese protéica (Newsholme 2003a(Newsholme , 2003b.…”

Section: Escores De Lesão Do Epitélio Intestinal E Contagem De Oocistosunclassified

“…A glutamina e ácido glutâmico, além de contribuírem com o fornecimento de energia necessário para o desempenho das atividades metabólicas de células que proliferam rapidamente, como as células do sistema imune e intestino (Newsholme 2003a(Newsholme , 2003b, também são considerados precursores para síntese de purinas e pirimidinas, constituintes básicos dos nucleotídeos, componentes das molé-culas de DNA e RNA e de outros aminoácidos, suportando a divisão (turnover) das células da cripta, resultando no aumento do número e altura dos vilos e auxiliando no reparo das injúrias no epitélio intestinal (Piva et al 2001). Outra importante função da glutamina é a indução mecanismos de transcrição gênica pela ativação da proteína quinase, que é uma enzima que ativa mitogênese na região das criptas do epitélio intestinal, levando ao aumento da proliferação celular, influenciando na manutenção da estrutura da mucosa (Blikslager & Roberts 1997, Rhoads et al 1997.…”

Section: Histomorfometria Da Mucosa Intestinalunclassified

“…A glutamina é muito utilizada em altas taxas por célu-las isoladas do sistema imune, como linfócitos, macrófagos e neutrófilos (Newsholme et al 1985, Newsholme 2001, Newsholme et al 2003a, 2003b. Segundo Newsholme (2001), o fato de o nitrogênio amínico da glutamina ser utilizado para síntese de nucleotídeos, seria um dos fatores que explica a alta necessidade de glutamina em células que se proliferam rapidamente, como as do sistema imune e da mucosa intestinal.…”

Section: Histomorfometria Da Bursa De Fabriciusunclassified

“…Pesquisadores têm demonstrado que glutamina e ácido glutâmico (Yoo et al 1997, Newsholme 2003a, 2003b, Yi et al 2005, Caldara et al 2010, Nascimento et al 2014, bem como óleos essenciais e extratos vegetais (Christaki et al 2004, Jamroz et al 2005, Awaad et al 2010, Vasconcelos et al 2010, Fascina et al 2012) são capazes de melhorar a resposta imune e a microbiota intestinal, prevenindo efeitos negativos na estrutura do intestino, melhorar a digestão e absorção dos nutrientes e consequentemente, o desempenho dos animais, o que os tornam aditivos interessantes para criação de frangos de corte alternativos durante períodos de desafio.…”

Section: Introductionunclassified

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Ação trófica de aditivos fitogênicos, glutamina e ácido glutâmico sobre a Bursa de Fabrícius e intestino delgado de frangos de corte

et al. 2015

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The aim of this study was to evaluate the effect of phytogenic additives and glutamine plus glutamic acid, associated or not, on histomorphometry of bursa of Fabricius and small intestine, oocyst count and lesion scores, and carbon turnover of duodenal mucosa of broiler chickens infected with Eimeria acervulina. A total of 450 male broiler chickens was distributed into a completely randomized design with six treatments and three replications. Treatments consisted of control diet (CD); CD + coccidiosis vaccine; CD + antibiotic performance enhancers and anticoccidial (APE/AC); CD + glutamine and glutamic acid (Gln/Glu); CD + phytogenic additives (PA); CD + Gln/Glu + PA. Birds on treatment CD + vaccine were vaccinated via drinking water at three days of age against coccidiosis. At 16 days of age all birds of all treatments were inoculated orally and individually with 500,000 oocysts of Eimeria acervulina. There was no treatment effect on lesion score in the intestinal epithelium of birds. The smaller number of excreted oocysts was observed in groups of birds fed diets containing APE/AC and PA. Were observed better results of villus height and crypt depth for duodenum and ileum of birds of treatments containing Gln/Glu at 7 days of age, and Gln/Glu and PA at 21 days of age. Higher percentage of cortical area from bursa follicles was observed in birds fed diets supplemented with Gln/Glu and PA at 7, 14 and 21 days of age. Increased turnover of intestinal mucosa was observed in treatments containing Gln/Glu, indicating acceleration in development and regeneration of damaged tissue. Glutamine plus glutamic acid and phytogenic additives can provide improvements to structure, and thus to intestinal function, as well as to better immune response against the infectious challenges. Phytogenic additives can be used for coccidiosis control of broiler chickens where the use of antibiotic performance enhancers and anticoccidials is prohibited.

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Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

et al. 2019

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IMPORTANCE The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. OBJECTIVE To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. DESIGN, SETTING, AND PARTICIPANTS We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. MAIN OUTCOMES AND MEASURES Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. RESULTS A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. CONCLUSIONS AND RELEVANCE We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.

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Glutamine and glutamate—their central role in cell metabolism and function

Cited by 538 publications

References 63 publications

Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation

Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation

Ação trófica de aditivos fitogênicos, glutamina e ácido glutâmico sobre a Bursa de Fabrícius e intestino delgado de frangos de corte

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

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