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[PMID]:28985504
[Au] Autor:Lin R; Mo Y; Zha H; Qu Z; Xie P; Zhu ZJ; Xu Y; Xiong Y; Guan KL
[Ad] Endereço:State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: rlin@
[Ti] Título:CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.
[So] Source:Mol Cell;68(1):198-209.e6, 2017 Oct 05.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic enzymes.
[Mh] Termos MeSH primário: Fatores de Transcrição ARNTL/genética
Argininossuccinato Sintase/genética
Proteínas CLOCK/genética
Ritmo Circadiano/genética
Processamento de Proteína Pós-Traducional
Ureia/metabolismo
[Mh] Termos MeSH secundário: Fatores de Transcrição ARNTL/metabolismo
Acetilação
Animais
Arginina/biossíntese
Argininossuccinato Sintase/metabolismo
Proteínas CLOCK/metabolismo
Linhagem Celular Tumoral
Relógios Circadianos
Complexo I de Transporte de Elétrons/genética
Complexo I de Transporte de Elétrons/metabolismo
Células HEK293
Hepatócitos/citologia
Hepatócitos/metabolismo
Seres Humanos
IMP Desidrogenase/genética
IMP Desidrogenase/metabolismo
Masculino
Camundongos
Camundongos Knockout
Osteoblastos/metabolismo
Osteoblastos/patologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARNTL Transcription Factors); 0 (Arntl protein, mouse); 8W8T17847W (Urea); 94ZLA3W45F (Arginine); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.1.1.205 (IMPDH2 protein, human); EC 1.6.5.3 (Electron Transport Complex I); EC 1.6.5.3 (NDUFA9 protein, human); EC 2.3.1.48 (CLOCK Proteins); EC 2.3.1.48 (Clock protein, mouse); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


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[PMID]:28938091
[Au] Autor:Luengo A; Gui DY; Vander Heiden MG
[Ad] Endereço:The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
[Ti] Título:Targeting Metabolism for Cancer Therapy.
[So] Source:Cell Chem Biol;24(9):1161-1180, 2017 Sep 21.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
[Mh] Termos MeSH primário: Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Antimetabólitos/química
Antimetabólitos/farmacologia
Antimetabólitos/uso terapêutico
Argininossuccinato Sintase/genética
Argininossuccinato Sintase/metabolismo
Metabolismo dos Carboidratos/efeitos dos fármacos
Ácidos Graxos/biossíntese
Glutamina/metabolismo
Glicólise/efeitos dos fármacos
Seres Humanos
Isocitrato Desidrogenase/antagonistas & inibidores
Isocitrato Desidrogenase/genética
Isocitrato Desidrogenase/metabolismo
Engenharia Metabólica
NAD/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Fatty Acids); 0RH81L854J (Glutamine); 0U46U6E8UK (NAD); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


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[PMID]:28587924
[Au] Autor:Verma M; Charles RCM; Chakrapani B; Coumar MS; Govindaraju G; Rajavelu A; Chavali S; Dhayalan A
[Ad] Endereço:Department of Biotechnology, Pondicherry University, Puducherry 605 014, India.
[Ti] Título:PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrupt the Interaction.
[So] Source:J Mol Biol;429(15):2278-2289, 2017 Jul 21.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein arginine methyltransferase 7 (PRMT7) catalyzes the introduction of monomethylation marks at the arginine residues of substrate proteins. PRMT7 plays important roles in the regulation of gene expression, splicing, DNA damage, paternal imprinting, cancer and metastasis. However, little is known about the interaction partners of PRMT7. To address this, we performed yeast two-hybrid screening of PRMT7 and identified argininosuccinate synthetase (ASS1) as a potential interaction partner of PRMT7. We confirmed that PRMT7 directly interacts with ASS1 using pull-down studies. ASS1 catalyzes the rate-limiting step of arginine synthesis in urea cycle and citrulline-nitric oxide cycle. We mapped the interface of PRMT7-ASS1 complex through computational approaches and validated the predicted interface in vivo by site-directed mutagenesis. Evolutionary analysis revealed that the ASS1 residues important for PRMT7-ASS1 interaction have co-evolved with PRMT7. We showed that ASS1 mutations linked to type I citrullinemia disrupt the ASS1-PRMT7 interaction, which might explain the molecular pathogenesis of the disease.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Argininossuccinato Sintase/metabolismo
Proteína-Arginina N-Metiltransferases/metabolismo
[Mh] Termos MeSH secundário: Centrifugação
Citrulinemia/fisiopatologia
Análise Mutacional de DNA
Seres Humanos
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Ligação Proteica
Mapeamento de Interação de Proteínas
Técnicas do Sistema de Duplo-Híbrido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (PRMT7 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE


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[PMID]:28388291
[Au] Autor:Beddowes E; Spicer J; Chan PY; Khadeir R; Corbacho JG; Repana D; Steele JP; Schmid P; Szyszko T; Cook G; Diaz M; Feng X; Johnston A; Thomson J; Sheaff M; Wu BW; Bomalaski J; Pacey S; Szlosarek PW
[Ad] Endereço:Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Kha
[Ti] Título:Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers.
[So] Source:J Clin Oncol;35(16):1778-1785, 2017 Jun 01.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m , 27 mg/m , or 36 mg/m , together with pemetrexed 500 mg/m and cisplatin 75 mg/m which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m plus three-weekly cisplatin 75 mg/m and pemetrexed 500 mg/m .
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Argininossuccinato Sintase/deficiência
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Mesotelioma/tratamento farmacológico
Neoplasias Pleurais/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Carcinoma Pulmonar de Células não Pequenas/enzimologia
Cisplatino/administração & dosagem
Cisplatino/efeitos adversos
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Hidrolases/administração & dosagem
Hidrolases/efeitos adversos
Neoplasias Pulmonares/enzimologia
Masculino
Mesotelioma/enzimologia
Meia-Idade
Pemetrexede/administração & dosagem
Pemetrexede/efeitos adversos
Neoplasias Pleurais/enzimologia
Polietilenoglicóis/administração & dosagem
Polietilenoglicóis/efeitos adversos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
04Q9AIZ7NO (Pemetrexed); 30IQX730WE (Polyethylene Glycols); EC 3.- (Hydrolases); EC 3.5.3.6 (ADI PEG20); EC 6.3.4.5 (Argininosuccinate Synthase); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2016.71.3230


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[PMID]:28302489
[Au] Autor:Yoshitoshi-Uebayashi EY; Toyoda T; Yasuda K; Kotaka M; Nomoto K; Okita K; Yasuchika K; Okamoto S; Takubo N; Nishikubo T; Soga T; Uemoto S; Osafune K
[Ad] Endereço:Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
[Ti] Título:Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.
[So] Source:Biochem Biophys Res Commun;486(3):613-619, 2017 May 06.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.
[Mh] Termos MeSH primário: Arginina/farmacologia
Argininossuccinato Sintase/deficiência
Ciclo do Ácido Cítrico/efeitos dos fármacos
Citrulinemia/genética
Hepatócitos/efeitos dos fármacos
Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Argininossuccinato Sintase/genética
Sequência de Bases
Diferenciação Celular
Ciclo do Ácido Cítrico/genética
Citrulinemia/enzimologia
Citrulinemia/patologia
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Hepatócitos/metabolismo
Hepatócitos/patologia
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Cariotipagem
Metaboloma
Camundongos
Camundongos Endogâmicos NOD
Modelos Biológicos
Cultura Primária de Células
Transdução de Sinais
Ureia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
8W8T17847W (Urea); 94ZLA3W45F (Arginine); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28229591
[Au] Autor:Bateman LA; Ku WM; Heslin MJ; Contreras CM; Skibola CF; Nomura DK
[Ad] Endereço:Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
[Ti] Título:Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity.
[So] Source:ACS Chem Biol;12(4):905-911, 2017 Apr 21.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Like many cancer types, colorectal cancers have dysregulated metabolism that promotes their pathogenic features. In this study, we used the activity-based protein profiling chemoproteomic platform to profile cysteine-reactive metabolic enzymes that are upregulated in primary human colorectal tumors. We identified argininosuccinate synthase 1 (ASS1) as an upregulated target in primary human colorectal tumors and show that pharmacological inhibition or genetic ablation of ASS1 impairs colorectal cancer pathogenicity. Using metabolomic profiling, we show that ASS1 inhibition leads to reductions in the levels of oncogenic metabolite fumarate, leading to impairments in glycolytic metabolism that supports colorectal cancer cell pathogenicity. We show here that ASS1 inhibitors may represent a novel therapeutic approach for attenuating colorectal cancer through compromising critical metabolic and metabolite signaling pathways and demonstrate the utility of coupling chemoproteomic and metabolomic strategies to map novel metabolic regulators of cancer.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/metabolismo
Neoplasias Colorretais/patologia
[Mh] Termos MeSH secundário: Argininossuccinato Sintase/antagonistas & inibidores
Neoplasias Colorretais/enzimologia
Neoplasias Colorretais/metabolismo
Inibidores Enzimáticos/farmacologia
Seres Humanos
Metaboloma
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.6b01158


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[PMID]:28216408
[Au] Autor:Querobino SM; Carrettiero DC; Costa MS; Alberto-Silva C
[Ad] Endereço:Natural and Humanities Sciences Center, Experimental Morphophysiology Laboratory Federal University of ABC (UFABC), Rua Arcturus, n° 03, Bloco Delta, São Bernardo do Campo, 09606-070, SP, Brazil.
[Ti] Título:Neuroprotective property of low molecular weight fraction from B. jararaca snake venom in H O -induced cytotoxicity in cultured hippocampal cells.
[So] Source:Toxicon;129:134-143, 2017 Apr.
[Is] ISSN:1879-3150
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In central nervous system cells, low molecular weight fractions (LMWF) from snake venoms can inhibit changes in mitochondrial membrane permeability, preventing the diffusion of cytochrome c to the cytoplasm, inhibiting the activation of pro-apoptotic factors. Here, we evaluated the neuroprotective activity of LMWF from Bothrops jararaca (Bj) snake venom in H O -induced cytotoxicity in cultured hippocampal cells. SDS-PAGE, FT-IR and MALDI-TOF analysis of LMWF (<14 kDa) confirmed the absence of high-molecular-weight proteins in the fraction. LMWF did not present cytotoxicity in all concentrations and time tested by MTT assay. Neuroprotection was evaluated in cells pretreated with LMWF for 4 h prior to the addition of 50 µM H O for 20 h. We demonstrated that LMWF reduced the argininosuccinate synthase (AsS) and superoxide dismutase (SOD1) expressions, suggesting that this fraction as an effective neuroprotective compound that could increase the hippocampal cells viability by attenuation of oxidative stress. In addition, LMWF protects against apoptosis induced by H O , reducing the expression of caspase-3 and caspase-8. Overall, this study opens new perspectives for the identification of new molecules for the development of drugs applied to the treatment of neurodegenerative diseases.
[Mh] Termos MeSH primário: Bothrops
Hipocampo/efeitos dos fármacos
Peróxido de Hidrogênio/toxicidade
Fármacos Neuroprotetores/farmacologia
Venenos de Serpentes/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Argininossuccinato Sintase/genética
Argininossuccinato Sintase/metabolismo
Caspase 3/genética
Caspase 3/metabolismo
Caspase 8/genética
Caspase 8/metabolismo
Caspase 9/genética
Caspase 9/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Hipocampo/citologia
Peso Molecular
Fármacos Neuroprotetores/química
Estresse Oxidativo/efeitos dos fármacos
Cultura Primária de Células
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos Wistar
Venenos de Serpentes/química
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuroprotective Agents); 0 (RNA, Messenger); 0 (Snake Venoms); BBX060AN9V (Hydrogen Peroxide); EC 1.15.1.1 (Superoxide Dismutase); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 8); EC 3.4.22.- (Caspase 9); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE


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[PMID]:28187218
[Au] Autor:Liu Q; Stewart J; Wang H; Rashid A; Zhao J; Katz MH; Lee JE; Fleming JB; Maitra A; Wolff RA; Varadhachary GR; Krishnan S; Wang H
[Ad] Endereço:Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
[Ti] Título:Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma.
[So] Source:PLoS One;12(2):e0171985, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme for arginine biosynthesis, is expressed in many types of human malignancies. Recent studies showed that ASS1 may have tumor suppressor function and that ASS1 deficiency is associated with clinical aggressiveness in nasopharyngeal carcinoma, myxofibrosarcomas and bladder cancer. The goal of this study was to evaluate the prognostic impact of ASS1 expression in patients with pancreatic ductal adenocarcinoma (PDAC). Our study included two independent cohorts: untreated cohort, which was comprised of 135 patients with PDAC who underwent pancreatoduodenectomy (PD) without pre-operative neoadjuvant therapy, and treated cohort, which was comprised of 122 patients with PDAC who have completed neoadjuvant therapy and PD. The expression level of ASS1 was evaluated by immunohistochemistry and the results were correlated with clinicopathologic parameters and survival using SPSS statistics. Our study showed that 12% of PDAC in untreated cohort and 15% of PDAC in treated cohort has low expression of ASS1 (ASS1-low). ASS1-low was associated with higher recurrence (p = 0.045), shorter disease-free survival (DFS, 4.8 ± 1.6 months vs 15.3 ± 2.2 months, p = 0.001) and shorter overall survival (OS, 14.6 ± 6.4 months vs 26.5 ± 3.5 months, p = 0.005) in untreated cohort and shorter OS in treated cohort compared to ASS1-high tumors. In multivariate analysis, ASS1-low (HR: 0.45, 95% CI: 0.26-0.79, p = 0.005) was an independent prognostic factor for DFS in untreated cohort and an independent prognostic factor for OS (HR: 0.56, 95% CI: 0.32-0.97, p = 0.04) in treated cohort. Our results provide supporting evidence for future clinical trial using arginine deprivation agents either alone or in combination with conventional chemotherapy in treating pancreatic cancer.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/metabolismo
Biomarcadores Tumorais/metabolismo
Carcinoma Ductal Pancreático/metabolismo
Neoplasias Pancreáticas/metabolismo
[Mh] Termos MeSH secundário: Argininossuccinato Sintase/genética
Biomarcadores Tumorais/genética
Carcinoma Ductal Pancreático/patologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Neoplasias Pancreáticas/patologia
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0171985


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[PMID]:28132756
[Au] Autor:Kose E; Unal O; Bulbul S; Gunduz M; Häberle J; Arslan N
[Ad] Endereço:Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey.
[Ti] Título:Identification of three novel mutations in fourteen patients with citrullinemia type 1.
[So] Source:Clin Biochem;50(12):686-689, 2017 Aug.
[Is] ISSN:1873-2933
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Citrullinemia type 1 (CTLN1) is an autosomal recessive genetic disorder caused by mutations in the argininosuccinate synthetase 1 (ASS1) gene, which encodes for the argininosuccinate synthetase enzyme. Here, we report genetic and clinical characterizations of 14 patients with citrullinemia type 1. DESIGN & METHODS: The study group consisted of 14 patients (4 females, 10 males) diagnosed with citrullinemia type 1 from three centers in Turkey. Age of onset, clinical presentation, initial citrulline and ammonia levels, family history and molecular genetic analysis were retrospectively evaluated. RESULTS: The mean age of the cohort and the mean age at the time of diagnosis were 48.3±36.5months (min: 12days, max: 10years) and 11.6±26.2months (min: 3days, max: 8years), respectively. In four patients, a homozygous p.Gly390Arg pathogenic variant was detected. All patients homozygous for p.Gly390Arg were diagnosed during the newborn period with the clinical presentation of classical citrullinemia. In each two patients, homozygous p.Arg86His, c.773+49C>T and p.Gly362Val pathogenic variants were detected. Clinical presentation was compatible with the mild form of the disease in patients homozygous for c.773+49C>T and for Gly362Val. Novel compound heterozygous genotypes (p.Ala164Pro/p.Gly390Arg; p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in five patients. Of these, three siblings with CTLN1 were diagnosed with the compound heterozygous genotype p.Ala164Pro/p.Gly390Arg at the age of 4days, 5days and 2years, respectively. The other two patients with novel compound heterozygous genotypes (p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in the first month of life as neonatal onset form and were born to non-consanguineous parents. CONCLUSION: In our study, consistent with the literature, a correlation was found between homozygous p.Gly390Arg mutation and the classic neonatal onset form. Mild citrullinemia was detected in patients with c.773+49C>T or p.Gly362Val pathogenic variants. This study adds to our understanding of the molecular genetic background of patients with CTLN1, and allows to infer on the correlation between the genotype and phenotype of the disease.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Citrulinemia/genética
Mutação
[Mh] Termos MeSH secundário: Idade de Início
Amônia/sangue
Argininossuccinato Sintase/sangue
Criança
Pré-Escolar
Citrulina/sangue
Citrulinemia/sangue
Citrulinemia/diagnóstico
Citrulinemia/patologia
Expressão Gênica
Genes Recessivos
Genótipo
Heterozigoto
Homozigoto
Seres Humanos
Lactente
Recém-Nascido
Linhagem
Fenótipo
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
29VT07BGDA (Citrulline); 7664-41-7 (Ammonia); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


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[PMID]:28111830
[Au] Autor:Diez-Fernandez C; Rüfenacht V; Häberle J
[Ad] Endereço:Division of Metabolism, University Children´s Hospital and Children's Research Center, Zurich, Switzerland.
[Ti] Título:Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.
[So] Source:Hum Mutat;38(5):471-484, 2017 May.
[Is] ISSN:1098-1004
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by defects in the argininosuccinate synthetase (ASS) enzyme due to mutations in ASS1 gene. An impairment of ASS function can lead to a wide spectrum of phenotypes, from life-threatening neonatal hyperammonemia to a later onset with mild symptoms, and even some asymptomatic patients exhibiting an only biochemical phenotype. The disease is panethnic. In this update, we report 137 mutations (64 of which are novel), consisting of 89 missense mutations, 19 nonsense mutations, 17 mutations that affect splicing, and 12 deletions. The change p.Gly390Arg is by far the most common mutation and is widely spread throughout the world. Other frequent mutations (p.Arg157His, p.Trp179Arg, p.Val263Met, p.Arg304Trp, p.Gly324Ser, p.Gly362Val, and p.Arg363Trp), each found in at least 12 independent families, are mainly carried by patients from the Indian subcontinent, Turkey, Germany, and Japan. To better understand the disease, we collected clinical data of >360 patients, including all published information available. This information is related to the patients' genetic background, the conservation of the mutated residues and a structural rationalization of the effect of the most frequent mutations. In addition, we review ASS regulation, animal models, diagnostic strategies, newborn screening, and treatment options.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Citrulinemia/diagnóstico
Citrulinemia/genética
Mutação
[Mh] Termos MeSH secundário: Alelos
Sequência de Aminoácidos
Animais
Argininossuccinato Sintase/química
Argininossuccinato Sintase/metabolismo
Citrulinemia/epidemiologia
Citrulinemia/terapia
Modelos Animais de Doenças
Ativação Enzimática
Estudos de Associação Genética
Genótipo
Geografia Médica
Seres Humanos
Modelos Moleculares
Fenótipo
Matrizes de Pontuação de Posição Específica
Diagnóstico Pré-Natal
Conformação Proteica
Índice de Gravidade de Doença
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE
[do] DOI:10.1002/humu.23184



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