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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28808226/atr-inhibition-facilitates-targeting-of-leukemia-dependence-on-convergent-nucleotide-biosynthetic-pathways
#1
Thuc M Le, Soumya Poddar, Joseph R Capri, Evan R Abt, Woosuk Kim, Liu Wei, Nhu T Uong, Chloe M Cheng, Daniel Braas, Mina Nikanjam, Peter Rix, Daria Merkurjev, Jesse Zaretsky, Harley I Kornblum, Antoni Ribas, Harvey R Herschman, Julian Whitelegge, Kym F Faull, Timothy R Donahue, Johannes Czernin, Caius G Radu
Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms...
August 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28808063/phylogenetic-sequence-analysis-and-functional-studies-reveal-compensatory-amino-acid-substitutions-in-loop-2-of-human-ribonucleotide-reductase
#2
Andrew J Knappenberger, Sneha Grandhi, Reena Sheth, Md Faiz Ahmad, Rajesh Viswanathan, Michael E Harris
Eukaryotic class I ribonucleotide reductases (RRs) generate deoxyribonucleotides for DNA synthesis. Binding of dNTP effectors is coupled to the formation of active dimers and induces conformational changes in a short loop (loop 2) to regulate RR's specificity among its nucleoside diphosphate (NDP) substrates. Moreover, ATP and dATP bind at an additional allosteric site 40 Å away from loop 2 and thereby drive formation of activated or inactive hexamers, respectively. To better understand how dNTP binding influences specificity, activity, and oligomerization of human RR, we aligned >300 eukaryotic RR sequences to examine natural sequence variation in loop 2...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28797284/gambogic-acid-sensitizes-gemcitabine-efficacy-in-pancreatic-cancer-by-reducing-the-expression-of-ribonucleotide-reductase-subunit-m2-rrm2
#3
Guanggai Xia, Hongcheng Wang, Ziliang Song, Qingcai Meng, Xiuyan Huang, Xinyu Huang
BACKGROUND: Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer...
August 10, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28778071/suppression-of-pancreatic-adenocarcinoma-upregulated-factor-pauf-increases-the-sensitivity-of-pancreatic-cancer-to-gemcitabine-and-5fu-and-inhibits-the-formation-of-pancreatic-cancer-stem-like-cells
#4
Jae Hee Cho, Sun A Kim, Soo Been Park, Hee Man Kim, Si Young Song
Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44+CD24+ESA+ pancreatic CSCs...
July 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28756660/spectroscopy-and-dft-calculations-of-a-flavo-diiron-enzyme-implicate-new-diiron-site-structures
#5
Andrew C Weitz, Nitai Giri, Jonathan D Caranto, Donald M Kurtz, Emile L Bominaar, Michael P Hendrich
Flavo-diiron proteins (FDPs) are non-heme iron containing enzymes that are widespread in anaerobic bacteria, archaea, and protozoa, serving as the terminal components to dioxygen and nitric oxide reductive scavenging pathways in these organisms. FDPs contain a dinuclear iron active site similar to that in hemerythrin, ribonucleotide reductase, and methane monooxygenase, all of which can bind NO and O2. However, only FDP competently turns over NO to N2O. Here, EPR and Mössbauer spectroscopies allow electronic characterization of the diferric and diferrous species of FDP...
August 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28750923/didox-3-4-dihydroxybenzohydroxamic-acid-suppresses-il-33-induced-cytokine-production-in-primary-mouse-mast-cells
#6
Heather L Caslin, Jamie Josephine Avila McLeod, Andrew J Spence, Amina Abdul Qayum, Elizabeth Motunrayo Kolawole, Marcela T Taruselli, Anuya Paranjape, Howard L Elford, John J Ryan
While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation...
July 11, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28745337/understanding-the-metabolism-of-the-anticancer-drug-triapine-electrochemical-oxidation-microsomal-incubation-and-in-vivo-analysis-using-lc-hrms
#7
Karla Pelivan, Lisa Frensemeier, Uwe Karst, Gunda Koellensperger, Bjoern Bielec, Sonja Hager, Petra Heffeter, Bernhard K Keppler, Christian R Kowol
α-N-Heterocyclic thiosemicarbazones are among the most promising ribonucleotide reductase inhibitors identified so far. Triapine, the most prominent representative of this class of substances, has been investigated in multiple phase I and II clinical trials. With regard to clinical practice, Triapine showed activity against hematological diseases, but ineffectiveness against a variety of solid tumors. However, the reasons are still vague and the amount of ADME (absorption, distribution, metabolism and excretion) data for Triapine available in the literature is very limited...
July 26, 2017: Analyst
https://www.readbyqxmd.com/read/28743817/bacterial-signaling-nucleotides-inhibit-yeast-cell-growth-by-impacting-mitochondrial-and-other-specifically-eukaryotic-functions
#8
Andy Hesketh, Marta Vergnano, Chris Wan, Stephen G Oliver
We have engineered Saccharomyces cerevisiae to inducibly synthesize the prokaryotic signaling nucleotides cyclic di-GMP (cdiGMP), cdiAMP, and ppGpp in order to characterize the range of effects these nucleotides exert on eukaryotic cell function during bacterial pathogenesis. Synthetic genetic array (SGA) and transcriptome analyses indicated that, while these compounds elicit some common reactions in yeast, there are also complex and distinctive responses to each of the three nucleotides. All three are capable of inhibiting eukaryotic cell growth, with the guanine nucleotides exhibiting stronger effects than cdiAMP...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28735680/dynamic-control-of-dntp-synthesis-in-early-embryos
#9
Yonghyun Song, Robert A Marmion, Junyoung O Park, Debopriyo Biswas, Joshua D Rabinowitz, Stanislav Y Shvartsman
Exponential increase of cell numbers in early embryos requires large amounts of DNA precursors (deoxyribonucleoside triphosphates (dNTPs)). Little is understood about how embryos satisfy this demand. We examined dNTP metabolism in the early Drosophila embryo, in which gastrulation is preceded by 13 sequential nuclear cleavages within only 2 hr of fertilization. Surprisingly, despite the breakneck speed at which Drosophila embryos synthesize DNA, maternally deposited dNTPs can generate less than half of the genomes needed to reach gastrulation...
August 7, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28726739/5-aza-2-2-difluroro-deoxycytidine-nuc013-a-novel-nucleoside-dna-methyl-transferase-inhibitor-and-ribonucleotide-reductase-inhibitor-for-the-treatment-of-cancer
#10
Richard Daifuku, Zhenbo Hu, Yogen Saunthararajah
Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2',2'-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0...
July 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28722661/dck-expression-a-potential-predictive-biomarker-in-the-adjuvant-gemcitabine-chemotherapy-for-biliary-tract-cancer-after-surgical-resection-results-from-a-phase-ii-study
#11
Sang Myung Woo, Kyong-Ah Yoon, Eun Kyung Hong, Weon Seo Park, Sung-Sik Han, Sang-Jae Park, Jungnam Joo, Eun Young Park, Ju Hee Lee, Yun-Hee Kim, Tae Hyun Kim, Woo Jin Lee
The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry...
July 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28717049/regulation-of-small-mitochondrial-dna-replicative-advantage-by-ribonucleotide-reductase-in-saccharomyces-cerevisiae
#12
Elliot Bradshaw, Minoru Yoshida, Feng Ling
Small mitochondrial genomes can behave as selfish elements by displacing wild-type genomes regardless of their detriment to the host organism. In the budding yeast Saccharomyces cerevisiae, small hypersuppressive mtDNA transiently co-exist with wild-type in a state of heteroplasmy, wherein the replicative advantage of the small mtDNA outcompetes wild-type and produces offspring without respiratory capacity in >95% of colonies. The cytosolic enzyme ribonucleotide reductase (RNR) catalyzes the rate-limiting step in dNTP synthesis and its inhibition has been correlated with increased petite colony formation, reflecting loss of respiratory function...
July 17, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28716944/potent-competitive-inhibition-of-human-ribonucleotide-reductase-by-a-nonnucleoside-small-molecule
#13
Md Faiz Ahmad, Intekhab Alam, Sarah E Huff, John Pink, Sheryl A Flanagan, Donna Shewach, Tessianna A Misko, Nancy L Oleinick, William E Harte, Rajesh Viswanathan, Michael E Harris, Chris Godfrey Dealwis
Human ribonucleotide reductase (hRR) is crucial for DNA replication and maintenance of a balanced dNTP pool, and is an established cancer target. Nucleoside analogs such as gemcitabine diphosphate and clofarabine nucleotides target the large subunit (hRRM1) of hRR. These drugs have a poor therapeutic index due to toxicity caused by additional effects, including DNA chain termination. The discovery of nonnucleoside, reversible, small-molecule inhibitors with greater specificity against hRRM1 is a key step in the development of more effective treatments for cancer...
August 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28716444/thiosemicarbazone-derivatives-thiazolyl-hydrazones-effectively-inhibit-leukemic-tumor-cell-growth-down-regulation-of-ribonucleotide-reductase-activity-and-synergism-with-arabinofuranosylcytosine
#14
Geraldine Graser-Loescher, Agnes Schoenhuber, Caroline Ciglenec, Sabine Eberl, Georg Krupitza, Robert M Mader, Surender S Jadav, Venkatesan Jayaprakash, Monika Fritzer-Szekeres, Thomas Szekeres, Philipp Saiko
Cellular growth inhibition exerted by thiosemicarbazones is mainly attributed to down-regulation of ribonucleotide reductase (RNR) activity, with RNR being responsible for the rate-limiting step of de novo DNA synthesis. In this study, we investigated the antineoplastic effects of three newly synthesized thiosemicarbazone derivatives, thiazolyl hydrazones, in human HL-60 promyelocytic leukemia cells. The cytotoxicity of compounds alone and in combination with arabinofuranosylcytosine (AraC) was determined by growth inhibition assays...
July 14, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28711946/cell-cycle-perturbation-induced-by-gemcitabine-in-human-tumor-cells-in-cell-culture-xenografts-and-bladder-cancer-patients-implications-for-clinical-trial-designs-combining-gemcitabine-with-a-chk1-inhibitor
#15
Ryan Montano, Nadeem Khan, Huagang Hou, John Seigne, Marc S Ernstoff, Lionel D Lewis, Alan Eastman
Gemcitabine irreversibly inhibits ribonucleotide reductase and induces S phase arrest but whether this occurs in tumors in mice or patients has not been established. Tumor cells in culture were incubated with gemcitabine for 6 h to approximate the administration schedule in a patient. Concentrations that induced persistent S phase arrest thereafter correlated with cell killing. Administration of gemcitabine to mice also demonstrated a persistent S phase arrest in their tumor. The minimum dose that induced almost complete S phase arrest after 24 h (40 mg/kg) was well below the maximum tolerated dose in mice...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28687003/inhibition-of-chk1-sensitizes-ewing-sarcoma-cells-to-the-ribonucleotide-reductase-inhibitor-gemcitabine
#16
Kelli L Goss, Stacia L Koppenhafer, Kathryn M Harmoney, William W Terry, David J Gordon
Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28678842/activation-of-dun1-in-response-to-nuclear-dna-instability-accounts-for-the-increase-in-mitochondrial-point-mutations-in-rad27-fen1-deficient-s-cerevisiae
#17
Aneta Kaniak-Golik, Renata Kuberska, Piotr Dzierzbicki, Ewa Sledziewska-Gojska
Rad27/FEN1 nuclease that plays important roles in the maintenance of DNA stability in the nucleus has recently been shown to reside in mitochondria. Accordingly, it has been established that Rad27 deficiency causes increased mutagenesis, but decreased microsatellite instability and homologous recombination in mitochondria. Our current analysis of mutations leading to erythromycin resistance indicates that only some of them arise in mitochondrial DNA and that the GC→AT transition is a hallmark of the mitochondrial mutagenesis in rad27 null background...
2017: PloS One
https://www.readbyqxmd.com/read/28672935/next-generation-sequencing-reveals-lymph-node-metastasis-associated-genetic-markers-in-colorectal-cancer
#18
Ni Xie, Yujiang Yao, Lili Wan, Ting Zhu, Litao Liu, Jianhui Yuan
Colorectal cancer is the third most prevalent type of cancer in the United States. Early diagnosis of lymph node metastases is essential to improve the prognosis for patients with colorectal cancer. Therefore, the present study aimed to screen genetic markers, including single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and mRNA expression, associated with lymph node metastases in patients with colorectal cancer to enable an early diagnosis. Targeted next-generation sequencing was applied to capture SNPs and CNVs in tumor-related candidate genes within tumor tissues from 39 colorectal cancer patients; reverse transcription-quantitative polymerase chain reaction was used to detect the specific mRNA level of tumor-related candidate genes, including vascular endothelial growth factor C, cyclin-A2, Interleukin-2, ATP-binding cassette sub-family G member 2, epidermal growth factor (EGF) and nuclear factor kappa B subunit 1 (NFKB1) on chromosome 4...
July 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28652233/potent-inhibition-of-hiv-1-replication-in-resting-cd4-t-cells-by-resveratrol-and-pterostilbene
#19
Chi N Chan, Benjamin Trinité, David N Levy
HIV-1 infection of resting CD4 T cells plays a crucial and numerically dominant role during virus transmission at mucosal sites and during subsequent acute replication and T cell depletion. Resveratrol and pterostilbene are plant stilbenoids associated with several health promoting benefits. Resveratrol has been shown to inhibit replication of several viruses, including herpes simplex 1 and 2, papillomaviruses, SARS virus and influenza virus. Alone, resveratrol does not inhibit HIV-1 infection of activated T cells, but it does synergize with nucleoside reverse transcriptase inhibitors in these cells to inhibit reverse transcription...
June 26, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28640807/lack-of-a-peroxiredoxin-suppresses-the-lethality-of-cells-devoid-of-electron-donors-by-channelling-electrons-to-oxidized-ribonucleotide-reductase
#20
Susanna Boronat, Alba Domènech, Mercè Carmona, Sarela García-Santamarina, M Carmen Bañó, José Ayté, Elena Hidalgo
The thioredoxin and glutaredoxin pathways are responsible of recycling several enzymes which undergo intramolecular disulfide bond formation as part of their catalytic cycles such as the peroxide scavengers peroxiredoxins or the enzyme ribonucleotide reductase (RNR). RNR, the rate-limiting enzyme of deoxyribonucleotide synthesis, is an essential enzyme relying on these electron flow cascades for recycling. RNR is tightly regulated in a cell cycle-dependent manner at different levels, but little is known about the participation of electron donors in such regulation...
June 2017: PLoS Genetics
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