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Ribonucleotide reductase

Yuan-Liang Zhang, Jie-Wen Sun, Yin-Yin Xie, Yan Zhou, Ping Liu, Jia-Chun Song, Chun-Hui Xu, Lan Wang, Dan Liu, Ai-Ning Xu, Zhu Chen, Sai-Juan Chen, Xiao-Jian Sun, Qiu-Hua Huang
The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired...
March 12, 2018: Cell Research
N O Elander, K Aughton, P Ghaneh, J P Neoptolemos, D H Palmer, T F Cox, F Campbell, E Costello, C M Halloran, J R Mackey, A G Scarfe, J W Valle, A C McDonald, R Carter, N C Tebbutt, D Goldstein, J Shannon, C Dervenis, B Glimelius, M Deakin, R M Charnley, A Anthoney, M M Lerch, J Mayerle, A Oláh, M W Büchler, W Greenhalf
BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups...
March 9, 2018: British Journal of Cancer
Edward J Brignole, Kuang-Lei Tsai, Johnathan Chittuluru, Haoran Li, Yimon Aye, Pawel A Penczek, JoAnne Stubbe, Catherine L Drennan, Francisco Asturias
Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the β subunit houses the radical cofactor. Here, we present a 3.3-Å resolution structure by cryo-electron microscopy (EM) of a dATP-inhibited state of human RNR. This structure, which was determined in the presence of substrate CDP and allosteric regulators ATP and dATP, has three α2 units arranged in an α6 ring...
February 20, 2018: ELife
Partha Sarathi Mohanty, Avi Kumar Bansal, Farah Naaz, Umesh Datta Gupta, Vivek Dhar Dwivedi, Umesh Yadava
Leprosy is a chronic infection of skin and nerve caused by Mycobacterium leprae. The treatment is based on standard multi drug therapy consisting of dapsone, rifampicin and clofazamine. The use of rifampicin alone or with dapsone led to the emergence of rifampicin-resistant Mycobacterium leprae strains. The emergence of drug-resistant leprosy put a hurdle in the leprosy eradication programme. The present study aims to predict the molecular model of ribonucleotide reductase (RNR), the enzyme responsible for biosynthesis of nucleotides, to screen new drugs for treatment of drug-resistant leprosy...
February 15, 2018: Infection, Genetics and Evolution
Divya T Babu, K Archana, Bhavya Kachiprath, Solly Solomon, G Jayanath, I S Bright Singh, Rosamma Philip
Actinomycetes (277Nos) isolated from marine environments and shrimp culture pond sediments were tested for hydrolytic enzyme production and biogranulation property. Potential isolates were screened for their efficacy in bioremediation of shrimp culture system. Based on the BOD reduction efficiency and water quality parameters, five actinomycete isolates viz., Streptomyces coelicoflavus (A6), Streptomyces diastaticus (A 44), Nocardiopsis alba (A 55), Streptomyces parvus (A 56) and Streptomyces champavatii (R 32) were subjected for tertiary screening in Penaeus monodon larval rearing system and the animals were challenged with white spot syndrome virus (WSSV)...
January 30, 2018: Fish & Shellfish Immunology
Christopher R Chitambar
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials...
February 5, 2018: Metal Ions in Life Sciences
Inna Rozman Grinberg, Daniel Lundin, Mahmudul Hasan, Mikael Crona, Venkateswara Rao Jonna, Christoph Loderer, Margareta Sahlin, Natalia Markova, Ilya Borovok, Gustav Berggren, Anders Hofer, Derek T Logan, Britt-Marie Sjöberg
Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, the ATP-cone, has been found exclusively in the catalytic subunit. In two class I RNR subclasses whose catalytic subunit lacks the ATP-cone, we discovered ATP-cones in the radical-generating subunit. The ATP-cone in the Leeuwenhoekiella blandensis radical-generating subunit regulates activity via quaternary structure induced by binding of nucleotides...
February 1, 2018: ELife
Ansheng Wang, Chengling Zhao, Xuegang Liu, Wen Su, Guixin Duan, Zongyu Xie, Shanshan Chu, Yuan Gao
The transforming growth factor β regulator 4 (TBRG4) gene, located on the 7p14-p13 chromosomal region, is implicated in numerous types of cancer. However, the contribution(s) of TBRG4 in human lung cancer remains unknown. In the present study, the expression of TBRG4 mRNA was investigated in the H1299 lung cancer cell line using the quantitative polymerase chain reaction (qPCR) following the knockdown of TBRG4 by a lentivirus-mediated small interfering RNA (siRNA). Results identified that the expression of TBRG4 within H1299 cells was significantly suppressed (P<0...
January 2018: Oncology Letters
Zhi-Gang Jiang, Gordon Winocur, J Martin Wojtowicz, Olga Shevtsova, Steven Fuller, Hossein A Ghanbari
Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals...
2018: PloS One
Heba H Mostafa, Thornton W Thompson, Adam J Konen, Steve D Haenchen, Joshua G Hilliard, Stuart J Macdonald, Lynda A Morrison, David J Davido
In the process of generating HSV-1 mutants in the viral regulatory gene encoding infected cell protein 0 (ICP0), we isolated a viral mutant, termed KOS-NA, that was severely impaired for acute replication in the eyes and trigeminal ganglia (TG) of mice, defective in establishing a latent infection, and reactivated poorly from explanted TG. To identify the secondary mutation(s) responsible for the impaired phenotypes of this mutant, we sequenced the KOS-NA genome and noted that it contained two nonsynonymous mutations in UL39, which encodes the large subunit of ribonucleotide reductase, ICP6...
January 10, 2018: Journal of Virology
Andrew B Das, Izabela Sadowska-Bartosz, Andreas Königstorfer, Anthony J Kettle, Christine C Winterbourn
Ribonucleotide reductase (RNR) catalyses the rate limiting step of DNA synthesis utilising a mechanism that requires a tyrosyl radical. We have previously shown that superoxide can quench protein tyrosyl radicals in vitro, either by oxidative addition, or reduction of the radical to tyrosine. Here, we observe that Saccharomyces cerevisiae strains lacking either copper-zinc SOD (SOD1) or manganese SOD (SOD2) had decreased RNR activity compared to SOD competent yeast. When superoxide production was increased by treatment with paraquat, RNR activity was further decreased, with yeast lacking SOD1 being the most sensitive...
January 3, 2018: Free Radical Biology & Medicine
Kaitlyn Beyfuss, David A Hood
BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases...
January 3, 2018: Redox Report: Communications in Free Radical Research
Min Liang, Tiangang Zhao, Linfeng Ma, Yingjie Guo
Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0...
December 20, 2017: Oncology Reports
Markus Dagnell, Edward E Schmidt, Elias S J Arnér
Mammalian thioredoxin reductases (TrxRs) are selenocysteine-containing proteins (selenoproteins) that propel a large number of functions through reduction of several substrates including the active site disulfide of thioredoxins (Trxs). Well-known enzymatic systems that in turn are supported by Trxs and TrxRs include deoxyribonucleotide synthesis through ribonucleotide reductase, antioxidant defense through peroxiredoxins and methionine sulfoxide reductases, and redox modulation of a number of transcription factors...
December 23, 2017: Free Radical Biology & Medicine
Xiao Zhao, Xiuchao Wang, Wei Sun, Keman Cheng, Hao Qin, Xuexiang Han, Yu Lin, Yongwei Wang, Jiayan Lang, Ruifang Zhao, Xiaowei Zheng, Ying Zhao, Jian Shi, Jihui Hao, Qing Robert Miao, Guangjun Nie, He Ren
Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2...
December 20, 2017: Biomaterials
Cassidy L Klima, Rahat Zaheer, Shaun R Cook, Jay Rasmussen, Trevor W Alexander, Andrew Potter, Steve Hendrick, Tim A McAllister
This study examined the use of comparative genomic analysis for vaccine design against Mannheimia haemolytica, a respiratory pathogen of ruminants. A total of 2,341genes were identified in at least half of the 23 genomes. Of these, a total of 240 were identified to code for N-terminal signal peptides with diverse sub-cellular localizations (78 periplasmic, 52 outer membrane, 15 extracellular, 13 cytoplasmic membrane and 82 unknown) and were examined in an ELISA assay using a coupled-cell free transcription/translation system for protein expressionwith antisera from cattle challenged with serovars 1, 2 or 6 of M...
January 2018: Veterinary Immunology and Immunopathology
Jiewei Chen, Shuman Li, Yongbo Xiao, Xuan Zou, Xinke Zhang, Mingshu Zhu, Muyan Cai, Dan Xie
BACKGROUND: p53R2 is a target of p53 gene, which is essential for DNA repair, mitochondrial DNA synthesis, protection against oxidative stress, chromosomal instability, chronic inflammation and tumorigenesis. This study is aimed to investigate the expression of ribonucleotide reductase (RR) subunit p53R2 in nasopharyngeal carcinoma and its significance in the prognosis. METHODS: The expression levels of p53R2 in 201 patients with NPC were examined by immunohistochemical assay...
December 13, 2017: BMC Cancer
Ang Zhou, Patrick M Crossland, Apparao Draksharapu, Andrew J Jasniewski, Scott T Kleespies, Lawrence Que
Nonheme oxoiron(IV) complexes can serve as synthons for generating heterobimetallic oxo-bridged dimetal complexes by reaction with divalent metal complexes. The formation of FeIII -O-CrIII and FeIII -O-MnIII complexes is described herein. The latter complexes may serve as models for the FeIII -X-MnIII active sites of an emerging class of Fe/Mn enzymes represented by the Class 1c ribonucleotide reductase from Chlamydia trachomatis and the R2-like ligand-binding oxidase (R2lox) found in Mycobacterium tuberculosis...
January 2018: Journal of Biological Inorganic Chemistry: JBIC
Q L Han, Y H Zhou, Y Lyu, H Yan, G H Dai
WHAT IS KNOWN AND OBJECTIVE: The prognostic value of ribonucleotide reductase M1 (RRM1) in patients with pancreatic cancer receiving gemcitabine chemotherapy has been evaluated in several studies. However, the conclusions remain controversial. METHODS: By searching the PubMed and Embase databases, we conducted a meta-analysis to evaluate the prognostic significance of RRM1 expression in patients with pancreatic cancer receiving gemcitabine chemotherapy. Studies were pooled, and the hazard ratio (HR) and its corresponding 95% confidence interval (CI) were calculated...
April 2018: Journal of Clinical Pharmacy and Therapeutics
Adriana Magherusan, Ang Zhou, Erik Farquhar, Max Garcia Melchor, Brendan Twamley, Lawrence Que, Aidan Richard McDonald
Class Ib RNRs require superoxide anion (O2*-), rather than dioxygen (O2), to access a high-valent Mn2 oxidant. Complex 1 ([Mn2(O2CCH3)(N-Et-HPTB)](ClO4)2, N-Et-HPTB = N,N,N',N'-tetrakis(2-(1-ethylbenzimidazolyl))-2-hydroxy-1,3-diaminopropane) was synthesised in high yield (90%). 1 was reacted with O2*- at -40 °C resulting in the formation of a metastable species (2). 2 displayed electronic absorption features (λmax = 460, 610 nm) typical of a Mn-peroxide species, and a 29 line EPR signal typical of a MnIIMnIII entity...
November 22, 2017: Angewandte Chemie
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