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[PMID]:27745548
[Au] Autor:Greer S; Han T; Dieguez C; McLean N; Saer R; Reis I; Levi J; Marquez VE
[Ad] Endereço:Deparment of Microbiology/ Immunology (R138), University of Miami, Miller School of Medicine, 1600 N.W.10th Ave Miami, FL 33136,United States.
[Ti] Título:Enzyme-Driven Chemo-and Radiation-Therapy with 12 Pyrimidine Nucleoside Analogs Not Yet in the Clinic.
[So] Source:Anticancer Agents Med Chem;17(2):250-264, 2017.
[Is] ISSN:1875-5992
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemotherapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U). Among patients with colon (19) and pancreatic tumors (40), 53 and 68 %, respectively, displayed T/N values >4 for CD suggesting chemotherapy with 5-FdC, 4-N-methylamino-5-FdC, 5-trifluoromethyldeoxycytidine and radiosensitization with 5- CldC, 4-N-methylamino-5-CldC, 5-iododeoxycytidine and 5-bromodeoxycytidine. The percent of patients with tumors with a T/N value >4 for U/CK in lung (72), colon (23) and breast (28) was 47, 61 and 68, respectively, suggesting zebularine (plus thymidine) treatment for tumors involving gene silencing. Evidence is presented that the 4-N-alkylamino-dC substituted nucleosides and those with large 5-substitutions are activated only via CD to thymidine kinase (TK) using end-points of cytotoxicity and/or radiosensitization: H4U, the inhibitor of CD is an antagonist, cells with low CD or no TK are resistant to the analogs, the end points are indifferent to the dCK status of cells, they are poor substrates for dCK and good substrates for CD, whereas 5-FdC and 5-CldC are good substrates for both enzymes. The analogs present opportunities for Collateral Sensitivity for 5-azacytidine and gemcitabine resistant tumors.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias/tratamento farmacológico
Neoplasias/radioterapia
Nucleosídeos de Pirimidina/uso terapêutico
[Mh] Termos MeSH secundário: Antineoplásicos/química
Linhagem Celular Tumoral
Citidina Desaminase/metabolismo
DCMP Desaminase/metabolismo
Desoxicitidina Quinase/metabolismo
Seres Humanos
Neoplasias/enzimologia
Nucleosídeos de Pirimidina/química
Radiossensibilizantes/química
Radiossensibilizantes/uso terapêutico
Uridina Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pyrimidine Nucleosides); 0 (Radiation-Sensitizing Agents); EC 2.7.1.48 (Uridine Kinase); EC 2.7.1.74 (Deoxycytidine Kinase); EC 3.5.4.12 (DCMP Deaminase); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE


  2 / 139 MEDLINE  
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[PMID]:27377385
[Au] Autor:Li Y; Guo Z; Jin L; Wang D; Gao Z; Su X; Hou H; Dong Y
[Ad] Endereço:Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
[Ti] Título:Mechanism of the allosteric regulation of Streptococcus mutans 2'-deoxycytidylate deaminase.
[So] Source:Acta Crystallogr D Struct Biol;72(Pt 7):883-91, 2016 07.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In cells, dUMP is the intermediate precursor of dTTP in its synthesis during deoxynucleotide metabolism. In Gram-positive bacteria and eukaryotes, zinc-dependent deoxycytidylate deaminases (dCDs) catalyze the conversion of dCMP to dUMP. The activity of dCD is allosterically activated by dCTP and inhibited by dTTP. Here, the crystal structure of Streptococcus mutans dCD (SmdCD) complexed with dTTP is presented at 2.35 Šresolution, thereby solving the first pair of activator-bound and inhibitor-bound structures from the same species to provide a more definitive description of the allosteric mechanism. In contrast to the dTTP-bound dCD from the bacteriophage S-TIM5 (S-TIM5-dCD), dTTP-bound SmdCD adopts an inactive conformation similar to the apo form. A structural comparison suggests that the distinct orientations of the triphosphate group in S-TIM5-dCD and SmdCD are a result of the varying protein binding environment. In addition, calorimetric data establish that the modulators bound to dCD can be mutually competitively replaced. The results reveal the mechanism underlying its regulator-specific activity and might greatly enhance the understanding of the allosteric regulation of other dCDs.
[Mh] Termos MeSH primário: DCMP Desaminase/metabolismo
Streptococcus mutans/enzimologia
[Mh] Termos MeSH secundário: Regulação Alostérica
Cristalografia por Raios X
DCMP Desaminase/química
Simulação de Acoplamento Molecular
Conformação Proteica
Streptococcus mutans/química
Streptococcus mutans/metabolismo
Especificidade por Substrato
Nucleotídeos de Timina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Thymine Nucleotides); EC 3.5.4.12 (DCMP Deaminase); QOP4K539MU (thymidine 5'-triphosphate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171117
[Lr] Data última revisão:
171117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160706
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798316009153


  3 / 139 MEDLINE  
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[PMID]:25746996
[Au] Autor:Oehlenschlæger CB; Løvgreen MN; Reinauer E; Lehtinen E; Pind ML; Harris P; Martinussen J; Willemoës M
[Ad] Endereço:Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
[Ti] Título:Bacillus halodurans Strain C125 Encodes and Synthesizes Enzymes from Both Known Pathways To Form dUMP Directly from Cytosine Deoxyribonucleotides.
[So] Source:Appl Environ Microbiol;81(10):3395-404, 2015 May 15.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Analysis of the genome of Bacillus halodurans strain C125 indicated that two pathways leading from a cytosine deoxyribonucleotide to dUMP, used for dTMP synthesis, were encoded by the genome of the bacterium. The genes that were responsible, the comEB gene and the dcdB gene, encoding dCMP deaminase and the bifunctional dCTP deaminase:dUTPase (DCD:DUT), respectively, were both shown to be expressed in B. halodurans, and both genes were subject to repression by the nucleosides thymidine and deoxycytidine. The latter nucleoside presumably exerts its repression after deamination by cytidine deaminase. Both comEB and dcdB were cloned, overexpressed in Escherichia coli, and purified to homogeneity. Both enzymes were active and displayed the expected regulatory properties: activation by dCTP for dCMP deaminase and dTTP inhibition for both enzymes. Structurally, the B. halodurans enzyme resembled the Mycobacterium tuberculosis enzyme the most. An investigation of sequenced genomes from other species of the genus Bacillus revealed that not only the genome of B. halodurans but also the genomes of Bacillus pseudofirmus, Bacillus thuringiensis, Bacillus hemicellulosilyticus, Bacillus marmarensis, Bacillus cereus, and Bacillus megaterium encode both the dCMP deaminase and the DCD:DUT enzymes. In addition, eight dcdB homologs from Bacillus species within the genus for which the whole genome has not yet been sequenced were registered in the NCBI Entrez database.
[Mh] Termos MeSH primário: Bacillus/enzimologia
Proteínas de Bactérias/metabolismo
Citosina/metabolismo
DCMP Desaminase/metabolismo
Desoxirribonucleotídeos/metabolismo
Nucleotídeos de Desoxiuracil/biossíntese
Nucleotídeo Desaminases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Bacillus/química
Bacillus/genética
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Vias Biossintéticas
Cristalografia por Raios X
DCMP Desaminase/química
DCMP Desaminase/genética
Cinética
Dados de Sequência Molecular
Nucleotídeo Desaminases/química
Nucleotídeo Desaminases/genética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Deoxyribonucleotides); 0 (Deoxyuracil Nucleotides); 8J337D1HZY (Cytosine); 964-26-1 (2'-deoxyuridylic acid); EC 3.5.4.- (Nucleotide Deaminases); EC 3.5.4.12 (DCMP Deaminase); EC 3.5.4.13 (dCTP deaminase)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150310
[St] Status:MEDLINE
[do] DOI:10.1128/AEM.00268-15


  4 / 139 MEDLINE  
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[PMID]:25404739
[Au] Autor:Marx A; Alian A
[Ad] Endereço:From the Faculty of Biology, Technion-Israel Institute of Technology, Haifa 320003, Israel.
[Ti] Título:The first crystal structure of a dTTP-bound deoxycytidylate deaminase validates and details the allosteric-inhibitor binding site.
[So] Source:J Biol Chem;290(1):682-90, 2015 Jan 02.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deoxycytidylate deaminase is unique within the zinc-dependent cytidine deaminase family as being allosterically regulated, activated by dCTP, and inhibited by dTTP. Here we present the first crystal structure of a dTTP-bound deoxycytidylate deaminase from the bacteriophage S-TIM5, confirming that this inhibitor binds to the same site as the dCTP activator. The molecular details of this structure, complemented by structures apo- and dCMP-bound, provide insights into the allosteric mechanism. Although the positioning of the nucleoside moiety of dTTP is almost identical to that previously described for dCTP, protonation of N3 in deoxythymidine and not deoxycytidine would facilitate hydrogen bonding of dTTP but not dCTP and may result in a higher affinity of dTTP to the allosteric site conferring its inhibitory activity. Further the functional group on C4 (O in dTTP and NH2 in dCTP) makes interactions with nonconserved protein residues preceding the allosteric motif, and the relative strength of binding to these residues appears to correspond to the potency of dTTP inhibition. The active sites of these structures are also uniquely occupied by dTMP and dCMP resolving aspects of substrate specificity. The methyl group of dTMP apparently clashes with a highly conserved tyrosine residue, preventing the formation of a correct base stacking shown to be imperative for deamination activity. The relevance of these findings to the wider zinc-dependent cytidine deaminase family is also discussed.
[Mh] Termos MeSH primário: DCMP Desaminase/química
Nucleotídeos de Desoxicitosina/química
Inibidores Enzimáticos/química
Nucleotídeos de Timina/química
Proteínas Virais/química
[Mh] Termos MeSH secundário: Regulação Alostérica
Sítio Alostérico
Sequência de Aminoácidos
Bacteriófagos/química
Bacteriófagos/enzimologia
Cristalografia por Raios X
DCMP Desaminase/antagonistas & inibidores
DCMP Desaminase/genética
DCMP Desaminase/metabolismo
Nucleotídeos de Desoxicitosina/metabolismo
Ativação Enzimática
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Ligações de Hidrogênio
Modelos Moleculares
Dados de Sequência Molecular
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Especificidade por Substrato
Nucleotídeos de Timina/metabolismo
Tirosina/química
Tirosina/metabolismo
Proteínas Virais/antagonistas & inibidores
Proteínas Virais/genética
Proteínas Virais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Deoxycytosine Nucleotides); 0 (Enzyme Inhibitors); 0 (Recombinant Proteins); 0 (Thymine Nucleotides); 0 (Viral Proteins); 2056-98-6 (2'-deoxycytidine 5'-triphosphate); 42HK56048U (Tyrosine); EC 3.5.4.12 (DCMP Deaminase); QOP4K539MU (thymidine 5'-triphosphate)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141119
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.617720


  5 / 139 MEDLINE  
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[PMID]:25438698
[Au] Autor:Xu J; Deng Y; Li Q; Zhu X; He Z
[Ad] Endereço:National Key Laboratory of Plant Molecular Genetics and National Center of Plant Gene Research, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
[Ti] Título:STRIPE2 encodes a putative dCMP deaminase that plays an important role in chloroplast development in rice.
[So] Source:J Genet Genomics;41(10):539-48, 2014 Oct 20.
[Is] ISSN:1673-8527
[Cp] País de publicação:China
[La] Idioma:eng
[Ab] Resumo:Mutants with abnormal leaf coloration are good genetic materials for understanding the mechanism of chloroplast development and chlorophyll biosynthesis. In this study, a rice mutant st2 (stripe2) with stripe leaves was identified from the γ-ray irradiated mutant pool. The st2 mutant exhibited decreased accumulation of chlorophyll and aberrant chloroplasts. Genetic analysis indicated that the st2 mutant was controlled by a single recessive locus. The ST2 gene was finely confined to a 27-kb region on chromosome 1 by the map-based cloning strategy and a 5-bp deletion in Os01g0765000 was identified by sequence analysis. The deletion happened in the joint of exon 3 and intron 3 and led to new spliced products of mRNA. Genetic complementation confirmed that Os01g0765000 is the ST2 gene. We found that the ST2 gene was expressed ubiquitously. Subcellular localization assay showed that the ST2 protein was located in mitochondria. ST2 belongs to the cytidine deaminase-like family and possibly functions as the dCMP deaminase, which catalyzes the formation of dUMP from dCMP by deamination. Additionally, exogenous application of dUMP could partially rescue the st2 phenotype. Therefore, our study identified a putative dCMP deaminase as a novel regulator in chloroplast development for the first time.
[Mh] Termos MeSH primário: Cloroplastos/metabolismo
DCMP Desaminase/metabolismo
Oryza/genética
Proteínas de Plantas/metabolismo
[Mh] Termos MeSH secundário: Mapeamento Cromossômico
Mutação
Oryza/crescimento & desenvolvimento
Oryza/metabolismo
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Plant Proteins); EC 3.5.4.12 (DCMP Deaminase)
[Em] Mês de entrada:1511
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


  6 / 139 MEDLINE  
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[PMID]:24496007
[Au] Autor:Zhu Y; Luo H; Zhang X; Song J; Sun C; Ji A; Xu J; Chen S
[Ad] Endereço:The National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
[Ti] Título:Abundant and selective RNA-editing events in the medicinal mushroom Ganoderma lucidum.
[So] Source:Genetics;196(4):1047-57, 2014 Apr.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RNA editing is a widespread, post-transcriptional molecular phenomenon that diversifies hereditary information across various organisms. However, little is known about genome-scale RNA editing in fungi. In this study, we screened for fungal RNA editing sites at the genomic level in Ganoderma lucidum, a valuable medicinal fungus. On the basis of our pipeline that predicted the editing sites from genomic and transcriptomic data, a total of 8906 possible RNA-editing sites were identified within the G. lucidum genome, including the exon and intron sequences and the 5'-/3'-untranslated regions of 2991 genes and the intergenic regions. The major editing types included C-to-U, A-to-G, G-to-A, and U-to-C conversions. Four putative RNA-editing enzymes were identified, including three adenosine deaminases acting on transfer RNA and a deoxycytidylate deaminase. The genes containing RNA-editing sites were functionally classified by the Kyoto Encyclopedia of Genes and Genomes enrichment and gene ontology analysis. The key functional groupings enriched for RNA-editing sites included laccase genes involved in lignin degradation, key enzymes involved in triterpenoid biosynthesis, and transcription factors. A total of 97 putative editing sites were randomly selected and validated by using PCR and Sanger sequencing. We presented an accurate and large-scale identification of RNA-editing events in G. lucidum, providing global and quantitative cataloging of RNA editing in the fungal genome. This study will shed light on the role of transcriptional plasticity in the growth and development of G. lucidum, as well as its adaptation to the environment and the regulation of valuable secondary metabolite pathways.
[Mh] Termos MeSH primário: Proteínas Fúngicas/genética
Edição de RNA
RNA Fúngico/metabolismo
Reishi/genética
[Mh] Termos MeSH secundário: Adenosina Desaminase/genética
Adenosina Desaminase/metabolismo
DCMP Desaminase/genética
DCMP Desaminase/metabolismo
Proteínas Fúngicas/metabolismo
Genoma Fúngico
Sequenciamento de Nucleotídeos em Larga Escala
Estrutura Molecular
Filogenia
Reishi/enzimologia
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (RNA, Fungal); EC 3.5.4.12 (DCMP Deaminase); EC 3.5.4.4 (Adenosine Deaminase)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140206
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.114.161414


  7 / 139 MEDLINE  
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[PMID]:22927644
[Au] Autor:Sánchez A; Sharma S; Rozenzhak S; Roguev A; Krogan NJ; Chabes A; Russell P
[Ad] Endereço:Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
[Ti] Título:Replication fork collapse and genome instability in a deoxycytidylate deaminase mutant.
[So] Source:Mol Cell Biol;32(21):4445-54, 2012 Nov.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ribonucleotide reductase (RNR) and deoxycytidylate deaminase (dCMP deaminase) are pivotal allosteric enzymes required to maintain adequate pools of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis and repair. Whereas RNR inhibition slows DNA replication and activates checkpoint responses, the effect of dCMP deaminase deficiency is largely unknown. Here, we report that deleting the Schizosaccharomyces pombe dcd1(+) dCMP deaminase gene (SPBC2G2.13c) increases dCTP ∼30-fold and decreases dTTP ∼4-fold. In contrast to the robust growth of a Saccharomyces cerevisiae dcd1Δ mutant, fission yeast dcd1Δ cells delay cell cycle progression in early S phase and are sensitive to multiple DNA-damaging agents, indicating impaired DNA replication and repair. DNA content profiling of dcd1Δ cells differs from an RNR-deficient mutant. Dcd1 deficiency activates genome integrity checkpoints enforced by Rad3 (ATR), Cds1 (Chk2), and Chk1 and creates critical requirements for proteins involved in recovery from replication fork collapse, including the γH2AX-binding protein Brc1 and Mus81 Holliday junction resolvase. These effects correlate with increased nuclear foci of the single-stranded DNA binding protein RPA and the homologous recombination repair protein Rad52. Moreover, Brc1 suppresses spontaneous mutagenesis in dcd1Δ cells. We propose that replication forks stall and collapse in dcd1Δ cells, burdening DNA damage and checkpoint responses to maintain genome integrity.
[Mh] Termos MeSH primário: DCMP Desaminase/genética
Replicação do DNA/genética
Instabilidade Genômica
Saccharomyces cerevisiae/genética
Schizosaccharomyces/genética
[Mh] Termos MeSH secundário: Ciclo Celular/genética
Quinase do Ponto de Checagem 1
DCMP Desaminase/deficiência
Dano ao DNA
DNA Helicases/metabolismo
Reparo do DNA/genética
Nucleotídeos de Desoxicitosina/biossíntese
Nucleotidiltransferases/metabolismo
Proteínas Quinases/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Proteínas de Schizosaccharomyces pombe/metabolismo
Nucleotídeos de Timina/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Brc1 protein, S pombe); 0 (Deoxycytosine Nucleotides); 0 (Saccharomyces cerevisiae Proteins); 0 (Schizosaccharomyces pombe Proteins); 0 (Thymine Nucleotides); 2056-98-6 (2'-deoxycytidine 5'-triphosphate); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (Checkpoint Kinase 1); EC 2.7.11.1 (Chk1 protein, S pombe); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.41 (phosphatidate cytidylyltransferase); EC 3.5.4.12 (DCMP Deaminase); EC 3.6.1.- (Rad3 protein, S cerevisiae); EC 3.6.4.- (DNA Helicases); QOP4K539MU (thymidine 5'-triphosphate)
[Em] Mês de entrada:1301
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120829
[St] Status:MEDLINE
[do] DOI:10.1128/MCB.01062-12


  8 / 139 MEDLINE  
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[PMID]:22257207
[Au] Autor:Waud WR; Parker WB; Gilbert KS; Secrist JA
[Ad] Endereço:Cancer Therapeutics and Immunology Department, Southern Research Institute, Birmingham, Alabama 35255-5305, USA. waud@southernresearch.org
[Ti] Título:Isolation and characterization of a murine P388 leukemia line resistant to thiarabine.
[So] Source:Nucleosides Nucleotides Nucleic Acids;31(1):14-27, 2012.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.
[Mh] Termos MeSH primário: Antimetabólitos/administração & dosagem
Antineoplásicos/administração & dosagem
Arabinonucleotídeos/administração & dosagem
Linhagem Celular Tumoral/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antimetabólitos/síntese química
Antineoplásicos/química
Arabinonucleotídeos/síntese química
Linhagem Celular Tumoral/citologia
Linhagem Celular Tumoral/enzimologia
DCMP Desaminase/metabolismo
Desoxicitidina Quinase/metabolismo
Feminino
Leucemia P388
Camundongos
Transplante de Neoplasias
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Antineoplastic Agents); 0 (Arabinonucleotides); EC 2.7.1.74 (Deoxycytidine Kinase); EC 3.5.4.12 (DCMP Deaminase)
[Em] Mês de entrada:1206
[Cu] Atualização por classe:120119
[Lr] Data última revisão:
120119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120120
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2011.637099


  9 / 139 MEDLINE  
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[PMID]:20199587
[Au] Autor:Jansen RS; Rosing H; Schellens JH; Beijnen JH
[Ad] Endereço:Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Robert.jansen@slz.nl
[Ti] Título:Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites?
[So] Source:Fundam Clin Pharmacol;25(2):172-85, 2011 Apr.
[Is] ISSN:1472-8206
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Deoxycytidine analogs (dCa's) are nucleosides widely used in anticancer and anti (retro) viral therapies. Intracellularly phosphorylated dCa anabolites are considered to be their main active metabolites. This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together, these observations show that the formation of dUa nucleotides is a common phenomenon in treatment with dCa's and these compounds may play a role in treatment outcome. We conclude that more attention should be given to these relatively unknown, but potentially important metabolites.
[Mh] Termos MeSH primário: DCMP Desaminase/metabolismo
Desoxicitidina/metabolismo
Nucleotídeos de Desoxiuracil/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/metabolismo
Antivirais/administração & dosagem
Antivirais/metabolismo
Desaminação
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Relação Dose-Resposta a Droga
Seres Humanos
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Antiviral Agents); 0 (Deoxyuracil Nucleotides); 0W860991D6 (Deoxycytidine); EC 3.5.4.12 (DCMP Deaminase)
[Em] Mês de entrada:1107
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100305
[St] Status:MEDLINE
[do] DOI:10.1111/j.1472-8206.2010.00823.x


  10 / 139 MEDLINE  
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[PMID]:19006382
[Au] Autor:Yoo CB; Valente R; Congiatu C; Gavazza F; Angel A; Siddiqui MA; Jones PA; McGuigan C; Marquez VE
[Ad] Endereço:Department of Biochemistry, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
[Ti] Título:Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2'-deoxyzebularine.
[So] Source:J Med Chem;51(23):7593-601, 2008 Dec 11.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma cells.
[Mh] Termos MeSH primário: Adenocarcinoma/metabolismo
Amidas/química
Citidina/análogos & derivados
Metilação de DNA/efeitos dos fármacos
Inativação Gênica/efeitos dos fármacos
Genes p16/efeitos dos fármacos
Neoplasias Pancreáticas/metabolismo
Ácidos Fosfóricos/química
[Mh] Termos MeSH secundário: Adenocarcinoma/genética
Adenocarcinoma/patologia
Citidina/síntese química
Citidina/química
Citidina/farmacologia
DCMP Desaminase/antagonistas & inibidores
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Estereoisomerismo
Timidilato Sintase/antagonistas & inibidores
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Amides); 0 (Phosphoric Acids); 5CSZ8459RP (Cytidine); 7A9Y5SX0GY (pyrimidin-2-one beta-ribofuranoside); 9Q189608GB (phosphoramidic acid); EC 2.1.1.45 (Thymidylate Synthase); EC 3.5.4.12 (DCMP Deaminase)
[Em] Mês de entrada:0904
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:081114
[St] Status:MEDLINE
[do] DOI:10.1021/jm8005965



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