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[PMID]: 28454702 [Au] Autor: Ellery SJ; Della Gatta PA; Bruce CR; Kowalski GM; Davies-Tuck M; Mockler JC; Murthi P; Walker DW; Snow RJ; Dickinson H [Ad] Endereço: The Ritchie Centre, Hudson Institute of Medical Research, Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. [Ti] Título: Creatine biosynthesis and transport by the term human placenta. [So] Source: Placenta;52:86-93, 2017 Apr. [Is] ISSN: 1532-3102 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Creatine is an amino acid derivative that is involved in preserving ATP homeostasis. Previous studies suggest an important role for the creatine kinase circuit for placental ATP turnover. Creatine is obtained from both the diet and endogenous synthesis, usually along the renal-hepatic axis. However, some tissues with a high-energy demand have an inherent capacity to synthesise creatine. In this study, we determined if the term human placenta has the enzymatic machinary to synthesise creatine. METHODS: Eleven placentae were collected following elective term caesarean section. Samples from the 4 quadrants of each placenta were either fixed in formalin or frozen. qPCR was used to determine the mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (SLC6A8). Protein expression of AGAT and GAMT was quantified by Western blot, and observations of cell localisation of AGAT, GAMT and SLC6A8 made with immunohistochemistry. Synthesis of guanidinoacetate (GAA; creatine precursor) and creatine in placental homogenates was determined via GC-MS and HPLC, respectively. RESULTS: AGAT, GAMT and SLC6A8 mRNA and protein were detected in the human placenta. AGAT staining was identified in stromal and endothelial cells of the fetal capillaries. GAMT and SLC6A8 staining was localised to the syncytiotrophoblast of the fetal villi. Ex vivo, tissue homogenates produce both GAA (4.6 nmol mg protein h ) and creatine (52.8 nmol mg protein h ). DISCUSSION: The term human placenta has the capacity to synthesise creatine. These data present a new understanding of placental energy metabolism. [Mh] Termos MeSH primário: Amidinotransferases/metabolismo Creatina/metabolismo Guanidinoacetato N-Metiltransferase/metabolismo Proteínas de Membrana Transportadoras/metabolismo Placenta/metabolismo [Mh] Termos MeSH secundário: Transporte Biológico Creatina/biossíntese Células Endoteliais/metabolismo Metabolismo Energético/fisiologia Feminino Seres Humanos Gravidez Células Estromais/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Membrane Transport Proteins); 0 (creatine transporter); EC 2.1.1.2 (GAMT protein, human); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); MU72812GK0 (Creatine) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180305 [Lr] Data última revisão: 180305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 27802572 [Au] Autor: Mei X; Alvarez J; Bon Ramos A; Samanta U; Iwata-Reuyl D; Swairjo MA [Ad] Endereço: Department of Chemistry and Biochemistry, San Diego State University- 5500 Campanile Drive, San Diego, California, 92182. [Ti] Título: Crystal structure of the archaeosine synthase QueF-like-Insights into amidino transfer and tRNA recognition by the tunnel fold. [So] Source: Proteins;85(1):103-116, 2017 Jan. [Is] ISSN: 1097-0134 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The tunneling-fold (T-fold) structural superfamily has emerged as a versatile protein scaffold of diverse catalytic activities. This is especially evident in the pathways to the 7-deazaguanosine modified nucleosides of tRNA queuosine and archaeosine. Four members of the T-fold superfamily have been confirmed in these pathways and here we report the crystal structure of a fifth enzyme; the recently discovered amidinotransferase QueF-Like (QueF-L), responsible for the final step in the biosynthesis of archaeosine in the D-loop of tRNA in a subset of Crenarchaeota. QueF-L catalyzes the conversion of the nitrile group of the 7-cyano-7-deazaguanine (preQ ) base of preQ -modified tRNA to a formamidino group. The structure, determined in the presence of preQ , reveals a symmetric T-fold homodecamer of two head-to-head facing pentameric subunits, with 10 active sites at the inter-monomer interfaces. Bound preQ forms a stable covalent thioimide bond with a conserved active site cysteine similar to the intermediate previously observed in the nitrile reductase QueF. Despite distinct catalytic functions, phylogenetic distributions, and only 19% sequence identity, the two enzymes share a common preQ binding pocket, and likely a common mechanism of thioimide formation. However, due to tight twisting of its decamer, QueF-L lacks the NADPH binding site present in QueF. A large positively charged molecular surface and a docking model suggest simultaneous binding of multiple tRNA molecules and structure-specific recognition of the D-loop by a surface groove. The structure sheds light on the mechanism of nitrile amidation, and the evolution of diverse chemistries in a common fold. Proteins 2016; 85:103-116. © 2016 Wiley Periodicals, Inc. [Mh] Termos MeSH primário: Amidinotransferases/química Proteínas Arqueais/química Guanosina/análogos & derivados Pirimidinonas/química Pyrobaculum/enzimologia Pirróis/química Processamento Pós-Transcricional do RNA [Mh] Termos MeSH secundário: Amidinotransferases/genética Amidinotransferases/metabolismo Sequência de Aminoácidos Proteínas Arqueais/genética Proteínas Arqueais/metabolismo Domínio Catalítico Clonagem Molecular Cristalografia por Raios X Escherichia coli/genética Escherichia coli/metabolismo Expressão Gênica Guanosina/química Guanosina/metabolismo Simulação de Acoplamento Molecular Ligação Proteica Conformação Proteica em alfa-Hélice Conformação Proteica em Folha beta Domínios e Motivos de Interação entre Proteínas Multimerização Proteica Subunidades Proteicas/química Subunidades Proteicas/genética Subunidades Proteicas/metabolismo Pirimidinonas/metabolismo Pyrobaculum/genética Pirróis/metabolismo RNA Arqueal/química RNA Arqueal/genética RNA Arqueal/metabolismo RNA de Transferência/química RNA de Transferência/genética RNA de Transferência/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/genética Proteínas Recombinantes/metabolismo Alinhamento de Sequência Homologia de Sequência de Aminoácidos Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (2-amino-5-cyanopyrrolo(2,3-d)pyrimidin-4-one); 0 (Archaeal Proteins); 0 (Protein Subunits); 0 (Pyrimidinones); 0 (Pyrroles); 0 (RNA, Archaeal); 0 (Recombinant Proteins); 12133JR80S (Guanosine); 148608-52-0 (archaeosine); 9014-25-9 (RNA, Transfer); EC 2.1.4.- (Amidinotransferases) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170724 [Lr] Data última revisão: 170724 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161102 [St] Status: MEDLINE [do] DOI: 10.1002/prot.25202

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[PMID]: 27784962 [Au] Autor: Osna NA; Feng D; Ganesan M; Maillacheruvu PF; Orlicky DJ; French SW; Tuma DJ; Kharbanda KK [Ad] Endereço: Natalia A Osna, Dan Feng, Murali Ganesan, Dean J Tuma, Kusum K Kharbanda, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States. [Ti] Título: Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury. [So] Source: World J Gastroenterol;22(38):8497-8508, 2016 Oct 14. [Is] ISSN: 2219-2840 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: AIM: To investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage. METHODS: Adult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS: Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol. CONCLUSION: To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage. [Mh] Termos MeSH primário: Etanol/efeitos adversos Glicina/análogos & derivados Hepatopatias/fisiopatologia [Mh] Termos MeSH secundário: Alanina Transaminase/sangue Amidinotransferases/metabolismo Animais Aspartato Aminotransferases/sangue Peso Corporal Proteínas de Ligação ao Cálcio/metabolismo Colesterol/química Proteínas de Ligação a DNA/metabolismo Suplementos Nutricionais Etanol/administração & dosagem Ácidos Graxos/química Fígado Gorduroso Glicina/administração & dosagem Guanidinoacetato N-Metiltransferase/metabolismo Homocisteína/sangue Inflamação Insulina/química Fígado/fisiopatologia Masculino Proteínas do Tecido Nervoso/metabolismo Complexo de Endopeptidases do Proteassoma/metabolismo Ratos Ratos Wistar S-Adenosil-Homocisteína/química S-Adenosilmetionina/química Triglicerídeos/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium-Binding Proteins); 0 (DNA-Binding Proteins); 0 (Fatty Acids); 0 (Insulin); 0 (Nerve Tissue Proteins); 0 (Triglycerides); 0 (nucleobindin); 0LVT1QZ0BA (Homocysteine); 3K9958V90M (Ethanol); 7LP2MPO46S (S-Adenosylmethionine); 979-92-0 (S-Adenosylhomocysteine); 97C5T2UQ7J (Cholesterol); EC 2.1.1.2 (Gamt protein, rat); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); EC 3.4.25.1 (Proteasome Endopeptidase Complex); GO52O1A04E (glycocyamine); TE7660XO1C (Glycine) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170627 [Lr] Data última revisão: 170627 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161028 [St] Status: MEDLINE

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[PMID]: 27581622 [Au] Autor: Ganesan M; Feng D; Barton RW; Thomes PG; McVicker BL; Tuma DJ; Osna NA; Kharbanda KK [Ad] Endereço: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska. [Ti] Título: Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis. [So] Source: Alcohol Clin Exp Res;40(11):2312-2319, 2016 Nov. [Is] ISSN: 1530-0277 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Alcohol-induced reduction in the hepatocellular S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio impairs the activities of many SAM-dependent methyltransferases. These impairments ultimately lead to the generation of several hallmark features of alcoholic liver injury including steatosis. Guanidinoacetate methyltransferase (GAMT) is an important enzyme that catalyzes the final reaction in the creatine biosynthetic process. The liver is a major site for creatine synthesis which places a substantial methylation burden on this organ as GAMT-mediated reactions consume as much as 40% of all the SAM-derived methyl groups. We hypothesized that dietary creatine supplementation could potentially spare SAM, preserve the hepatocellular SAM:SAH ratio, and thereby prevent the development of alcoholic steatosis and other consequences of impaired methylation reactions. METHODS: For these studies, male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol (EtOH) diet with or without 1% creatine supplementation. At the end of 4 to 5 weeks of feeding, relevant biochemical and histological analyses were performed. RESULTS: We observed that creatine supplementation neither prevented alcoholic steatosis nor attenuated the alcohol-induced impairments in proteasome activity. The lower hepatocellular SAM:SAH ratio seen in the EtOH-fed rats was also not normalized or SAM levels spared when these rats were fed the creatine-supplemented EtOH diet. However, a >10-fold increased level of creatine was observed in the liver, serum, and hearts of rats fed the creatine-supplemented diets. CONCLUSIONS: Overall, dietary creatine supplementation did not prevent alcoholic liver injury despite its known efficacy in preventing high-fat-diet-induced steatosis. Betaine, a promethylating agent that maintains the hepatocellular SAM:SAH, still remains our best option for treating alcoholic steatosis. [Mh] Termos MeSH primário: Creatina/uso terapêutico Fígado Gorduroso Alcoólico/prevenção & controle [Mh] Termos MeSH secundário: Amidinotransferases/metabolismo Animais Suplementos Nutricionais Guanidinoacetato N-Metiltransferase/metabolismo Rim/enzimologia Fígado/enzimologia Masculino Miocárdio/metabolismo Ratos Wistar S-Adenosil-Homocisteína/metabolismo S-Adenosilmetionina/metabolismo [Pt] Tipo de publicação: EVALUATION STUDIES; JOURNAL ARTICLE [Nm] Nome de substância: 7LP2MPO46S (S-Adenosylmethionine); 979-92-0 (S-Adenosylhomocysteine); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); MU72812GK0 (Creatine) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170621 [Lr] Data última revisão: 170621 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160902 [St] Status: MEDLINE [do] DOI: 10.1111/acer.13214

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[PMID]: 27289319 [Au] Autor: Ogasawara Y; Fujimori M; Kawata J; Dairi T [Ad] Endereço: Graduate School of Engineering, Hokkaido University, N 13 W 8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan. Electronic address: yogasawa@eng.hokudai.ac.jp. [Ti] Título: Characterization of three amidinotransferases involved in the biosynthesis of ketomemicins. [So] Source: Bioorg Med Chem Lett;26(15):3662-4, 2016 08 01. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: We recently reported a novel class of amide bond forming enzymes (peptide ligases) involved in the biosynthesis of pheganomycins, resorcinomycins and ketomemicins. This class of enzymes exclusively utilizes Nα-amidino amino acids as the N-terminal substrate. In this Letter, we characterized three new amidinotransferases involved in the biosynthesis of ketomemicins and showed that l-arginine was the amidino-acceptor of amidinotransferases in both the Micromonospora sp. and Streptomyces mobaraensis clusters, while the Salinispora tropica enzyme recognized l-valine. Unexpectedly, the S. tropica enzyme accepted several different amino acids as amidino acceptors in addition to l-valine. Accordingly, we re-investigated the specific metabolites governed by the gene cluster of S. tropica and identified several minor congeners of ketomemicin C with different N-terminal amidino-amino acids. These results indicate that the amidinotransferase of S. tropica is promiscuous and could be useful to generate new ketomemicin-type natural products. [Mh] Termos MeSH primário: Amidinotransferases/metabolismo Produtos Biológicos/metabolismo Oligopeptídeos/biossíntese [Mh] Termos MeSH secundário: Amidinotransferases/química Produtos Biológicos/química Estrutura Molecular Oligopeptídeos/química [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Biological Products); 0 (Oligopeptides); EC 2.1.4.- (Amidinotransferases) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 171122 [Lr] Data última revisão: 171122 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160613 [St] Status: MEDLINE

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[PMID]: 27001789 [Au] Autor: Koshoridze N; Kuchukashvili Z; Menabde K; Lekiashvili Sh; Koshoridze M [Ad] Endereço: I. Javakhishvili Tbilisi State University, Faculty of Exact and Natural Sciences, Department of Biology, Georgia. [Ti] Título: ALTERATIONS IN BRAIN CREATINE CONCENTRATIONS UNDER LONG-TERM SOCIAL ISOLATION (EXPERIMENTAL STUDY). [So] Source: Georgian Med News;(251):70-7, 2016 Feb. [Is] ISSN: 1512-0112 [Cp] País de publicação: Georgia (Republic) [La] Idioma: eng [Ab] Resumo: Stress represents one of the main problems of modern humanity. This study was done for understanding more clearly alterations in creatine content of the brain under psycho-emotional stress induced by long-term social isolation. It was shown that under 30 days social isolation creatine amount in the brain was arisen, while decreasing concentrations of synthesizing enzymes (AGAT, GAMT) and creatine transporter protein (CrT). Another important point was that such changes were accompanied by down-regulation of creatine kinase (CK), therefore the enzyme's concentration was lowered. In addition, it was observed that content of phosphocreatine (PCr) and ATP were also reduced, thus indicating down-regulation of energy metabolism of brain that is really a crucial point for its normal functioning. To sum up the results it can be underlined that long-term social isolation has negative influence on energy metabolism of brain; and as a result reduce ATP content, while increase of free creatine concentration, supposedly maintaining maximal balance for ATP amount, but here must be also noted that up-regulated oxidative pathways might have impact on blood brain barrier, resulting on its permeability. [Mh] Termos MeSH primário: Encéfalo/metabolismo Creatina/metabolismo Isolamento Social [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Amidinotransferases/metabolismo Animais Creatina Quinase/metabolismo Metabolismo Energético Guanidinoacetato N-Metiltransferase/metabolismo Masculino Proteínas de Membrana Transportadoras/metabolismo Fosfocreatina/metabolismo Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Membrane Transport Proteins); 0 (creatine transporter); 020IUV4N33 (Phosphocreatine); 8L70Q75FXE (Adenosine Triphosphate); EC 2.1.1.2 (Gamt protein, rat); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); EC 2.7.3.2 (Creatine Kinase); MU72812GK0 (Creatine) [Em] Mês de entrada: 1609 [Cu] Atualização por classe: 160322 [Lr] Data última revisão: 160322 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160323 [St] Status: MEDLINE

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[PMID]: 26928755 [Au] Autor: Terlemez S; Demir F; Bulut Y; Carti Ö; Gökdogan D; Tokgöz Y; Yenigün A [Ad] Endereço: Pediatric Cardiology department, Adnan Menderes University Medicine Faculty, Aydin, Turkey. semihaterlemez@yahoo.com. [Ti] Título: DRESS syndrome developed related to acetylsalicylic acid use. [So] Source: Pediatr Allergy Immunol;27(2):227-30, 2016 Mar. [Is] ISSN: 1399-3038 [Cp] País de publicação: England [La] Idioma: eng [Mh] Termos MeSH primário: Aspirina/efeitos adversos Síndrome de Hipersensibilidade a Medicamentos/diagnóstico Eosinófilos/fisiologia Linfócitos/patologia Febre Reumática/tratamento farmacológico [Mh] Termos MeSH secundário: Amidinotransferases/sangue Aspirina/uso terapêutico Criança Síndrome de Hipersensibilidade a Medicamentos/etiologia Diagnóstico Precoce Feminino Seres Humanos Febre Reumática/complicações Febre Reumática/diagnóstico [Pt] Tipo de publicação: LETTER [Nm] Nome de substância: EC 2.1.4.- (Amidinotransferases); R16CO5Y76E (Aspirin) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160302 [St] Status: MEDLINE [do] DOI: 10.1111/pai.12484

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[PMID]: 26729229 [Au] Autor: Khan A; Tian L; Zhang C; Yuan K; Xu S [Ad] Endereço: Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese academy of Sciences, Shanghai 200031, China. [Ti] Título: Genetic diversity and natural selection footprints of the glycine amidinotransferase gene in various human populations. [So] Source: Sci Rep;6:18755, 2016 Jan 05. [Is] ISSN: 2045-2322 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The glycine amidinotransferase gene (GATM) plays a vital role in energy metabolism in muscle tissues and is associated with multiple clinically important phenotypes. However, the genetic diversity of the GATM gene remains poorly understood within and between human populations. Here we analyzed the 1,000 Genomes Project data through population genetics approaches and observed significant genetic diversity across the GATM gene among various continental human populations. We observed considerable variations in GATM allele frequencies and haplotype composition among different populations. Substantial genetic differences were observed between East Asian and European populations (FST = 0.56). In addition, the frequency of a distinct major GATM haplotype in these groups was congruent with population-wide diversity at this locus. Furthermore, we identified GATM as the top differentiated gene compared to the other statin drug response-associated genes. Composite multiple analyses identified signatures of positive selection at the GATM locus, which was estimated to have occurred around 850 generations ago in European populations. As GATM catalyzes the key step of creatine biosynthesis involved in energy metabolism, we speculate that the European prehistorical demographic transition from hunter-gatherer to farming cultures was the driving force of selection that fulfilled creatine-based metabolic requirement of the populations. [Mh] Termos MeSH primário: Amidinotransferases/genética Variação Genética Genética Populacional Seleção Genética [Mh] Termos MeSH secundário: Grupos de Populações Continentais/genética Loci Gênicos Genoma Humano Estudo de Associação Genômica Ampla Haplótipos Seres Humanos Desequilíbrio de Ligação Característica Quantitativa Herdável [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160106 [St] Status: MEDLINE [do] DOI: 10.1038/srep18755

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[PMID]: 26542286 [Au] Autor: Joncquel-Chevalier Curt M; Voicu PM; Fontaine M; Dessein AF; Porchet N; Mention-Mulliez K; Dobbelaere D; Soto-Ares G; Cheillan D; Vamecq J [Ad] Endereço: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France; RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France. [Ti] Título: Creatine biosynthesis and transport in health and disease. [So] Source: Biochimie;119:146-65, 2015 Dec. [Is] ISSN: 1638-6183 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures. [Mh] Termos MeSH primário: Amidinotransferases/metabolismo Creatina/metabolismo Guanidinoacetato N-Metiltransferase/metabolismo Proteínas do Tecido Nervoso/metabolismo Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo [Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo Amidinotransferases/deficiência Amidinotransferases/genética Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico Erros Inatos do Metabolismo dos Aminoácidos/enzimologia Erros Inatos do Metabolismo dos Aminoácidos/genética Erros Inatos do Metabolismo dos Aminoácidos/metabolismo Sistemas de Transporte de Aminoácidos Básicos/deficiência Sistemas de Transporte de Aminoácidos Básicos/genética Sistemas de Transporte de Aminoácidos Básicos/metabolismo Animais Transporte Biológico Ativo Encefalopatias Metabólicas Congênitas/diagnóstico Encefalopatias Metabólicas Congênitas/enzimologia Encefalopatias Metabólicas Congênitas/genética Encefalopatias Metabólicas Congênitas/metabolismo Creatina/biossíntese Creatina/deficiência Creatina/genética Deficiências do Desenvolvimento/diagnóstico Deficiências do Desenvolvimento/enzimologia Deficiências do Desenvolvimento/genética Deficiências do Desenvolvimento/metabolismo Metabolismo Energético Guanidinoacetato N-Metiltransferase/deficiência Guanidinoacetato N-Metiltransferase/genética Atrofia Girata/diagnóstico Atrofia Girata/enzimologia Atrofia Girata/genética Atrofia Girata/metabolismo Seres Humanos Hiperamonemia/diagnóstico Hiperamonemia/enzimologia Hiperamonemia/genética Hiperamonemia/metabolismo Deficiência Intelectual/diagnóstico Deficiência Intelectual/enzimologia Deficiência Intelectual/genética Deficiência Intelectual/metabolismo Transtornos do Desenvolvimento da Linguagem/diagnóstico Transtornos do Desenvolvimento da Linguagem/enzimologia Transtornos do Desenvolvimento da Linguagem/genética Transtornos do Desenvolvimento da Linguagem/metabolismo Retardo Mental Ligado ao Cromossomo X/diagnóstico Retardo Mental Ligado ao Cromossomo X/enzimologia Retardo Mental Ligado ao Cromossomo X/genética Retardo Mental Ligado ao Cromossomo X/metabolismo Metilação Transtornos dos Movimentos/congênito Transtornos dos Movimentos/diagnóstico [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Basic); 0 (Nerve Tissue Proteins); 0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (SLC25A15 protein, human); 0 (SLC6A8 protein, human); 7LP2MPO46S (S-Adenosylmethionine); E524N2IXA3 (Ornithine); EC 2.1.1.2 (GAMT protein, human); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); EC 2.7.11.31 (AMP-Activated Protein Kinases); MU72812GK0 (Creatine) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151107 [St] Status: MEDLINE

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[PMID]: 26490222 [Au] Autor: Stockler-Ipsiroglu S; Apatean D; Battini R; DeBrosse S; Dessoffy K; Edvardson S; Eichler F; Johnston K; Koeller DM; Nouioua S; Tazir M; Verma A; Dowling MD; Wierenga KJ; Wierenga AM; Zhang V; Wong LJ [Ad] Endereço: Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Child & Family Research Institute, BC Children's Hospital, Vancouver, BC, Canada. Electronic address: sstockler@cw.bc.ca. [Ti] Título: Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide. [So] Source: Mol Genet Metab;116(4):252-9, 2015 Dec. [Is] ISSN: 1096-7206 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing. [Mh] Termos MeSH primário: Amidinotransferases/deficiência Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico Creatina/uso terapêutico Deficiência Intelectual/tratamento farmacológico Doenças Musculares/tratamento farmacológico Distúrbios da Fala/tratamento farmacológico [Mh] Termos MeSH secundário: Adolescente Amidinotransferases/química Amidinotransferases/genética Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico Erros Inatos do Metabolismo dos Aminoácidos/genética Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia Criança Pré-Escolar Creatina/deficiência Deficiências do Desenvolvimento/diagnóstico Deficiências do Desenvolvimento/tratamento farmacológico Deficiências do Desenvolvimento/genética Deficiências do Desenvolvimento/fisiopatologia Feminino Expressão Gênica Genes Recessivos Glicina/análogos & derivados Glicina/sangue Glicina/deficiência Glicina/urina Seres Humanos Deficiência Intelectual/diagnóstico Deficiência Intelectual/genética Deficiência Intelectual/fisiopatologia Espectroscopia de Ressonância Magnética Masculino Modelos Moleculares Doenças Musculares/diagnóstico Doenças Musculares/genética Doenças Musculares/fisiopatologia Mutação Estrutura Secundária de Proteína Estrutura Terciária de Proteína Análise de Sequência de DNA Distúrbios da Fala/diagnóstico Distúrbios da Fala/genética Distúrbios da Fala/fisiopatologia Resultado do Tratamento Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); GO52O1A04E (glycocyamine); MU72812GK0 (Creatine); TE7660XO1C (Glycine) [Em] Mês de entrada: 1609 [Cu] Atualização por classe: 151222 [Lr] Data última revisão: 151222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151023 [St] Status: MEDLINE

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