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https://www.readbyqxmd.com/read/29142246/a-comprehensive-structural-biochemical-and-biological-profiling-of-the-human-nudix-hydrolase-family
#1
Jordi Carreras-Puigvert, Marinka Zitnik, Ann-Sofie Jemth, Megan Carter, Judith E Unterlass, Björn Hallström, Olga Loseva, Zhir Karem, José Manuel Calderón-Montaño, Cecilia Lindskog, Per-Henrik Edqvist, Damian J Matuszewski, Hammou Ait Blal, Ronnie P A Berntsson, Maria Häggblad, Ulf Martens, Matthew Studham, Bo Lundgren, Carolina Wählby, Erik L L Sonnhammer, Emma Lundberg, Pål Stenmark, Blaz Zupan, Thomas Helleday
The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes...
November 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29113256/nudt-expression-is-predictive-of-prognosis-in-patients-with-clear-cell-renal-cell-carcinoma
#2
Yue Wang, Fangning Wan, Kun Chang, Xiaolin Lu, Bo Dai, Dingwei Ye
The nudix hydroxylase (NUDT) family of genes may have notable roles in cancer growth and metastasis. The present study aimed to determine the prognostic ability of NUDT genes in clear cell renal cell carcinoma (ccRCC). Data from 509 patients with ccRCC was obtained from The Cancer Genome Atlas (TCGA) database and 192 patient samples from Fudan University Shanghai Cancer Center (FUSCC) were analyzed in the present study. The expression profile of NUDT gene family members in the TCGA cohort was obtained from the TCGA RNA sequencing database...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29065511/novel-tetra-primer-arms-pcr-assays-for-thiopurine-intolerance-susceptibility-mutations-nudt15-c-415c-t-and-tpmt-c-719a-g-tpmt-3c-in-east-asians
#3
Chi-Chun Ho, Wai-Ying Fong, Yuen-Hon Lee, Wing-Tat Poon
Thiopurines are clinically useful in the management of diverse immunological and malignant conditions. Nevertheless, these purine analogues can cause lethal myelosuppression, which may be prevented by prospective testing for variants in the thiopurine S-methyltransferase (TPMT) and, in East Asians, Nudix hydrolase 15 (NUDT15) genes. Two single-tube, tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) assays were developed to genotype the common loss-of-function variants NUDT15 c...
October 23, 2017: Genes
https://www.readbyqxmd.com/read/29021398/characterization-of-the-african-swine-fever-virus-decapping-enzyme-during-infection
#4
Ana Quintas, Daniel Pérez-Núñez, Elena G Sánchez, Maria L Nogal, Matthias W Hentze, Alfredo Castelló, Yolanda Revilla
African swine fever virus (ASFV) infection is characterized by a progressive decrease in cellular protein synthesis with a concomitant increase in viral protein synthesis, though the mechanism by which the virus achieves this phenomenon is still unknown. Decrease of cellular mRNA is observed during ASFV infection, suggesting that inhibition of cellular proteins is due to an active mRNA degradation process. ASFV carries a gene (Ba71V D250R/Malawi g5R) that encodes a decapping protein (ASFV-DP) which has a Nudix hydrolase motif and decapping activity in vitro Here we show that ASFV-DP was expressed from early times and accumulated throughout the infection with a subcellular localization typical of the endoplasmic reticulum, co-localizing with the cap structure and interacting with the ribosomal protein L23a...
October 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28960137/galleria-mellonella-as-an-infection-model-to-investigate-virulence-of-vibrio-parahaemolyticus
#5
Sariqa Wagley, Richard Borne, Jamie Harrison, Craig Baker-Austin, Donatella Ottaviani, Francesca Leoni, Varaporn Vuddhakul, Richard W Titball
Non-toxigenic V. parahaemolyticus isolates (tdh(-)/trh(-)/T3SS2(-)) have recently been isolated from patients with gastroenteritis. In this study we report that the larvae of the wax moth (Galleria mellonella) are susceptible to infection by toxigenic or non-toxigenic clinical isolates of V. parahaemolyticus. In comparison larvae inoculated with environmental isolates of V. parahaemolyticus did not succumb to disease. Whole genome sequencing of clinical non-toxigenic isolates revealed the presence of a gene encoding a nudix hydrolase, identified as mutT...
September 29, 2017: Virulence
https://www.readbyqxmd.com/read/28833678/nudix-type-rna-pyrophosphohydrolase-provides-homeostasis-of-virulence-factor-pyocyanin-and-functions-as-a-global-regulator-in-pseudomonas-aeruginosa
#6
Martyna Kujawa, Maciej Lirski, Mateusz Ziecina, Joanna Drabinska, Marta Modzelan, Elzbieta Kraszewska
The PA0336 protein from Pseudomonas aeruginosa belongs to the family of widely distributed Nudix pyrophosphohydrolases, which catalyze the hydrolysis of pyrophosphate bonds in a variety of nucleoside diphosphate derivatives. The amino acid sequence of the PA0336 protein is highly similar to that of the RppH Nudix RNA pyrophosphohydrolase from Escherichia coli, which removes pyrophosphate from 5'-end of triphosphorylated RNA transcripts. Trans-complementation experiments showed that the P. aeruginosa enzyme can functionally substitute for RppH in E...
November 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28755312/mouse-nudt13-is-a-mitochondrial-nudix-hydrolase-with-nad-p-h-pyrophosphohydrolase-activity
#7
Salama R Abdelraheim, David G Spiller, Alexander G McLennan
The mammalian NUDT13 protein possesses a sequence motif characteristic of the NADH pyrophosphohydrolase subfamily of Nudix hydrolases. Due to the persistent insolubility of the recombinant product expressed in Escherichia coli, active mouse Nudt13 was expressed in insect cells from a baculovirus vector as a histidine-tagged recombinant protein. In vitro, it efficiently hydrolysed NADH to NMNH and AMP and NADPH to NMNH and 2',5'-ADP and had a marked preference for the reduced pyridine nucleotides. Much lower activity was obtained with other nucleotide substrates tested...
October 2017: Protein Journal
https://www.readbyqxmd.com/read/28742822/metal-ion-coordination-in-the-e-coli-nudix-hydrolase-dihydroneopterin-triphosphate-pyrophosphatase-new-clues-into-catalytic-mechanism
#8
Shannon E Hill, Elaine Nguyen, Chiamaka U Ukachukwu, Dana M Freeman, Stephen Quirk, Raquel L Lieberman
Dihydroneopterin triphosphate pyrophosphatase (DHNTPase), a member of the Mg2+ dependent Nudix hydrolase superfamily, is the recently-discovered enzyme that functions in the second step of the pterin branch of the folate biosynthetic pathway in E. coli. DHNTPase is of interest because inhibition of enzymes in bacterial folate biosynthetic pathways is a strategy for antibiotic development. We determined crystal structures of DHNTPase with and without activating, Mg2+-mimicking metals Co2+ and Ni2+. Four metal ions, identified by anomalous scattering, and stoichiometrically confirmed in solution by isothermal titration calorimetry, are held in place by Glu56 and Glu60 within the Nudix sequence motif, Glu117, waters, and a sulfate ion, of which the latter is further stabilized by a salt bridge with Lys7...
2017: PloS One
https://www.readbyqxmd.com/read/28705712/hydrolysis-of-diadenosine-polyphosphates-exploration-of-an-additional-role-of-mycobacterium-smegmatis-mutt1
#9
S M Arif, U Varshney, M Vijayan
Diadenosine polyphosphates (ApnA, n=2-6), particularly Ap4A, are involved in several important physiological processes. The substantial sequence identity of the Nudix hydrolase domain (domain 1) of Mycobacterium smegmatis MutT1 (MsMutT1) with a known Ap4A hydrolase suggested that MsMutT1 could also hydrolyse diadenosine polyphosphates. Biochemical experiments yielded results in conformity with this suggestion, with Ap4A as the best among the substrates. ATP is a product in all experiments; small amounts of ADP were also observed in the experiments involving Ap4A and Ap6A...
July 10, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/28628654/the-apah-like-phosphatase-tbalph1-is-the-major-mrna-decapping-enzyme-of-trypanosomes
#10
Susanne Kramer
5'-3' decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5'-3' exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5'-3' degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding...
June 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28559906/drawing-links-from-transcriptome-to-metabolites-the-evolution-of-aroma-in-the-ripening-berry-of-moscato-bianco-vitis-vinifera-l
#11
Laura Costantini, Christian D Kappel, Massimiliano Trenti, Juri Battilana, Francesco Emanuelli, Maddalena Sordo, Marco Moretto, Céline Camps, Roberto Larcher, Serge Delrot, Maria S Grando
Monoterpenes confer typical floral notes to "Muscat" grapevine varieties and, to a lesser extent, to other aromatic non-Muscat varieties. Previous studies have led to the identification and functional characterization of some enzymes and genes in this pathway. However, the underlying genetic map is still far from being complete. For example, the specific steps of monoterpene metabolism and its regulation are largely unknown. With the aim of identifying new candidates for the missing links, we applied an integrative functional genomics approach based on the targeted metabolic and genome-wide transcript profiling of Moscato Bianco ripening berries...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28498350/comparison-of-direct-sequencing-real-time-pcr-high-resolution-melt-pcr-hrm-and-pcr-restriction-fragment-length-polymorphism-pcr-rflp-analysis-for-genotyping-of-common-thiopurine-intolerant-variant-alleles-nudt15-c-415c-t-and-tpmt-c-719a-g-tpmt-3c
#12
Wai-Ying Fong, Chi-Chun Ho, Wing-Tat Poon
Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard...
May 12, 2017: Diagnostics
https://www.readbyqxmd.com/read/28391009/the-promise-of-pharmacogenomics-in-reducing-toxicity-during-acute-lymphoblastic-leukemia-maintenance-treatment
#13
REVIEW
Shoshana Rudin, Marcus Marable, R Stephanie Huang
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity...
April 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/28375146/biochemical-and-structural-studies-of-mycobacterium-smegmatis-mutt1-a-sanitization-enzyme-with-unusual-modes-of-association
#14
S M Arif, A G Patil, U Varshney, M Vijayan
Mycobacterium smegmatis MutT1, which is made up of a Nudix domain (domain 1) and a histidine phosphatase domain (domain 2), efficiently hydrolyses 8-oxo-GTP and 8-oxo-dGTP to the corresponding nucleoside diphosphates and phosphate in the presence of magnesium ions. Domain 1 alone hydrolyses nucleoside triphosphates less efficiently. Under high concentrations and over long periods, the full-length enzyme as well as domain 1 catalyses the hydrolysis of the nucleoside triphosphates to the respective nucleoside monophosphates and pyrophosphate...
April 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28336669/a-conserved-nad-binding-pocket-that-regulates-protein-protein-interactions-during-aging
#15
Jun Li, Michael S Bonkowski, Sébastien Moniot, Dapeng Zhang, Basil P Hubbard, Alvin J Y Ling, Luis A Rajman, Bo Qin, Zhenkun Lou, Vera Gorbunova, L Aravind, Clemens Steegborn, David A Sinclair
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD(+) (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD(+) to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein...
March 24, 2017: Science
https://www.readbyqxmd.com/read/28302504/mitochondrial-nudix-hydrolases-a-metabolic-link-between-nad-catabolism-gtp-and-mitochondrial-dynamics
#16
Aaron Long, Nina Klimova, Tibor Kristian
NAD(+) catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD(+) catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism...
October 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28258148/biosynthesis-of-2-chloropentostatin-and-2-amino-2-deoxyadenosine-highlights-a-single-gene-cluster-responsible-for-two-independent-pathways-in-actinomadura-sp-strain-atcc-39365
#17
Yaojie Gao, Gudan Xu, Pan Wu, Jin Liu, You-Sheng Cai, Zixin Deng, Wenqing Chen
2'-Chloropentostatin (2'-Cl PTN, 2'-chloro-2'-deoxycoformycin) and 2'-amino-2'-deoxyadenosine (2'-amino dA) are two adenosine-derived nucleoside antibiotics coproduced by Actinomadura sp. strain ATCC 39365. 2'-Cl PTN is a potent adenosine deaminase (ADA) inhibitor featuring an intriguing 1,3-diazepine ring, as well as a chlorination at C-2' of ribose, and 2'-amino dA is an adenosine analog showing bioactivity against RNA-type virus infection. However, the biosynthetic logic of them has remained poorly understood...
May 15, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28167526/vibrio-phage-kvp40-encodes-a-functional-nad-salvage-pathway
#18
Jae Yun Lee, Zhiqun Li, Eric S Miller
The genome of T4-type Vibrio bacteriophage KVP40 has five genes predicted to encode proteins of pyridine nucleotide metabolism, of which two, nadV and natV, would suffice for an NAD(+) salvage pathway. NadV is an apparent nicotinamide phosphoribosyltransferase (NAmPRTase), and NatV is an apparent bifunctional nicotinamide mononucleotide adenylyltransferase (NMNATase) and nicotinamide-adenine dinucleotide pyrophosphatase (Nudix hydrolase). Genes encoding the predicted salvage pathway were cloned and expressed in Escherichia coli, the proteins were purified, and their enzymatic properties were examined...
May 1, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28089905/nudix-type-motif-2-contributes-to-cancer-proliferation-through-the-regulation-of-rag-gtpase-mediated-mammalian-target-of-rapamycin-complex-1-localization
#19
Ohman Kwon, Dongoh Kwak, Sang Hoon Ha, Hyeona Jeon, Mangeun Park, Yeonho Chang, Pann-Ghill Suh, Sung Ho Ryu
Lysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2-silenced cells arrest in G0/G1 phases...
January 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28035004/structural-and-kinetic-studies-of-the-human-nudix-hydrolase-mth1-reveal-the-mechanism-for-its-broad-substrate-specificity
#20
Shaimaa Waz, Teruya Nakamura, Keisuke Hirata, Yukari Koga-Ogawa, Mami Chirifu, Takao Arimori, Taro Tamada, Shinji Ikemizu, Yusaku Nakabeppu, Yuriko Yamagata
The human MutT homolog 1 (hMTH1, human NUDT1) hydrolyzes oxidatively damaged nucleoside triphosphates and is the main enzyme responsible for nucleotide sanitization. hMTH1 recently has received attention as an anticancer target because hMTH1 blockade leads to accumulation of oxidized nucleotides in the cell, resulting in mutations and death of cancer cells. Unlike Escherichia coli MutT, which shows high substrate specificity for 8-oxoguanine nucleotides, hMTH1 has broad substrate specificity for oxidized nucleotides, including 8-oxo-dGTP and 2-oxo-dATP...
February 17, 2017: Journal of Biological Chemistry
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