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Pesquisa : D03.633.100.759.646.138.382 [Categoria DeCS]
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[PMID]:28863176
[Au] Autor:Arber C; Angelova PR; Wiethoff S; Tsuchiya Y; Mazzacuva F; Preza E; Bhatia KP; Mills K; Gout I; Abramov AY; Hardy J; Duce JA; Houlden H; Wray S
[Ad] Endereço:Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
[Ti] Título:iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.
[So] Source:PLoS One;12(9):e0184104, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.
[Mh] Termos MeSH primário: Células-Tronco Pluripotentes Induzidas/citologia
Doenças Mitocondriais/fisiopatologia
Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
[Mh] Termos MeSH secundário: Acetilcoenzima A/química
Adolescente
Biópsia
Encéfalo/metabolismo
Diferenciação Celular
Criança
Coenzima A/metabolismo
Feminino
Fibroblastos/metabolismo
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Ferro/química
Cariotipagem
Peroxidação de Lipídeos
Masculino
Potencial da Membrana Mitocondrial
Mitocôndrias/patologia
Mutação
NAD/química
Neurônios/metabolismo
Ácido Pantotênico/química
Fenótipo
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Plasmídeos/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 0U46U6E8UK (NAD); 19F5HK2737 (Pantothenic Acid); 72-89-9 (Acetyl Coenzyme A); E1UOL152H7 (Iron); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.33 (pantothenate kinase); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184104


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[PMID]:28832133
[Au] Autor:Arnott ZLP; Nozaki S; Monteiro DCF; Morgan HE; Pearson AR; Niki H; Webb ME
[Ad] Endereço:Astbury Centre for Structural Molecular Biology and School of Chemistry, University of Leeds , Leeds LS2 9JT, U.K.
[Ti] Título:The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ·AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan).
[So] Source:Biochemistry;56(37):4931-4939, 2017 Sep 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of ß-alanine in response to coenzyme A concentration. We show that formation of such a complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked ß-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development.
[Mh] Termos MeSH primário: Acetilcoenzima A/metabolismo
Carboxiliases/metabolismo
Escherichia coli K12/metabolismo
Proteínas de Escherichia coli/metabolismo
Glutamato Descarboxilase/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Acetilcoenzima A/análogos & derivados
Acetilcoenzima A/química
Substituição de Aminoácidos
Antibacterianos/farmacologia
Antimetabólitos/farmacologia
Sítios de Ligação
Calorimetria
Carboxiliases/química
Carboxiliases/genética
Coenzima A/síntese química
Coenzima A/química
Coenzima A/metabolismo
Cristalografia por Raios X
Ativação Enzimática/efeitos dos fármacos
Escherichia coli K12/efeitos dos fármacos
Escherichia coli K12/crescimento & desenvolvimento
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Deleção de Genes
Glutamato Descarboxilase/antagonistas & inibidores
Glutamato Descarboxilase/química
Glutamato Descarboxilase/genética
Cinética
Mutação
Ácido Pantotênico/análogos & derivados
Ácido Pantotênico/farmacologia
Conformação Proteica
Multimerização Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Titulometria
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antimetabolites); 0 (Escherichia coli Proteins); 0 (N-pentylpantothenamide); 0 (PanZ protein, E coli); 0 (Recombinant Proteins); 19F5HK2737 (Pantothenic Acid); 72-89-9 (Acetyl Coenzyme A); EC 4.1.1.- (Carboxy-Lyases); EC 4.1.1.- (PanD protein, E coli); EC 4.1.1.11 (aspartate-alpha-decarboxylase); EC 4.1.1.15 (Glutamate Decarboxylase); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00509


  3 / 4594 MEDLINE  
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[PMID]:28798160
[Au] Autor:Ley SC; de Carvalho LPS
[Ad] Endereço:The Francis Crick Institute, London, U.K.
[Ti] Título:Protein CoAlation: a redox-linked post-translational modification.
[So] Source:Biochem J;474(16):2897-2899, 2017 Aug 10.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Regulation of metabolic pathways by signal transduction and transcriptional cascades can alter cellular levels of metabolites. Metabolites themselves can also have regulatory activity as shown in a new study published in the Tsuchiya et al. describe a novel antibody and mass spectrometry-based method for identifying proteins that are reversibly modified with Coenzyme A (CoA). Analysis of the 'CoAlated proteome' under conditions of oxidative and metabolic stress revealed a bias towards the modification of metabolic enzymes by CoA. Furthermore, CoAlation was shown to alter the activity of target proteins. These results suggest that CoAlation is a widespread post-translational modification that may have important roles in the metabolic response to stress.
[Mh] Termos MeSH primário: Coenzima A/metabolismo
Fígado/metabolismo
Miocárdio/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Animais
Anticorpos/química
Cisteína/metabolismo
Células HEK293
Seres Humanos
Masculino
Redes e Vias Metabólicas
Técnicas de Cultura de Órgãos
Oxirredução
Pirofosfatases/química
Ratos
Ratos Sprague-Dawley
Transdução de Sinais
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); EC 3.6.1.- (Pyrophosphatases); EC 3.6.1.- (nudix hydrolases); K848JZ4886 (Cysteine); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170168


  4 / 4594 MEDLINE  
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[PMID]:28703494
[Au] Autor:Reidl C; Majorek KA; Dang J; Tran D; Jew K; Law M; Payne Y; Minor W; Becker DP; Kuhn ML
[Ad] Endereço:Department of Chemistry, Loyola University Chicago, IL, USA.
[Ti] Título:Generating enzyme and radical-mediated bisubstrates as tools for investigating Gcn5-related N-acetyltransferases.
[So] Source:FEBS Lett;591(15):2348-2361, 2017 Aug.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gcn5-related N-acetyltransferases (GNATs) are found in all kingdoms of life and catalyze important acyl transfer reactions in diverse cellular processes. While many 3D structures of GNATs have been determined, most do not contain acceptor substrates in their active sites. To expand upon existing crystallographic strategies for improving acceptor-bound GNAT structures, we synthesized peptide substrate analogs and reacted them with CoA in PA4794 protein crystals. We found two separate mechanisms for bisubstrate formation: (a) a novel X-ray induced radical-mediated alkylation of CoA with an alkene peptide and (b) direct alkylation of CoA with a halogenated peptide. Our approach is widely applicable across the GNAT superfamily and can be used to improve the success rate of obtaining liganded structures of other acyltransferases.
[Mh] Termos MeSH primário: Acetiltransferases/química
Acetiltransferases/metabolismo
Bioquímica/métodos
Coenzima A/química
[Mh] Termos MeSH secundário: Acetiltransferases/genética
Domínio Catalítico
Cristalização
Dipeptídeos/química
Dipeptídeos/metabolismo
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Dipeptides); EC 2.3.1.- (Acetyltransferases); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12753


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[PMID]:28590752
[Au] Autor:Grünewald J; Jin Y; Vance J; Read J; Wang X; Wan Y; Zhou H; Ou W; Klock HE; Peters EC; Uno T; Brock A; Geierstanger BH
[Ad] Endereço:Genomics Institute of the Novartis Research Foundation (GNF) , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
[Ti] Título:Optimization of an Enzymatic Antibody-Drug Conjugation Approach Based on Coenzyme A Analogs.
[So] Source:Bioconjug Chem;28(7):1906-1915, 2017 Jul 19.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphopantetheine transferases (PPTases) can be used to efficiently prepare site-specific antibody-drug conjugates (ADCs) by enzymatically coupling coenzyme A (CoA)-linker payloads to 11-12 amino acid peptide substrates inserted into antibodies. Here, a two-step strategy is established wherein in a first step, CoA analogs with various bioorthogonal reactivities are enzymatically installed on the antibody for chemical conjugation with a cytotoxic payload in a second step. Because of the high structural similarity of these CoA analogs to the natural PPTase substrate CoA-SH, the first step proceeds very efficiently and enables the use of peptide tags as short as 6 amino acids compared to the 11-12 amino acids required for efficient one-step coupling of the payload molecule. Furthermore, two-step conjugation provides access to diverse linker chemistries and spacers of varying lengths. The potency of the ADCs was largely independent of linker architecture. In mice, proteolytic cleavage was observed for some C-terminally linked auristatin payloads. The in vivo stability of these ADCs was significantly improved by reduction of the linker length. In addition, linker stability was found to be modulated by attachment site, and this, together with linker length, provides an opportunity for maximizing ADC stability without sacrificing potency.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/química
Coenzima A/química
Citotoxinas/química
Imunoconjugados/química
[Mh] Termos MeSH secundário: Aminobenzoatos/administração & dosagem
Aminobenzoatos/química
Animais
Citotoxinas/administração & dosagem
Estabilidade de Medicamentos
Camundongos
Oligopeptídeos/administração & dosagem
Oligopeptídeos/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminobenzoates); 0 (Antibodies, Monoclonal); 0 (Cytotoxins); 0 (Immunoconjugates); 0 (Oligopeptides); 0 (auristatin); SAA04E81UX (Coenzyme A)
[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:170608
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00236


  6 / 4594 MEDLINE  
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[PMID]:28542252
[Au] Autor:Boyle NR; Sengupta N; Morgan JA
[Ad] Endereço:School of Chemical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
[Ti] Título:Metabolic flux analysis of heterotrophic growth in Chlamydomonas reinhardtii.
[So] Source:PLoS One;12(5):e0177292, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite the wealth of knowledge available for C. reinhardtii, the central metabolic fluxes of growth on acetate have not yet been determined. In this study, 13C-metabolic flux analysis (13C-MFA) was used to determine and quantify the metabolic pathways of primary metabolism in C. reinhardtii cells grown under heterotrophic conditions with acetate as the sole carbon source. Isotopic labeling patterns of compartment specific biomass derived metabolites were used to calculate the fluxes. It was found that acetate is ligated with coenzyme A in the three subcellular compartments (cytosol, mitochondria and plastid) included in the model. Two citrate synthases were found to potentially be involved in acetyl-coA metabolism; one localized in the mitochondria and the other acting outside the mitochondria. Labeling patterns demonstrate that Acetyl-coA synthesized in the plastid is directly incorporated in synthesis of fatty acids. Despite having a complete TCA cycle in the mitochondria, it was also found that a majority of the malate flux is shuttled to the cytosol and plastid where it is converted to oxaloacetate providing reducing equivalents to these compartments. When compared to predictions by flux balance analysis, fluxes measured with 13C-MFA were found to be suboptimal with respect to biomass yield; C. reinhardtii sacrifices biomass yield to produce ATP and reducing equivalents.
[Mh] Termos MeSH primário: Chlamydomonas reinhardtii/crescimento & desenvolvimento
Chlamydomonas reinhardtii/metabolismo
Processos Heterotróficos/fisiologia
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Trifosfato de Adenosina/metabolismo
Carbono/metabolismo
Isótopos de Carbono
Citrato (si)-Sintase/metabolismo
Coenzima A/metabolismo
Citosol/metabolismo
Ácidos Graxos/metabolismo
Malatos/metabolismo
Análise do Fluxo Metabólico
Mitocôndrias/metabolismo
Modelos Biológicos
Ácido Oxaloacético/metabolismo
Proteínas de Plantas/metabolismo
Plastídeos/metabolismo
Acetato de Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbon Isotopes); 0 (Fatty Acids); 0 (Malates); 0 (Plant Proteins); 2F399MM81J (Oxaloacetic Acid); 72-89-9 (Acetyl Coenzyme A); 7440-44-0 (Carbon); 817L1N4CKP (malic acid); 8L70Q75FXE (Adenosine Triphosphate); EC 2.3.3.1 (Citrate (si)-Synthase); FM5526K07A (Zinc Acetate); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177292


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[PMID]:28365341
[Au] Autor:Ye W; Li J; Han R; Xu G; Dong J; Ni Y
[Ad] Endereço:Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China; Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China.
[Ti] Título:Engineering coenzyme A-dependent pathway from Clostridium saccharobutylicum in Escherichia coli for butanol production.
[So] Source:Bioresour Technol;235:140-148, 2017 Jul.
[Is] ISSN:1873-2976
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Clostridium saccharobutylicum has been proved to be efficient in butanol fermentation from various feedstocks. Whereas, lack of genetic manipulation system has severely hindered the engineering of C. saccharobutylicum for more extensive applications. In this study, recombinant Escherichia coli harboring heterologous coenzyme A-dependent pathway from C. saccharobutylicum DSM 13864 was constructed, which consisted of solventogenic pathway genes: acetoacetyl-CoA thiolase (thlA), aldehyde/alcohol dehydrogenase (adhE2) and bcs-operon (crt-bcd1-etfB2-fixB2-hbd). Then, a butanol titer of 67mg/L was attained. After replacing thlA with acetyl-CoA acetyltransferase (atoB) from E. coli and deleting the competitive branch genes lactate dehydrogenase (ldhA), aldehyde/alcohol dehydrogenase (adhE1) and fumarate reductase (frdBC), the butanol titer was successfully improved for 3.8-fold (254mg/L). Under the optimum fermentation conditions, the final butanol titer reached 584mg/L after 120h. This result demonstrates the feasibility of adapting CoA-dependent solventogenic pathway from C. saccharobutylicum in E. coli for butanol synthesis.
[Mh] Termos MeSH primário: Coenzima A/metabolismo
Escherichia coli/metabolismo
[Mh] Termos MeSH secundário: Butanóis/metabolismo
Clostridium/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Butanols); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170403
[St] Status:MEDLINE


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[PMID]:28341808
[Au] Autor:Tsuchiya Y; Peak-Chew SY; Newell C; Miller-Aidoo S; Mangal S; Zhyvoloup A; Bakovic J; Malanchuk O; Pereira GC; Kotiadis V; Szabadkai G; Duchen MR; Campbell M; Cuenca SR; Vidal-Puig A; James AM; Murphy MP; Filonenko V; Skehel M; Gout I
[Ad] Endereço:Department of Structural and Molecular Biology, University College London, London WC1E 6BT, U.K.
[Ti] Título:Protein CoAlation: a redox-regulated protein modification by coenzyme A in mammalian cells.
[So] Source:Biochem J;474(14):2489-2508, 2017 Jul 11.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Coenzyme A (CoA) is an obligatory cofactor in all branches of life. CoA and its derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. Abnormal biosynthesis and homeostasis of CoA and its derivatives have been associated with various human pathologies, including cancer, diabetes and neurodegeneration. Using an anti-CoA monoclonal antibody and mass spectrometry, we identified a wide range of cellular proteins which are modified by covalent attachment of CoA to cysteine thiols (CoAlation). We show that protein CoAlation is a reversible post-translational modification that is induced in mammalian cells and tissues by oxidising agents and metabolic stress. Many key cellular enzymes were found to be CoAlated and in ways that modified their activities. Our study reveals that protein CoAlation is a widespread post-translational modification which may play an important role in redox regulation under physiological and pathophysiological conditions.
[Mh] Termos MeSH primário: Coenzima A/metabolismo
Proteínas/metabolismo
[Mh] Termos MeSH secundário: Animais
Cisteína/metabolismo
Células HEK293
Células Hep G2
Seres Humanos
Rim/metabolismo
Fígado/metabolismo
Masculino
Miocárdio/metabolismo
Especificidade de Órgãos
Oxirredução
Estresse Oxidativo
Processamento de Proteína Pós-Traducional
Coelhos
Ratos Sprague-Dawley
Compostos de Sulfidrila/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteins); 0 (Sulfhydryl Compounds); K848JZ4886 (Cysteine); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170129


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[PMID]:28262353
[Au] Autor:Goldford JE; Hartman H; Smith TF; Segrè D
[Ad] Endereço:Bioinformatics Program, Boston University, Boston, MA 02215, USA.
[Ti] Título:Remnants of an Ancient Metabolism without Phosphate.
[So] Source:Cell;168(6):1126-1134.e9, 2017 Mar 09.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility. We used systems biology approaches to explore the alternative hypothesis that a protometabolism could have emerged prior to the incorporation of phosphate. Surprisingly, we identified a cryptic phosphate-independent core metabolism producible from simple prebiotic compounds. This network is predicted to support the biosynthesis of a broad category of key biomolecules. Its enrichment for enzymes utilizing iron-sulfur clusters, and the fact that thermodynamic bottlenecks are more readily overcome by thioester rather than phosphate couplings, suggest that this network may constitute a "metabolic fossil" of an early phosphate-free nonenzymatic biochemistry. Our results corroborate and expand previous proposals that a putative thioester-based metabolism could have predated the incorporation of phosphate and an RNA-based genetic system. PAPERCLIP.
[Mh] Termos MeSH primário: Simulação por Computador
Redes e Vias Metabólicas
Fosfatos/metabolismo
[Mh] Termos MeSH secundário: Nucleotídeos de Adenina/química
Algoritmos
Coenzima A
Coenzimas
Origem da Vida
Fosfatos/química
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Adenine Nucleotides); 0 (Coenzymes); 0 (Phosphates); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170622
[Lr] Data última revisão:
170622
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE


  10 / 4594 MEDLINE  
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[PMID]:28230972
[Au] Autor:Muchiri R; Walker KD
[Ad] Endereço:Department of Chemistry, Michigan State University , East Lansing, Michigan 48824, United States.
[Ti] Título:Paclitaxel Biosynthesis: Adenylation and Thiolation Domains of an NRPS TycA PheAT Module Produce Various Arylisoserine CoA Thioesters.
[So] Source:Biochemistry;56(10):1415-1425, 2017 Mar 14.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Structure-activity relationship studies show that the phenylisoserinyl moiety of paclitaxel (Taxol) is largely necessary for the effective anticancer activity. Several paclitaxel analogues with a variant isoserinyl side chain have improved pharmaceutical properties versus those of the parent drug. To produce the isoserinyl CoAs as intermediates needed for enzyme catalysis on a semibiosynthetic pathway to paclitaxel analogues, we repurposed the adenylation and thiolation domains (Phe-AT) of a nonribosomal peptide synthetase (TycA) so that they would function as a CoA ligase. Twenty-eight isoserine analogue racemates were synthesized by an established procedure based on the Staudinger [2+2] cycloaddition reaction. Phe-AT converted 16 substituted phenylisoserines, one ß-(heteroaryl)isoserine, and one ß-(cyclohexyl)isoserine to their corresponding isoserinyl CoAs. We imagine that these CoA thioesters can likely serve as linchpin biosynthetic acyl donors transferred by a 13-O-acyltransferase to a paclitaxel precursor baccatin III to make drug analogues with better efficacy. It was also interesting to find that an active site mutant [Phe-AT (W227S)] turned over 2-pyridylisoserine and the sterically demanding p-methoxyphenylisoserine substrates to their CoA thioesters, while Phe-AT did not. This mutant is promising for further development to make 3-fluoro-2-pyridylisoserinyl CoA, a biosynthetic precursor of the oral pharmaceutical tesetaxel used for gastric cancers.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/biossíntese
Coenzima A/química
Escherichia coli/genética
Peptídeo Sintases/química
Proteínas de Plantas/química
Engenharia de Proteínas
[Mh] Termos MeSH secundário: Alcaloides/biossíntese
Alcaloides/síntese química
Antineoplásicos Fitogênicos/síntese química
Brevibacillus/química
Brevibacillus/enzimologia
Domínio Catalítico
Clonagem Molecular
Coenzima A/metabolismo
Escherichia coli/enzimologia
Expressão Gênica
Cinética
Modelos Moleculares
Paclitaxel/biossíntese
Paclitaxel/síntese química
Peptídeo Sintases/genética
Peptídeo Sintases/metabolismo
Proteínas de Plantas/metabolismo
Domínios Proteicos
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Taxoides/síntese química
Taxoides/metabolismo
Taxus/química
Taxus/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Antineoplastic Agents, Phytogenic); 0 (Plant Proteins); 0 (Recombinant Proteins); 0 (Taxoids); 0 (phenylisoserinyl CoA, Taxus); 40K5PZ0K67 (baccatin III); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (tyrocidine synthetase); P88XT4IS4D (Paclitaxel); SAA04E81UX (Coenzyme A); UG97LO5M8Y (tesetaxel)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b01188



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