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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28327155/vasohibin-2-reduces-chemosensitivity-to-gemcitabine-in-pancreatic-cancer-cells-via-jun-proto-oncogene-dependent-transactivation-of-ribonucleotide-reductase-regulatory-subunit-m2
#1
Min Tu, Haifeng Li, Nan Lv, Chunhua Xi, Zipeng Lu, Jishu Wei, Jianmin Chen, Feng Guo, Kuirong Jiang, Guoxin Song, Wentao Gao, Yi Miao
BACKGROUND: Vasohibin 2 (VASH2) has previously been identified as an agiogenenic factor and a cancer related protein. Here we investigated the association of VASH2 expression and chemoresistance in pancreatic cancer. METHODS: Immunohistochemical staining for VASH2 was performed on 102 human pancreatic cancer samples. Pancreatic cancer cell line models exhibiting overexpression or knockdown of VASH2 were generated. Gene expression analyses were carried out to determine genes differentially regulated by VASH2...
March 21, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28324147/genotoxicity-kinetics-in-murine-normoblasts-as-an-approach-for-the-in-vivo-action-of-difluorodeoxycytidine
#2
Pedro Morales-Ramírez, Teresita Vallarino-Kelly, Virginia Cruz-Vallejo
PURPOSE: This study analyzed the kinetics of in vivo micronucleus induction in normoblasts by determining the kinetics of difluorodeoxycytidine (dFdC)-induced micronucleated polychromatic erythrocytes (MN-PCEs) in the peripheral blood of mice. The kinetic indexes of MN-PCE induction of dFdC were correlated with the previously reported mechanisms DNA damage induction by this compound. In general, this study aimed to establish an in vivo approach for discerning the processes underlying micronucleus induction by antineoplastic agents or mutagens in general...
March 21, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28322141/lessons-learned-from-gemcitabine-impact-of-therapeutic-carrier-systems-and-gemcitabine-s-drug-conjugates-on-cancer-therapy
#3
Sathish Dyawanapelly, Animesh Kumar, Manish K Chourasia
Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored...
2017: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/28289079/deletion-of-f4l-ribonucleotide-reductase-in-vaccinia-virus-produces-a-selective-oncolytic-virus-and-promotes-anti-tumor-immunity-with-superior-safety-in-bladder-cancer-models
#4
Kyle G Potts, Chad R Irwin, Nicole A Favis, Desmond B Pink, Krista M Vincent, John D Lewis, Ronald B Moore, Mary M Hitt, David H Evans
Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high-grade disease, Bacillus Calmette-Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell-cycle-regulated small subunit of ribonucleotide reductase (RRM2). The F4L-deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor-selective replication and cell killing...
March 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28253714/microarray-expression-analysis-of-mycn-amplified-neuroblastoma-cells-after-inhibition-of-cdk2
#5
H Song, F Wu, S Li, Z Wang, X Liu, Y Cui, C Lin
The study was aimed to explore the underlying molecular mechanisms of CDK2 inhibition in neuroblastoma by bioinformatics analysis. Gene expression profile GSE16480 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were identified from IMR32 between each time point and average expression of all time points. Gene significance was calculated using dSVDsig algorithm of dnet package. Protein-protein interaction (PPI) network was built. Then, integrated with gene significance, a core PPI network was detected by dNetPipeline algorithm in dnet package...
March 3, 2017: Neoplasma
https://www.readbyqxmd.com/read/28252952/new-iminodiacetate-thiosemicarbazone-hybrids-and-their-copper-ii-complexes-are-potential-ribonucleotide-reductase-r2-inhibitors-with-high-antiproliferative-activity
#6
Mirela F Zaltariov, Marta Hammerstad, Homayon J Arabshahi, Katarina Jovanović, Klaus W Richter, Maria Cazacu, Sergiu Shova, Mihaela Balan, Niels H Andersen, Siniša Radulović, Jóhannes Reynisson, K Kristoffer Andersson, Vladimir B Arion
As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate-thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV-vis; (1)H and (13)C NMR), electrospray ionization mass spectrometry, and X-ray diffraction...
March 2, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28250468/drop-on-demand-sample-delivery-for-studying-biocatalysts-in-action-at-x-ray-free-electron-lasers
#7
Franklin D Fuller, Sheraz Gul, Ruchira Chatterjee, E Sethe Burgie, Iris D Young, Hugo Lebrette, Vivek Srinivas, Aaron S Brewster, Tara Michels-Clark, Jonathan A Clinger, Babak Andi, Mohamed Ibrahim, Ernest Pastor, Casper de Lichtenberg, Rana Hussein, Christopher J Pollock, Miao Zhang, Claudiu A Stan, Thomas Kroll, Thomas Fransson, Clemens Weninger, Markus Kubin, Pierre Aller, Louise Lassalle, Philipp Bräuer, Mitchell D Miller, Muhamed Amin, Sergey Koroidov, Christian G Roessler, Marc Allaire, Raymond G Sierra, Peter T Docker, James M Glownia, Silke Nelson, Jason E Koglin, Diling Zhu, Matthieu Chollet, Sanghoon Song, Henrik Lemke, Mengning Liang, Dimosthenis Sokaras, Roberto Alonso-Mori, Athina Zouni, Johannes Messinger, Uwe Bergmann, Amie K Boal, J Martin Bollinger, Carsten Krebs, Martin Högbom, George N Phillips, Richard D Vierstra, Nicholas K Sauter, Allen M Orville, Jan Kern, Vittal K Yachandra, Junko Yano
X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method...
February 27, 2017: Nature Methods
https://www.readbyqxmd.com/read/28220209/s-phase-checkpoint-regulations-that-preserve-replication-and-chromosome-integrity-upon-dntp-depletion
#8
REVIEW
Michele Giannattasio, Dana Branzei
DNA replication stress, an important source of genomic instability, arises upon different types of DNA replication perturbations, including those that stall replication fork progression. Inhibitors of the cellular pool of deoxynucleotide triphosphates (dNTPs) slow down DNA synthesis throughout the genome. Following depletion of dNTPs, the highly conserved replication checkpoint kinase pathway, also known as the S-phase checkpoint, preserves the functionality and structure of stalled DNA replication forks and prevents chromosome fragmentation...
February 20, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28196013/prognostic-implications-of-expression-profiling-for-gemcitabine-related-genes-hent1-dck-rrm1-rrm2-in-patients-with-resectable-pancreatic-adenocarcinoma-receiving-adjuvant-chemotherapy
#9
Marek Sierzega, Radosław Pach, Piotr Kulig, Janusz Legutko, Jan Kulig
OBJECTIVES: The aim of this study was to examine the relevance of expression profiling of 4 genes involved in the action of gemcitabine among patients with pancreatic ductal-cell adenocarcinoma (PDAC). METHODS: A group of 100 patients who underwent pancreatic resections for PDAC and received adjuvant chemotherapy with gemcitabine between 2007 and 2010 was identified. Expression of mRNAs for human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunits (RRM1, RRM2), and deoxycytidine kinase (dCK) was examined by quantitative real-time polymerase chain reaction, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and dichotomized into groups of low and moderate/high expression levels grouped by tertiles...
February 14, 2017: Pancreas
https://www.readbyqxmd.com/read/28171730/formal-reduction-potentials-of-difluorotyrosine-and-trifluorotyrosine-protein-residues-defining-the-thermodynamics-of-multistep-radical-transfer
#10
Kanchana R Ravichandran, Allan B Zong, Alexander T Taguchi, Daniel G Nocera, JoAnne Stubbe, Cecilia Tommos
Redox-active tyrosines (Ys) play essential roles in enzymes involved in primary metabolism including energy transduction and deoxynucleotide production catalyzed by ribonucleotide reductases (RNRs). Thermodynamic characterization of Ys in solution and in proteins remains a challenge due to the high reduction potentials involved and the reactive nature of the radical state. The structurally characterized α3Y model protein has allowed the first determination of formal reduction potentials (E°') for a Y residing within a protein (Berry, B...
February 21, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28130843/insufficient-levels-of-the-nrdab-encoded-ribonucleotide-reductase-underlie-the-severe-growth-defect-of-the-%C3%AE-hda-e-coli-strain
#11
Vignesh M P Babu, Mark Itsko, Jamie C Baxter, Roel M Schaaper, Mark D Sutton
The ATP-bound form of the Escherichia coli DnaA replication initiator protein remodels the chromosomal origin of replication, oriC, to load the replicative helicase. The primary mechanism for regulating the activity of DnaA involves the Hda and β clamp proteins, which act together to dramatically stimulate the intrinsic DNA-dependent ATPase activity of DnaA via a process termed Regulatory Inactivation of DnaA (RIDA). In addition to hyper-initiation, strains lacking hda function also exhibit cold sensitive growth at 30°C...
January 27, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28115631/ligand-binding-to-2-deoxyguanosine-sensing-riboswitch-in-metabolic-context
#12
Yong-Boum Kim, Anna Wacker, Karl von Laer, Vladimir V Rogov, Beatrix Suess, Harald Schwalbe
The mfl-riboswitch is a transcriptional off-switch, which down-regulates expression of subunit β of ribonucleotide reductase in Mesoplasma florum upon 2'-deoxyguanosine binding. We characterized binding of 2'-deoxyguanosine to the mfl-aptamer domain (WT aptamer) and a sequence-stabilized aptamer (MT aptamer) under in vitro and 'in-cell-like' conditions by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. 'In-cell-like' environment was simulated by Bacillus subtilis cell extract, in which both aptamers remained sufficiently stable to detect the resonances of structural elements and ligand binding in 2D NMR experiments...
January 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28103007/glutamate-350-plays-an-essential-role-in-conformational-gating-of-long-range-radical-transport-in-escherichia-coli-class-ia-ribonucleotide-reductase
#13
Kanchana Ravichandran, Ellen C Minnihan, Qinghui Lin, Kenichi Yokoyama, Alexander T Taguchi, Jimin Shao, Daniel G Nocera, JoAnne Stubbe
Escherichia coli class Ia ribonucleotide reductase (RNR) is composed of two subunits that form an active α2β2 complex. The nucleoside diphosphate substrates (NDP) are reduced in α2, 35 Å from the essential diferric-tyrosyl radical (Y122(•)) cofactor in β2. The Y122(•)-mediated oxidation of C439 in α2 occurs by a pathway (Y122 ⇆ [W48] ⇆ Y356 in β2 to Y731 ⇆ Y730 ⇆ C439 in α2) across the α/β interface. The absence of an α2β2 structure precludes insight into the location of Y356 and Y731 at the subunit interface...
February 2, 2017: Biochemistry
https://www.readbyqxmd.com/read/28096683/clinicopathological-and-immunohistochemical-features-of-lung-invasive-mucinous-adenocarcinoma-based-on-computed-tomography-findings
#14
Katsuhiko Shimizu, Riki Okita, Shinsuke Saisho, Ai Maeda, Yuji Nojima, Masao Nakata
BACKGROUND: We performed an analysis to clarify differences in clinicopathological and molecular features of lung invasive mucinous adenocarcinoma (IMA) based on computed tomography (CT) findings and their impact on prognosis. PATIENTS AND METHODS: On the basis of CT findings, we divided lung IMA into three subtypes: solid, bubbling, and pneumonic. We then investigated differences in clinicopathological characteristics, prognosis, and the expressions of well-identified biomarkers, including cyclooxygenase-2 (Cox-2), excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), class III beta-tubulin, thymidylate synthase (TS), secreted protein acidic and rich in cysteine (SPARC), programmed cell death-1 ligand-1 (PD-L1), and epidermal growth factor receptor mutation, among the three subtypes...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28091524/formate-simultaneously-reduces-oxidase-activity-and-enhances-respiration-in-campylobacter-jejuni
#15
Issmat I Kassem, Rosario A Candelero-Rueda, Kawthar A Esseili, Gireesh Rajashekara
The foodborne microaerophilic pathogen, Campylobacter jejuni, possesses a periplasmic formate dehydrogenase and two terminal oxidases, which serve to metabolize formate and facilitate the use of oxygen as a terminal electron acceptor, respectively. Formate, a primary energy source for C. jejuni, inhibits oxidase activity in other bacteria. Here, we hypothesized that formate might affect both energy metabolism and microaerobic survival in C. jejuni. Subsequently, we showed that C. jejuni 81-176 (wildtype) exhibited enhanced chemoattraction to and respiration of formate in comparison to other organic acids...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28075562/evidence-for-a-di-%C3%AE-oxo-diamond-core-in-the-mn-iv-fe-iv-activation-intermediate-of-ribonucleotide-reductase-from-chlamydia-trachomatis
#16
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 27, 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
#17
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
#18
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
#19
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
#20
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
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