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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28075562/evidence-for-a-di-%C3%A2%C2%B5-oxo-diamond-core-in-the-mn-iv-fe-iv-activation-intermediate-of-ribonucleotide-reductase-from-chlamydia-trachomatis
#1
Ryan J Martinie, Elizabeth J Blaesi, Carsten Krebs, J Martin Bollinger, Alexey Silakov, Christopher J Pollock
High-valent iron and manganese complexes effect some of the most challenging biochemical reactions known, including hydrocarbon and water oxidations associated with the global carbon cycle and oxygenic photosynthesis, respectively. Their extreme reactivity presents an impediment to structural characterization, but their biological importance and potential chemical utility have, nevertheless, motivated extensive efforts toward that end. Several such intermediates accumulate during activation of class I ribonucleotide reductase (RNR) β subunits, which self-assemble dimetal cofactors with stable one-electron oxidants that serve to initiate the enzyme's free-radical mechanism...
January 11, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28074342/the-presence-of-modified-nucleosides-in-extracellular-fluids-leads-to-the-specific-incorporation-of-5-chlorocytidine-into-rna-and-modulates-the-transcription-and-translation
#2
Caroline Noyon, Thierry Roumeguère, Cédric Delporte, Damien Dufour, Melissa Cortese, Jean-Marc Desmet, Christophe Lelubre, Alexandre Rousseau, Philippe Poelvoorde, Jean Nève, Luc Vanhamme, Karim Zouaoui Boudjeltia, Pierre Van Antwerpen
Myeloperoxidase (MPO) is able to promote several kinds of damage and is involved in mechanisms leading to various diseases such as atherosclerosis or cancers. An example of these damages is the chlorination of nucleic acids, which is considered as a specific marker of the MPO activity. Since 5-chlorocytidine has been recently shown in healthy donor plasmas, this study aimed at discovering if these circulating modified nucleosides could be incorporated into RNA and DNA and if their presence impacts the ability of enzymes involved in the incorporation, transcription, and translation processes...
January 10, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28074332/functional-analysis-of-ribonucleotide-reductase-from-cordyceps-militaris-expressed-in-escherichia-coli
#3
Tatsuya Kato, Suparmin Ahmad, Enoch Y Park
Cordyceps militaris produces cordycepin (3'-deoxyadenosine), which has various activities, including anti-oxidant, anti-tumoral, anti-viral, and anti-inflammatory. Ribonucleotide reductase (RNR) seems to be a candidate to produce cordycepin in C. militaris because RNR catalyzes the reduction of nucleotides to 2'-deoxynucleotides, whose structures are similar to that of cordycepin. However, the role of RNR has not been confirmed yet. In this study, complementary DNAs (cDNAs) of C. militaris RNR (CmRNR) large and small subunits (CmR1 and CmR2) were cloned from C...
January 10, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28068088/a-200-mev-uphill-thermodynamic-landscape-for-radical-transport-in-escherichia-coli-ribonucleotide-reductase-determined-using-fluorotyrosine-substituted-enzymes
#4
Kanchana R Ravichandran, Alexander T Taguchi, Yifeng Wei, Cecilia Tommos, Daniel G Nocera, JoAnne Stubbe
Escherichia coli class Ia ribonucleotide reductase (RNR) converts ribonucleotides to deoxynucleotides. A diferric-tyrosyl radical (Y122•) in one subunit (β2) generates a transient thiyl radical in another subunit (α2) via long-range radical transport (RT) through aromatic amino acid residues (Y122 ⇆ [W48] ⇆ Y356 in β2 to Y731 ⇆ Y730 ⇆ C439 in α2). Equilibration of Y356•, Y731•, and Y730• was recently observed using site specifically incorporated unnatural tyrosine analogs; however, equilibration between Y122• and Y356• has not been detected...
October 19, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28066957/overexpression-of-ribonucleotide-reductase-subunit-m1-protein-predicts-shorter-survival-in-metastatic-bladder-cancer-patients-treated-with-gemcitabine-containing-combination-chemotherapy
#5
Nagahide Matsumura, Yasushi Nakamura, Yasuo Kohjimoto, Satoshi Nishizawa, Kazuro Kikkawa, Akinori Iba, Yoshiki Kodama, Isao Hara
OBJECTIVES: To identify biomarkers predicting prognosis in bladder cancer patients undergoing the gemcitabine and cisplatin regimen. METHODS: We studied 52 patients with metastatic bladder cancer treated with the gemcitabine and cisplatin regimen by evaluating the relationship between the expression of two biomarkers, ribonucleotide reductase subunit M1 and excision repair cross complementing 1, by immunohistochemistry and clinical outcomes. RESULTS: The patients with low expression of ribonucleotide reductase subunit M1 showed a higher objective response rate by the gemcitabine and cisplatin regimen than those with high expression of ribonucleotide reductase subunit M1 (80...
January 9, 2017: International Journal of Urology: Official Journal of the Japanese Urological Association
https://www.readbyqxmd.com/read/28061880/phospho-akt-overexpression-is-prognostic-and-can-be-used-to-tailor-the-synergistic-interaction-of-akt-inhibitors-with-gemcitabine-in-pancreatic-cancer
#6
Daniela Massihnia, Amir Avan, Niccola Funel, Mina Maftouh, Anne van Krieken, Carlotta Granchi, Rajiv Raktoe, Ugo Boggi, Babette Aicher, Filippo Minutolo, Antonio Russo, Leticia G Leon, Godefridus J Peters, Elisa Giovannetti
BACKGROUND: There is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine. METHODS: Phospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100)...
January 6, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27980346/cytotoxic-gallium-complexes-containing-thiosemicarbazones-derived-from-9-anthraldehyde-molecular-docking-with-biomolecules
#7
Floyd A Beckford, Alyssa Brock, Antonio Gonzalez-Sarrías, Navindra P Seeram
We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 - 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index...
October 5, 2016: Journal of Molecular Structure
https://www.readbyqxmd.com/read/27958354/unusual-five-copies-and-dual-forms-of-nrdb-in-candidatus-liberibacter-asiaticus-biological-implications-and-pcr-detection-application
#8
Zheng Zheng, Meirong Xu, Minli Bao, Fengnian Wu, Jianchi Chen, Xiaoling Deng
"Candidatus Liberibacter asiaticus" (CLas), a non-culturable α-proteobacterium, is associated with citrus Huanglongbing (HLB, yellow shoot disease) currently threatening citrus production worldwide. Here, the whole genome sequence of CLas strain A4 from Guangdong of China was analyzed. Five copies of nrdB, encoding β-subunit of ribonucleotide reductase (RNR), a critical enzyme involving bacterial proliferation, were found. Three nrdB copies were in long form (nrdB(L), 1,059 bp) and two were in short form (nrdB(S), 378 bp)...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27941687/low-dose-methylmercury-induced-genes-regulate-mitochondrial-biogenesis-via-mir-25-in-immortalized-human-embryonic-neural-progenitor-cells
#9
Xinjin Wang, Mengling Yan, Lina Zhao, Qing Wu, Chunhua Wu, Xiuli Chang, Zhijun Zhou
Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2'-deoxyuridine (EdU)-positive cells...
December 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27932760/-satb1-promotes-the-malignant-of-human-non-hodgkin-lymphoma-by-activating-the-ribonucleotide-reductase-%C3%A2-small-subunit-m2
#10
Dayong Yan, Wei Wang
To explore the role of the special AT rich sequence binding protein-1 (SATB1) and ribonucleotide reductase M2 (RRM2) in enhancing malignant progression of non-Hodgkin lymphoma (NHL). 
 Methods: A total of 42 NHL and 42 chronic lymphadenitis patients were recruited. The protein expressions of SATB1 and RRM2 in cervical lymph nodes were determined by Western blot. After overexpression of SATB1, siSATB1 or siRRM2, the mRNA levels of SATB1 and RRM2 in cells were analyzed via RT-PCR, the cell proliferation was evaluated via MTT and EdU assays, while the migration and invasion of cells were assessed by transwell assays...
November 28, 2016: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/27924826/iron-chelators-target-both-proliferating-and-quiescent-cancer-cells
#11
Mårten Fryknäs, Xiaonan Zhang, Ulf Bremberg, Wojciech Senkowski, Maria Hägg Olofsson, Peter Brandt, Ingmar Persson, Padraig D'Arcy, Joachim Gullbo, Peter Nygren, Leoni Kunz Schughart, Stig Linder, Rolf Larsson
Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation...
December 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27920297/role-of-ribonucleotide-reductase-on-bacillus-subtilis-stress-associated-mutagenesis
#12
Karla Viridiana Castro-Cerritos, Ronald E Yasbin, Eduardo A Robleto, Mario Pedraza-Reyes
: The Gram-positive microorganism Bacillus subtilis relies on a single class Ib ribonucleotide reductase (RNR) to generate 2' -deoxyribonucleotides (dNDPs) for DNA replication and repair. In this work, we investigated the influence of RNR levels on B. subtilis stationary-phase-associated mutagenesis (SPM). Since RNR is essential in this bacterium, we engineered a conditional mutant in the strain B. subtilis YB955 (hisC952, metB5, leu427) in which expression of the nrdEF operon was modulated by isopropyl-β-D-thiogalactopyranoside (IPTG)...
December 5, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27919952/molecular-factors-associated-with-pemetrexed-sensitivity-according-to-histological-type-in-non-small-cell-lung-cancer
#13
Tsukihisa Yoshida, Tatsuro Okamoto, Tokujiro Yano, Kazuki Takada, Mikihiro Kohno, Kenichi Suda, Mitsuhiro Takenoyama, Yoshinao Oda, Yoshihiko Maehara
BACKGROUND: This study was designed to investigate potential molecules that predict chemosensitivity to pemetrexed (Alimta®) in surgically resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Chemosensitivity to ALM and other drugs was assessed by succinate dehydrogenase inhibition (SDI) test in 69 NSCLC samples (55 adenocarcinomas, and 14 squamous cell carcinomas). The mRNA expression levels of Alimta®-target enzymes [thymidylate synthase (TYMS); dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT)], Alimta®-metabolizing enzymes [γ-glutamyl hydrase (GGH) and folylpolyglutamate synthase] and an Alimta® transporter [reduce folate carrier (RFC)] were measured and examined for potential correlations to chemosensitivity...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27908619/correlation-of-dna-repair-gene-polymorphisms-with-clinical-outcome-in-patients-with-locally-advanced-non-small-cell-lung-cancer-receiving-induction-chemotherapy-followed-by-surgery
#14
Mariacarmela Santarpia, Jose Luis Ramirez, Itziar de Aguirre, Pilar Garrido, Maria Pérez Cano, Cristina Queralt, Jose Luis Gonzalez-Larriba, Amelia Insa, Mariano Provencio, Dolores Isla, Carlos Camps, Remei Blanco, Teresa Moran, Rafael Rosell
OBJECTIVE: The aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non-small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery. MATERIALS AND METHODS: A total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (-37 C/A) polymorphisms with response and survival...
November 9, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27906631/mitochondrial-purine-and-pyrimidine-metabolism-and-beyond
#15
Liya Wang
Carefully balanced deoxynucleoside triphosphate (dNTP) pools are essential for both nuclear and mitochondrial genome replication and repair. Two synthetic pathways operate in cells to produce dNTPs, e.g., the de novo and the salvage pathways. The key regulatory enzymes for de novo synthesis are ribonucleotide reductase (RNR) and thymidylate synthase (TS), and this process is considered to be cytosolic. The salvage pathway operates both in the cytosol (TK1 and dCK) and the mitochondria (TK2 and dGK). Mitochondrial dNTP pools are separated from the cytosolic ones owing to the double membrane structure of the mitochondria, and are formed by the salvage enzymes TK2 and dGK together with NMPKs and NDPK in postmitotic tissues, while in proliferating cells the mitochondrial dNTPs are mainly imported from the cytosol produced by the cytosolic pathways...
December 2016: Nucleosides, Nucleotides & Nucleic Acids
https://www.readbyqxmd.com/read/27878356/phase-i-trial-of-daily-triapine-in-combination-with-cisplatin-chemotherapy-for-advanced-stage-malignancies
#16
Charles A Kunos, Edward Chu, Jan H Beumer, Mario Sznol, S Percy Ivy
PURPOSE: Advanced-stage malignancies have increased deoxyribonucleotide demands in DNA replication and repair, making deoxyribonucleotide supply a potential exploitable target for therapy based on ribonucleotide reductase (RNR) inhibition. METHODS: A dose-finding phase I trial was conducted of intravenous (i.v.) triapine, a small-molecule RNR inhibitor, and cisplatin chemotherapy in patients with advanced-stage solid tumor malignancies. Patients received dose-finding levels of i...
January 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27869662/the-cell-killing-mechanisms-of-hydroxyurea
#17
REVIEW
Amanpreet Singh, Yong-Jie Xu
Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative disorders. Due to its reversible inhibitory effect on DNA replication in various organisms, hydroxyurea is also commonly used in laboratories for cell cycle synchronization or generating replication stress. However, incubation with high concentrations or prolonged treatment with low doses of hydroxyurea can result in cell death and the DNA damage generated at arrested replication forks is generally believed to be the direct cause...
November 17, 2016: Genes
https://www.readbyqxmd.com/read/27866984/p53r2-regulates-thioredoxin-reductase-activity-through-interaction-with-trxr2
#18
Seon-Joo Park, Hong Beum Kim, Chunmei Piao, Mi Yeong Kang, Sang-Gon Park, Seok Won Kim, Jung-Hee Lee
Ribonucleotide reductase small subunit p53R2 is a member of the ribonucleotide reductase family that supplies dNTPs for nuclear and mitochondrial DNA replication and repair. Here, we have identified a mitochondrial thioredoxin reductase 2 (TrxR2) as a novel p53R2-binding protein. We demonstrated a direct interaction between the two, and observed that p53R2 stimulated the enzymatic activity of TrxR in vitro. Moreover, TrxR2 activity was significantly lower in p53R2 knockdown cells, and increased when p53R2 was overexpressed, effects that were independent of p53...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27856328/the-therapeutic-potential-of-iron-targeting-gallium-compounds-in-human-disease-from-basic-research-to-clinical-application
#19
REVIEW
Christopher R Chitambar
Gallium, group IIIa metal, shares certain chemical characteristics with iron which enable it to function as an iron mimetic that can disrupt iron-dependent tumor cell growth. Gallium may also display antimicrobial activity by disrupting iron homeostasis in certain bacteria and fungi. Gallium's action on iron homeostasis leads to inhibition of ribonucleotide reductase, mitochondrial function, and changes in proteins of iron transport and storage. In addition, gallium induces an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1...
January 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27845436/profiling-ribonucleotide-and-deoxyribonucleotide-pools-perturbed-by-gemcitabine-in-human-non-small-cell-lung-cancer-cells
#20
Jian-Ru Guo, Qian-Qian Chen, Christopher Wai Kei Lam, Cai-Yun Wang, Vincent Kam Wai Wong, Zee-Fen Chang, Wei Zhang
In this study, we investigated the dosage effect of gemcitabine, an inhibitor of ribonucleotide reductase (RR), on cellular levels of ribonucleotides and deoxyribonucleotides using high performance liquid chromatography-electrospray ionization tandem mass spectrometric method. As anticipated, after 4-h incubation of non-small cell lung cancer (A549) cells with gemcitabine at 0.5 and 2 μM, there were consistent reductions in levels of deoxyribonucleoside diphosphates (dNDP) and their corresponding deoxyribonucleoside triphosphates (dNTP)...
November 15, 2016: Scientific Reports
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