S42003-019-0587-Z.Pdf
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
TRYPTOPHANYL TRANSF'er RNA SYNTHETASE and EXPRESSION of the TRYPTOPHAN OPERON in the Trp8 MUTANTS of ESCHERICHIA COLI I N Additi
TRYPTOPHANYL TRANSF'ER RNA SYNTHETASE AND EXPRESSION OF THE TRYPTOPHAN OPERON IN THE trp8 MUTANTS OF ESCHERICHIA COLI KOREAKI ITO, SOTA HIRAGA AND TAKASHI WRA Institute for Virus Research, Kyoto Uniuersity, Kyoto, Japan Received November 15, 1968 INaddition to their role in protein synthesis, aminoacyl tRNA synthetases in bacteria have been shown to have a regulatory role in the formation of enzymes involved in the synthesis of corresponding amino acids. This has been demon- strated at least in the case of isoleucine and valine (EIDLICand NEIDHARDT1965; YANIV,JACOB and GROS1965) and histidine (SCHLESINGERand MAGASANIK1964; ROTH, ANTONand HARTMAN1966; ROTH and AMES1966). Transfer RNA (tRNA) also appears to be involved in the regulation of these systems (FREUND- LICH 1967; SILBERT,FINK and AMES1966). The expression of the genes determining the tryptophan biosynthetic enzymes, the tryptophan operon in Escherichia coli, is subject to repression by excess L-tryptophan, the end product of the pathway. The mutants of a regulatory gene, trpR, located outside of this operon, exhibit constitutive synthesis of the biosyn- thetic enzymes (COHENand JACOB1959). In addition, we have previously reported tryptophan auxotrophic mutants in which the known structural genes of the tryptophan operon remain intact. One of these mutants, designated trpiS5, has been mapped near strA on the chromosome (HIRAGA,ITO, HAMADA and YURA 1967a). In the present paper, we report on further characterization of the trpS5 mutant and discuss the possible role of the trpS gene in the regulation of the tryptophan operon. The results suggest that trpS, located between strA and maZA, is the structural gene for tryptophanyl tRNA synthetase, and that tryptophanyl tRNA synthetase is somehow involved in the repression of the tryptophan operon. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Type of the Paper (Article
Supplementary Material A Proteomics Study on the Mechanism of Nutmeg-induced Hepatotoxicity Wei Xia 1, †, Zhipeng Cao 1, †, Xiaoyu Zhang 1 and Lina Gao 1,* 1 School of Forensic Medicine, China Medical University, Shenyang 110122, P. R. China; lessen- [email protected] (W.X.); [email protected] (Z.C.); [email protected] (X.Z.) † The authors contributed equally to this work. * Correspondence: [email protected] Figure S1. Table S1. Peptide fraction separation liquid chromatography elution gradient table. Time (min) Flow rate (mL/min) Mobile phase A (%) Mobile phase B (%) 0 1 97 3 10 1 95 5 30 1 80 20 48 1 60 40 50 1 50 50 53 1 30 70 54 1 0 100 1 Table 2. Liquid chromatography elution gradient table. Time (min) Flow rate (nL/min) Mobile phase A (%) Mobile phase B (%) 0 600 94 6 2 600 83 17 82 600 60 40 84 600 50 50 85 600 45 55 90 600 0 100 Table S3. The analysis parameter of Proteome Discoverer 2.2. Item Value Type of Quantification Reporter Quantification (TMT) Enzyme Trypsin Max.Missed Cleavage Sites 2 Precursor Mass Tolerance 10 ppm Fragment Mass Tolerance 0.02 Da Dynamic Modification Oxidation/+15.995 Da (M) and TMT /+229.163 Da (K,Y) N-Terminal Modification Acetyl/+42.011 Da (N-Terminal) and TMT /+229.163 Da (N-Terminal) Static Modification Carbamidomethyl/+57.021 Da (C) 2 Table S4. The DEPs between the low-dose group and the control group. Protein Gene Fold Change P value Trend mRNA H2-K1 0.380 0.010 down Glutamine synthetase 0.426 0.022 down Annexin Anxa6 0.447 0.032 down mRNA H2-D1 0.467 0.002 down Ribokinase Rbks 0.487 0.000 -
Folate Cycle Enzyme MTHFD1L Confers Metabolic Advantages in Hepatocellular Carcinoma
RESEARCH ARTICLE The Journal of Clinical Investigation Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma Derek Lee,1 Iris Ming-Jing Xu,1 David Kung-Chun Chiu,1 Robin Kit-Ho Lai,1 Aki Pui-Wah Tse,1 Lynna Lan Li,1 Cheuk-Ting Law,1 Felice Ho-Ching Tsang,1 Larry Lai Wei,1 Cerise Yuen-Ki Chan,1 Chun-Ming Wong,1,2 Irene Oi-Lin Ng,1,2 and Carmen Chak-Lui Wong1,2 1Department of Pathology and 2State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China. Cancer cells preferentially utilize glucose and glutamine, which provide macromolecules and antioxidants that sustain rapid cell division. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of these nutrients. The folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Here, using hepatocellular carcinoma (HCC) as a cancer model, we have observed a reduction in growth rate upon withdrawal of folate. We found that an enzyme in the folate cycle, methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L), plays an essential role in support of cancer growth. We determined that MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. Our observations further suggest that MTHFD1L contributes to the production and accumulation of NADPH to levels that are sufficient to combat oxidative stress in cancer cells. The elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for HCC. -
Differential Requirements for Tousled-Like Kinases 1 and 2 in Mammalian Development
Cell Death and Differentiation (2017) 24, 1872–1885 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd Differential requirements for Tousled-like kinases 1 and 2 in mammalian development Sandra Segura-Bayona1,8, Philip A Knobel1,8, Helena González-Burón1,8, Sameh A Youssef2,3, Aida Peña-Blanco1, Étienne Coyaud4,5, Teresa López-Rovira1, Katrin Rein1, Lluís Palenzuela1, Julien Colombelli1, Stephen Forrow1, Brian Raught4,5, Anja Groth6, Alain de Bruin2,7 and Travis H Stracker*,1 The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance. -
Sarcoma Metabolomics: Current Horizons and Future Perspectives
cells Review Sarcoma Metabolomics: Current Horizons and Future Perspectives Miguel Esperança-Martins 1,2,3,* , Isabel Fernandes 1,3,4 , Joaquim Soares do Brito 4,5, Daniela Macedo 6, Hugo Vasques 4,7, Teresa Serafim 2, Luís Costa 1,3,4 and Sérgio Dias 2,4 1 Centro Hospitalar Universitário Lisboa Norte, Medical Oncology Department, Hospital Santa Maria, 1649-028 Lisboa, Portugal; [email protected] (I.F.); [email protected] (L.C.) 2 Vascular Biology & Cancer Microenvironment Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; tserafi[email protected] (T.S.); [email protected] (S.D.) 3 Translational Oncobiology Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal 4 Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; [email protected] (J.S.d.B.); [email protected] (H.V.) 5 Centro Hospitalar Universitário Lisboa Norte, Orthopedics and Traumatology Department, Hospital Santa Maria, 1649-028 Lisboa, Portugal 6 Medical Oncology Department, Hospital Lusíadas Lisboa, 1500-458 Lisboa, Portugal; [email protected] 7 General Surgery Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal * Correspondence: [email protected] Abstract: The vast array of metabolic adaptations that cancer cells are capable of assuming, not Citation: Esperança-Martins, M.; only support their biosynthetic activity, but also fulfill their bioenergetic demands and keep their Fernandes, I.; Soares do Brito, J.; intracellular reduction–oxidation (redox) balance. Spotlight has recently been placed on the en- Macedo, D.; Vasques, H.; Serafim, T.; ergy metabolism reprogramming strategies employed by cancer cells to proliferate. -
Novel Derivatives of Nicotinamide Adenine Dinucleotide (NAD) and Their Biological Evaluation Against NAD- Consuming Enzymes
Novel derivatives of nicotinamide adenine dinucleotide (NAD) and their biological evaluation against NAD- Consuming Enzymes Giulia Pergolizzi University of East Anglia School of Pharmacy Thesis submitted for the degree of Doctor of Philosophy July, 2012 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that use of any information derived there from must be in accordance with current UK Copyright Law. In addition, any quotation or extract must include full attribution. ABSTRACT Nicotinamide adenine dinucleotide (β-NAD+) is a primary metabolite involved in fundamental biological processes. Its molecular structure with characteristic functional groups, such as the quaternary nitrogen of the nicotinamide ring, and the two high- energy pyrophosphate and nicotinamide N-glycosidic bonds, allows it to undergo different reactions depending on the reactive moiety. Well known as a redox substrate owing to the redox properties of the nicotinamide ring, β-NAD+ is also fundamental as a substrate of NAD+-consuming enzymes that cleave either high-energy bonds to catalyse their reactions. In this study, a panel of novel adenine-modified NAD+ derivatives was synthesized and biologically evaluated against different NAD+-consuming enzymes. The synthesis of NAD+ derivatives, modified in position 2, 6 or 8 of the adenine ring with aryl/heteroaryl groups, was accomplished by Suzuki-Miyaura cross-couplings. Their biological activity as inhibitors and/or non-natural substrates was assessed against a selected range of NAD+-consuming enzymes. The fluorescence of 8-aryl/heteroaryl NAD+ derivatives allowed their use as biochemical probes for the development of continuous biochemical assays to monitor NAD+-consuming enzyme activities. -
Formate Metabolism in Health and Disease
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Enlighten Review Formate metabolism in health and disease Matthias Pietzke 1, Johannes Meiser 2, Alexei Vazquez 1,3,* ABSTRACT Background: Formate is a one-carbon molecule at the crossroad between cellular and whole body metabolism, between host and microbiome metabolism, and between nutrition and toxicology. This centrality confers formate with a key role in human physiology and disease that is currently unappreciated. Scope of review: Here we review the scientific literature on formate metabolism, highlighting cellular pathways, whole body metabolism, and interactions with the diet and the gut microbiome. We will discuss the relevance of formate metabolism in the context of embryonic development, cancer, obesity, immunometabolism, and neurodegeneration. Major conclusions: We will conclude with an outlook of some open questions bringing formate metabolism into the spotlight. Ó 2019 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords Formate metabolism; One-carbon-metabolism; Cancer; Immune system; Neurodegeneration; Obesity 1. INTRODUCTION product of anaerobic fermentation of some bacteria species popu- lating the gut microbiome [7]. The formate generated by the gut Formic acid (HCOOH) was first isolated from distillation of ant bodies, bacteria can enter the circulation, adding to the endogenous pool of and it was subsequently named using the Latin word for ant, formica formate or being used as substrate for the growth of other bacteria [1]. Ants and other insects accumulate formic acid in secretory with aerobic metabolism [8]. -
The Roles of Mitochondrial Folate Metabolism in Supporting
REVIEW CURRENT DEVELOPMENTS IN NUTRITION Basic Science Section The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function Downloaded from https://academic.oup.com/cdn/article/4/10/nzaa153/5911573 by guest on 24 September 2021 Yuwen Xiu and Martha S Field Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA ABSTRACT Folate-mediated one-carbon metabolism (FOCM) is compartmentalized within human cells to the cytosol, nucleus, and mitochondria. The recent identifications of mitochondria-specific, folate-dependent thymidylate [deoxythymidine monophosphate (dTMP)] synthesis together with discoveries indicating the critical role of mitochondrial FOCM in cancer progression have renewed interest in understanding this metabolic pathway. The goal of this narrative review is to summarize recent advances in the field of one-carbon metabolism, with an emphasis on the biological importance of mitochondrial FOCM in maintaining mitochondrial DNA integrity and mitochondrial function, as well as the reprogramming of mitochondrial FOCM in cancer. Elucidation of the roles and regulation of mitochondrial FOCM will contribute to a better understanding of the mechanisms underlying folate-associated pathologies. Curr Dev Nutr 2020;4:nzaa153. Keywords: folate, thymidylate, mitochondrial DNA, mitochondrial metabolism, cancer metabolism C The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Manuscript received August 10, 2020. -
Metabolic Enzyme Expression Highlights a Key Role for MTHFD2 and the Mitochondrial Folate Pathway in Cancer
ARTICLE Received 1 Nov 2013 | Accepted 17 Dec 2013 | Published 23 Jan 2014 DOI: 10.1038/ncomms4128 Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer Roland Nilsson1,2,*, Mohit Jain3,4,5,6,*,w, Nikhil Madhusudhan3,4,5, Nina Gustafsson Sheppard1,2, Laura Strittmatter3,4,5, Caroline Kampf7, Jenny Huang8, Anna Asplund7 & Vamsi K. Mootha3,4,5 Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta- analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses. 1 Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden. 2 Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden. 3 Broad Institute, Cambridge, Massachusetts 02142, USA. 4 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. -
Isolation of a Pyrophosphoryl Form of Pyruvate, Phosphate Dikinase from Propionibacteria* (Phosphoenolpyruvate/ATP/Enzyme) YORAM MILNER and HARLAND G
Proc. Nat. Acad. Sci. USA Vol. 69, No. 9, pp. 2463-2468, September 1972 Isolation of a Pyrophosphoryl Form of Pyruvate, Phosphate Dikinase from Propionibacteria* (phosphoenolpyruvate/ATP/enzyme) YORAM MILNER AND HARLAND G. WOOD Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 Contributed by Harland G. Wood, June 15, 1972 ABSTRACT Pyruvate, phosphate dikinase from Pro- Enzyme-P + pyruvate ;. enzyme + P-enolpyruvate [ic] pionibacterium shermanii catalyzes the formation of P- enolpyruvate, AMP, and inorganic pyrophosphate from P-enolpyruvate synthase of Escherichia coli, which catalyzes pyruvate, ATP, and orthophosphate; the mechanism reaction 2, likewise uses a mechanism that does not involve a involves three partial reactions and three forms of the enzyme: pyrophosphoryl-enzyme, phosphoryl-enzyme, stable, free diphosphoryl-enzyme (3). and free enzyme. The phosphoryl-enzyme was prepared by -- AMP Pi incubation with P-enolpyruvate and isolated by gel- ATP + pyruvate P-enolpyruvate + + [2] chromatography. The phosphoryl-enzyme was converted These observations led us to reinvestigate the validity of the to 32P31P-enzyme and [32P]Pi by incubation with [32P]PPi; 1 mol of pyrophosphoryl-enzyme was formed per mol of Evans-Wood mechanism. Steady-state and exchange kinetics enzyme of molecular weight 150,000. The labeled enzyme have shown clearly that the pyruvate, phosphate dikinase of released its radioactivity upon incubation with Pi or propionibacteria proceeds via a tri(uni,uni) ping-pong se- AMP to produce the expected [33PJPPi or [y-y3P]ATP, re- quence, as expected from the Evans-Wood mechanism (4). We spectively. Hydrolysis of the pyrophosphoryl-enzyme with here the isolation of the form of the dilute acid yielded PPi. -
Quantification of Pyrophosphate in Soil Solution by Pyrophosphatase
Soil Biology & Biochemistry 74 (2014) 95e97 Contents lists available at ScienceDirect Soil Biology & Biochemistry journal homepage: www.elsevier.com/locate/soilbio Short communication Quantification of pyrophosphate in soil solution by pyrophosphatase hydrolysis Kasper Reitzel a,*, Benjamin L. Turner b a Department of Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark b Smithsonian Tropical Research Institute, Apartado 0843-03092, Balboa, Ancon, Panama article info abstract Article history: A commercial pyrophosphatase from Saccharomyces cerevisiae selectively hydrolyzed sodium pyro- Received 20 December 2013 phosphate, but showed no significant activity towards a range of other organic and condensed inorganic Received in revised form phosphorus compounds. Pyrophosphate determined by pyrophosphatase hydrolysis accounted for 8 February 2014 38 Æ 12% (mean Æ standard error of 19 sites) of the non-reactive phosphorus in soil solution obtained by Accepted 3 March 2014 centrifugation from a series of lowland tropical rain forest soils. Pyrophosphate concentrations were up Available online 17 March 2014 À to 89 mgPl 1 and correlated positively with microbial phosphorus, soil solution pH, and native phos- phomonoesterase activity in soil solution, but not with total soil pyrophosphate determined by NaOH Keywords: e 31 Pyrophosphate EDTA extraction and solution P NMR spectroscopy. In summary, we identify pyrophosphate as a major Phosphatase constituent of soil solution phosphorus in lowland tropical rain forests, and demonstrate that a com- Soil solution mercial pyrophosphatase can be used as a selective tool to quantify trace concentrations of pyrophos- Phosphorus phate in soil solution. Tropical forests Ó 2014 Elsevier Ltd. All rights reserved. Pyrophosphate is ubiquitous in soils, where it appears to origi- Bünemann, 2008).