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Pesquisa : D03.383.742.686.246.370 [Categoria DeCS]
Referências encontradas : 663 [refinar]
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[PMID]:29289891
[Au] Autor:Szymanska-Michalak A; Wawrzyniak D; Framski G; Stawinski J; Barciszewski J; Kraszewski A
[Ad] Endereço:Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
[Ti] Título:New antiglioma zwitterionic pronucleotides with an FdUMP framework.
[So] Source:Eur J Med Chem;144:682-691, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, anticancer drugs.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Citidina Monofosfato/análogos & derivados
Glioblastoma/tratamento farmacológico
Nucleotídeos/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Citidina Monofosfato/química
Citidina Monofosfato/farmacologia
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Glioblastoma/patologia
Seres Humanos
Estrutura Molecular
Nucleotídeos/síntese química
Nucleotídeos/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Nucleotides); 847-22-3 (5-fluoro-2'-deoxycytidine 5'-monophosphate); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29022704
[Au] Autor:Walton T; Szostak JW
[Ad] Endereço:Howard Hughes Medical Institute, Department of Molecular Biology, and Center for Computational and Integrative Biology, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
[Ti] Título:A Kinetic Model of Nonenzymatic RNA Polymerization by Cytidine-5'-phosphoro-2-aminoimidazolide.
[So] Source:Biochemistry;56(43):5739-5747, 2017 Oct 31.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The nonenzymatic polymerization of RNA may have enabled copying of functional sequences during the origin of life. Recent progress utilizing 5'-phosphoro-2-aminoimidazole activation has reinvigorated the possibility of using nonenzymatic RNA polymerization for copying arbitrary sequences. However, the reasons why 2-aminoimidazole (AI) is a superior activation group remain unclear. Here we report that the predominant mechanism of polymerization using cytidine-5'-phosphoro-2-aminoimidazolide (Cp*) involves a 2-aminoimidazolium-bridged dinucleotide (Cp*pC) intermediate. To explore the role of this intermediate, we first identify and quantify four reactions involving the synthesis and breakdown of Cp*pC that occur in the absence of the primer-template duplex. We then analyze the dependence of the rate of polymerization on the concentration of the Cp*pC intermediate in the presence and absence of the competitive inhibitor Cp. We also show that the contribution of the monomer Cp* to the polymerization rate is negligible under our primer extension conditions. Finally, we use the experimentally determined rate constants of these reactions to develop a kinetic model that helps explain the changing rate of nonenzymatic RNA polymerization over time. Our model accounts for the concentration of Cp*pC formed by Cp* under primer extension conditions. The model does not completely account for the decline in polymerization rate observed over long times, which indicates that additional important inhibitory processes have not yet been identified. Our results suggest that the superiority of 2-aminoimidazole over the traditional 2-methylimidazole activation is mostly due to the higher level of accumulation of the imidazolium-bridged intermediate under primer extension conditions.
[Mh] Termos MeSH primário: Citidina Monofosfato/análogos & derivados
Citidina Monofosfato/química
RNA Polimerases Dirigidas por DNA/química
Modelos Químicos
RNA/síntese química
[Mh] Termos MeSH secundário: Cinética
RNA/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
63231-63-0 (RNA); EC 2.7.7.6 (DNA-Directed RNA Polymerases); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00792


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[PMID]:28678474
[Au] Autor:Sato S; Kudo F; Kim SY; Kuzuyama T; Eguchi T
[Ad] Endereço:Department of Chemistry, Tokyo Institute of Technology , 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan.
[Ti] Título:Methylcobalamin-Dependent Radical SAM C-Methyltransferase Fom3 Recognizes Cytidylyl-2-hydroxyethylphosphonate and Catalyzes the Nonstereoselective C-Methylation in Fosfomycin Biosynthesis.
[So] Source:Biochemistry;56(28):3519-3522, 2017 Jul 18.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A methylcobalamin (MeCbl)-dependent radical S-adenosyl-l-methionine (SAM) methyltransferase Fom3 was found to catalyze the C-methylation of cytidylyl-2-hydroxyethylphosphonate (HEP-CMP) to give cytidylyl-2-hydroxypropylphosphonate (HPP-CMP), although it was originally proposed to catalyze the C-methylation of 2-hydroxyethylphosphonate to give 2-hydroxypropylphosphonate in the biosynthesis of a unique C-P bond containing antibiotic fosfomycin in Streptomyces. Unexpectedly, the Fom3 reaction product from HEP-CMP was almost a 1:1 diastereomeric mixture of HPP-CMP, indicating that the C-methylation is not stereoselective. Presumably, only the CMP moiety of HEP-CMP is critical for substrate recognition; on the other hand, the enzyme does not fix the 2-hydroxy group of the substrate and either of the prochiral hydrogen atoms at the C2 position can be abstracted by the 5'-deoxyadenosyl radical generated from SAM to form the substrate radical intermediates, which react with MeCbl to afford the corresponding products. This strict substrate recognition mechanism with no stereoselectivity of a MeCbl-dependent radical SAM methyltransferase is remarkable in natural product biosynthetic chemistry, because such a hidden clue for selective substrate recognition is likely to be found in the other biosynthetic pathways.
[Mh] Termos MeSH primário: Fosfomicina/metabolismo
Metiltransferases/metabolismo
Organofosfonatos/metabolismo
Streptomyces/enzimologia
Vitamina B 12/análogos & derivados
[Mh] Termos MeSH secundário: Vias Biossintéticas
Citidina Monofosfato/metabolismo
Metilação
S-Adenosilmetionina/metabolismo
Streptomyces/metabolismo
Especificidade por Substrato
Vitamina B 12/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-hydroxyethyl phosphonate); 0 (Organophosphonates); 2N81MY12TE (Fosfomycin); 7LP2MPO46S (S-Adenosylmethionine); BR1SN1JS2W (mecobalamin); EC 2.1.1.- (Methyltransferases); EC 2.1.1.12 (methionine S-methyltransferase); F469818O25 (Cytidine Monophosphate); P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170804
[Lr] Data última revisão:
170804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170706
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00472


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[PMID]:28650160
[Au] Autor:Zhen L; Dai L; Wen X; Yao L; Jin X; Yang XW; Zhao W; Yu SQ; Yuan H; Wang G; Sun H
[Ad] Endereço:Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University , 24 Tongjia Xiang, Nanjing 210009, China.
[Ti] Título:Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation.
[So] Source:J Med Chem;60(14):6077-6088, 2017 Jul 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-ß-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N -modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC = 0.19-0.25 µM) exhibited comparable potency to that of sofosbuvir (EC = 0.15 µM) on inhibition of wild-type replicons. Notably, 4c (EC = 0.366 µM) was 1.5-fold more potent than sofosbuvir (EC = 0.589 µM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.
[Mh] Termos MeSH primário: Alanina/análogos & derivados
Antivirais/química
Citidina Monofosfato/análogos & derivados
Hepacivirus/efeitos dos fármacos
Nucleotídeos/síntese química
Pró-Fármacos/síntese química
[Mh] Termos MeSH secundário: Alanina/síntese química
Alanina/farmacocinética
Alanina/farmacologia
Animais
Antivirais/síntese química
Antivirais/farmacologia
Linhagem Celular Tumoral
Citidina Monofosfato/síntese química
Citidina Monofosfato/farmacocinética
Citidina Monofosfato/farmacologia
Cães
Feminino
Hepacivirus/genética
Seres Humanos
Fígado/metabolismo
Masculino
Mutação
Nucleotídeos/farmacocinética
Nucleotídeos/farmacologia
Pró-Fármacos/farmacocinética
Pró-Fármacos/farmacologia
RNA Replicase/genética
Replicon
Estereoisomerismo
Relação Estrutura-Atividade
Proteínas não Estruturais Virais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (NS-5 protein, hepatitis C virus); 0 (Nucleotides); 0 (Prodrugs); 0 (Viral Nonstructural Proteins); 0 (isopropyl 2-((((5-(4-butyramido-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate); EC 2.7.7.48 (RNA Replicase); F469818O25 (Cytidine Monophosphate); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00262


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[PMID]:28472541
[Au] Autor:Ehrit J; Keys TG; Sutherland M; Wolf S; Meier C; Falconer RA; Gerardy-Schahn R
[Ad] Endereço:Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
[Ti] Título:Exploring and Exploiting Acceptor Preferences of the Human Polysialyltransferases as a Basis for an Inhibitor Screen.
[So] Source:Chembiochem;18(13):1332-1337, 2017 Jul 04.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:α2,8-Linked polysialic acid (polySia) is an oncofoetal antigen with high abundance during embryonic development. It reappears in malignant tumours of neuroendocrine origin. Two polysialyltransferases (polySTs) ST8SiaII and IV are responsible for polySia biosynthesis. During development, both enzymes are essential to control polySia expression. However, in tumours ST8SiaII is the prevalent enzyme. Consequently, ST8SiaII is an attractive target for novel cancer therapeutics. A major challenge is the high structural and functional conservation of ST8SiaII and -IV. An assay system that enables differential testing of ST8SiaII and -IV would be of high value to search for specific inhibitors. Here we exploited the different modes of acceptor recognition and elongation for this purpose. With DMB-DP3 and DMB-DP12 (fluorescently labelled sialic acid oligomers with a degree of polymerisation of 3 and 12, respectively) we identified stark differences between the two enzymes. The new acceptors enabled the simple comparative testing of the polyST initial transfer rate for a series of CMP-activated and N-substituted sialic acid derivatives. Of these derivatives, the non-transferable CMP-Neu5Cyclo was found to be a new, competitive ST8SiaII inhibitor.
[Mh] Termos MeSH primário: Antineoplásicos/química
Citidina Monofosfato/análogos & derivados
Inibidores Enzimáticos/química
Ácidos Siálicos/química
Sialiltransferases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Ciclização
Citidina Monofosfato/síntese química
Citidina Monofosfato/química
Inibidores Enzimáticos/síntese química
Corantes Fluorescentes/química
Expressão Gênica
Ensaios de Triagem em Larga Escala
Seres Humanos
Cinética
Fenilenodiaminas/química
Ácidos Siálicos/síntese química
Sialiltransferases/química
Sialiltransferases/genética
Sialiltransferases/metabolismo
Coloração e Rotulagem/métodos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Fluorescent Dyes); 0 (Phenylenediamines); 0 (Sialic Acids); 0 (cytidine-5'-monophosphosialic acid); 38608-07-0 (1,2-diamino-4,5-methylenedioxybenzene); EC 2.4.99.- (CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase); EC 2.4.99.- (Sialyltransferases); EC 3.4.99.- (ST8SIA4 protein, human); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700157


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[PMID]:28395125
[Au] Autor:Noel M; Gilormini PA; Cogez V; Yamakawa N; Vicogne D; Lion C; Biot C; Guérardel Y; Harduin-Lepers A
[Ad] Endereço:Université de Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France.
[Ti] Título:Probing the CMP-Sialic Acid Donor Specificity of Two Human ß-d-Galactoside Sialyltransferases (ST3Gal I and ST6Gal I) Selectively Acting on O- and N-Glycosylproteins.
[So] Source:Chembiochem;18(13):1251-1259, 2017 Jul 04.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Sialylation of glycoproteins and glycolipids is catalyzed by sialyltransferases in the Golgi of mammalian cells, whereby sialic acid residues are added at the nonreducing ends of oligosaccharides. Because sialylated glycans play critical roles in a number of human physio-pathological processes, the past two decades have witnessed the development of modified sialic acid derivatives for a better understanding of sialic acid biology and for the development of new therapeutic targets. However, nothing is known about how individual mammalian sialyltransferases tolerate and behave towards these unnatural CMP-sialic acid donors. In this study, we devised several approaches to investigate the donor specificity of the human ß-d-galactoside sialyltransferases ST6Gal I and ST3Gal I by using two CMP-sialic acids: CMP-Neu5Ac, and CMP-Neu5N-(4pentynoyl)neuraminic acid (CMP-SiaNAl), an unnatural CMP-sialic acid donor with an extended and functionalized N-acyl moiety.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Ácido N-Acetilneuramínico Citidina Monofosfato/metabolismo
Citidina Monofosfato/análogos & derivados
Glicolipídeos/metabolismo
Glicoproteínas/metabolismo
Polissacarídeos/metabolismo
Ácidos Siálicos/metabolismo
Sialiltransferases/metabolismo
[Mh] Termos MeSH secundário: Antígenos CD/química
Antígenos CD/genética
Proteínas de Bactérias/química
Proteínas de Bactérias/metabolismo
Clonagem Molecular
Citidina Monofosfato/química
Citidina Monofosfato/metabolismo
Ácido N-Acetilneuramínico Citidina Monofosfato/química
Expressão Gênica
Glicolipídeos/química
Glicoproteínas/química
Glicoproteínas/genética
Glicosilação
Células HEK293
Seres Humanos
Cinética
N-Acilneuraminato Citidililtransferase/genética
N-Acilneuraminato Citidililtransferase/metabolismo
Neisseria meningitidis/química
Neisseria meningitidis/enzimologia
Polissacarídeos/química
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Ácidos Siálicos/química
Sialiltransferases/química
Sialiltransferases/genética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Bacterial Proteins); 0 (Glycolipids); 0 (Glycoproteins); 0 (Polysaccharides); 0 (Recombinant Proteins); 0 (Sialic Acids); 0 (cytidine-5'-monophosphosialic acid); 3063-71-6 (Cytidine Monophosphate N-Acetylneuraminic Acid); EC 2.4.99.- (Sialyltransferases); EC 2.4.99.1 (ST6GAL1 protein, human); EC 2.4.99.4 (beta-galactoside alpha-2,3-sialyltransferase); EC 2.7.7.43 (N-Acylneuraminate Cytidylyltransferase); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170723
[Lr] Data última revisão:
170723
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700024


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[PMID]:27994034
[Au] Autor:Mentegari E; Crespan E; Bavagnoli L; Kissova M; Bertoletti F; Sabbioneda S; Imhof R; Sturla SJ; Nilforoushan A; Hübscher U; van Loon B; Maga G
[Ad] Endereço:DNA Enzymology & Molecular Virology and Cell Nucleus & DNA replication Units, Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy.
[Ti] Título:Ribonucleotide incorporation by human DNA polymerase η impacts translesion synthesis and RNase H2 activity.
[So] Source:Nucleic Acids Res;45(5):2600-2614, 2017 Mar 17.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ribonucleotides (rNs) incorporated in the genome by DNA polymerases (Pols) are removed by RNase H2. Cytidine and guanosine preferentially accumulate over the other rNs. Here we show that human Pol η can incorporate cytidine monophosphate (rCMP) opposite guanine, 8-oxo-7,8-dihydroguanine, 8-methyl-2΄-deoxyguanosine and a cisplatin intrastrand guanine crosslink (cis-PtGG), while it cannot bypass a 3-methylcytidine or an abasic site with rNs as substrates. Pol η is also capable of synthesizing polyribonucleotide chains, and its activity is enhanced by its auxiliary factor DNA Pol δ interacting protein 2 (PolDIP2). Human RNase H2 removes cytidine and guanosine less efficiently than the other rNs and incorporation of rCMP opposite DNA lesions further reduces the efficiency of RNase H2. Experiments with XP-V cell extracts indicate Pol η as the major basis of rCMP incorporation opposite cis-PtGG. These results suggest that translesion synthesis by Pol η can contribute to the accumulation of rCMP in the genome, particularly opposite modified guanines.
[Mh] Termos MeSH primário: Dano ao DNA
Reparo do DNA
DNA Polimerase Dirigida por DNA/metabolismo
Ribonuclease H/metabolismo
Ribonucleotídeos/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Citidina Monofosfato/metabolismo
DNA/biossíntese
Guanina/análogos & derivados
Guanina/metabolismo
Seres Humanos
RNA/biossíntese
Xeroderma Pigmentoso/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ribonucleotides); 5614-64-2 (8-hydroxyguanine); 5Z93L87A1R (Guanine); 63231-63-0 (RNA); 9007-49-2 (DNA); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (Rad30 protein); EC 3.1.26.- (ribonuclease HII); EC 3.1.26.4 (Ribonuclease H); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkw1275


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[PMID]:27614914
[Au] Autor:Crous W; Naidoo KJ
[Ad] Endereço:Scientific Computing Research Unit and Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
[Ti] Título:Conformational and electrostatic analysis of S 1 donor analogue glycomimetic inhibitors of ST3Gal-I mammalian sialyltransferase.
[So] Source:Bioorg Med Chem;24(20):4998-5005, 2016 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mammalian sialyltransferases play a role in the metastasis of various cancers in humans. Inhibitors of these enzymes will in principle be able to directly inhibit aberrant sialylation in cancer. Inhibitors of ST3Gal-I resembling the donor component of S 1 Transition State structures were previously evaluated as part of a kinetics study. Here, using classical dynamics simulations and free energy perturbation calculations, we rationalize the performance of three of these donor analogue ST3Gal-I enzyme inhibitors. We find to inhibit the mammalian ST3Gal-I enzyme a donor analogue requires configurationally limited functionality. This is mediated by the binding of the inhibitor to the enzyme. The inhibitor's ability to interact with Y194 and T272 through a charged group such as a carboxylate is especially important. Furthermore, a conformational rigid form approximating the donor substrate is central. Here this is achieved by an intramolecular hydrogen bond formed between the carboxylate group and one of the ribose hydroxyl groups of the cytidine monophosphate (CMP) leaving group. This intramolecular interaction results in the donor substrate conformer complimenting the form of the catalytic binding site. Finally the carboxylate charge is essential for electrostatic pairing with the binding site. Substituting this group for an alcohol or amide results in severe weakening of the ligand binding. The carboxylate thus proves an to be an irreplaceable functional group and an essential pharmacophore.
[Mh] Termos MeSH primário: Carboidratos/farmacologia
Citidina Monofosfato/farmacologia
Inibidores Enzimáticos/farmacologia
Sialiltransferases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Carboidratos/química
Cristalografia por Raios X
Citidina Monofosfato/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/química
Modelos Moleculares
Conformação Molecular
Sialiltransferases/metabolismo
Eletricidade Estática
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbohydrates); 0 (Enzyme Inhibitors); EC 2.4.99.- (Sialyltransferases); EC 2.4.99.4 (beta-galactoside alpha-2,3-sialyltransferase); F469818O25 (Cytidine Monophosphate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170910
[Lr] Data última revisão:
170910
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160912
[St] Status:MEDLINE


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[PMID]:26980148
[Au] Autor:Chen SC; Huang CH; Lai SJ; Yang CS; Hsiao TH; Lin CH; Fu PK; Ko TP; Chen Y
[Ad] Endereço:Department of Biotechnology, Hungkuang University, Taichung, Taiwan.
[Ti] Título:Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.
[So] Source:Sci Rep;6:23274, 2016 Mar 16.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme.
[Mh] Termos MeSH primário: Ácido N-Acetilneuramínico/biossíntese
[Mh] Termos MeSH secundário: Regulação Alostérica
Sequência de Aminoácidos
Carboidratos Epimerases/antagonistas & inibidores
Carboidratos Epimerases/química
Domínio Catalítico
Sequência Conservada
Cristalografia por Raios X
Citidina Monofosfato/análogos & derivados
Citidina Monofosfato/química
Inibidores Enzimáticos/química
Seres Humanos
Ligações de Hidrogênio
Hidrólise
Cinética
Modelos Moleculares
Ligação Proteica
Estrutura Quaternária de Proteína
Ácidos Siálicos/química
Difosfato de Uridina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Sialic Acids); 0 (cytidine-5'-monophosphosialic acid); 58-98-0 (Uridine Diphosphate); EC 5.1.3.- (Carbohydrate Epimerases); EC 5.1.3.14 (UDP acetylglucosamine-2-epimerase); F469818O25 (Cytidine Monophosphate); GZP2782OP0 (N-Acetylneuraminic Acid)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160317
[St] Status:MEDLINE
[do] DOI:10.1038/srep23274


  10 / 663 MEDLINE  
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[PMID]:26783088
[Au] Autor:Lim SM; Yeung K; Trésaugues L; Ling TH; Nordlund P
[Ad] Endereço:Division of Biomedical Structural Biology, School of Biological Sciences, Nanyang Technological University, Singapore.
[Ti] Título:The structure and catalytic mechanism of human sphingomyelin phosphodiesterase like 3a--an acid sphingomyelinase homologue with a novel nucleotide hydrolase activity.
[So] Source:FEBS J;283(6):1107-23, 2016 Mar.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Human sphingomyelinase phosphodiesterase like 3a (SMPDL3a) is a secreted enzyme that shares a conserved catalytic domain with human acid sphingomyelinase (aSMase), the enzyme carrying mutations causative of Niemann-Pick disease. We have solved the structure of SMPDL3a revealing a calcineurin-like fold. A dimetal site, glycosylation pattern and a disulfide bond network are likely to be conserved also in human aSMase. We show that the binuclear site of SMPDL3a is occupied by two Zn(2+) ions and that excess Zn(2+) leads to inhibition of enzyme activity through binding to additional sites. As an extension of recent biochemical work we uncovered that SMPDL3a catalyses the hydrolysis of several modified nucleotides that include cytidine 5'-diphosphocholine, cytidine diphosphate ethanolamine and ADP-ribose, but not the aSMase substrate, sphingomyelin. We subsequently determined the structure of SMPDL3a in complex with the product 5'-cytidine monophosphate (CMP), a structure that is consistent with several distinct coordination modes of the substrate/product in the active site during the reaction cycle. Based on the structure of CMP complexes, we propose a phosphoryl transfer mechanism for SMPDL3a. Finally, a homology model of human aSMase was constructed to allow for the mapping of selected Niemann-Pick disease mutations on a three-dimensional framework to guide further characterization of their effects on aSMase function. DATABASE: Structural data are available in the PDB database under the accession numbers 5EBB and 5EBE.
[Mh] Termos MeSH primário: Esfingomielina Fosfodiesterase/química
Esfingomielina Fosfodiesterase/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Domínio Catalítico
Sequência Conservada
Cristalografia por Raios X
Citidina Monofosfato/metabolismo
Dissulfetos/química
Glicosilação
Seres Humanos
Modelos Moleculares
Dados de Sequência Molecular
Proteínas Mutantes/química
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Doenças de Niemann-Pick/enzimologia
Doenças de Niemann-Pick/genética
Filogenia
Mutação Puntual
Conformação Proteica
Homologia de Sequência de Aminoácidos
Esfingomielina Fosfodiesterase/genética
Eletricidade Estática
Especificidade por Substrato
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Disulfides); 0 (Mutant Proteins); EC 3.1.4.12 (SMPDL3A protein, human); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); F469818O25 (Cytidine Monophosphate); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160323
[Lr] Data última revisão:
160323
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160120
[St] Status:MEDLINE
[do] DOI:10.1111/febs.13655



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