Formate Metabolism in Health and Disease
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Methionine Synthase Supports Tumor Tetrahydrofolate Pools
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284521; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Methionine synthase supports tumor tetrahydrofolate pools Joshua Z. Wang1,2,#, Jonathan M. Ghergurovich1,3,#, Lifeng Yang1,2, and Joshua D. Rabinowitz1,2,* 1 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA 2 Department of Chemistry, Princeton University, Princeton, New Jersey, USA 3 Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA # These authors contributed equally to this work. *Corresponding author: Joshua Rabinowitz Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics, Princeton University, Washington Rd, Princeton, NJ 08544, USA Phone: (609) 258-8985; e-mail: [email protected] Conflict of Interest Disclosure: J.D.R. is a paid advisor and stockholder in Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals, and Rafael Pharmaceuticals; a paid consultant of Pfizer; a founder, director, and stockholder of Farber Partners and Serien Therapeutics. JDR and JMG are inventors of patents in the area of folate metabolism held by Princeton University. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284521; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl- THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). -
Defining Sources of Nutrient Limitation for Tumors By
Defining sources of nutrient limitation for tumors by Mark Robert Sullivan B.S. Molecular Biology and Chemistry University of Pittsburgh (2013) Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2019 © 2019 Mark R. Sullivan. All rights reserved. The author hereby grants to MIT permission to reproduce and to distribute publicly paper and electronic copies of this thesis document in whole or in part in any medium now known or hereafter created. Signature of Author.......................................................................................................................... Department of Biology April 30, 2019 Certified by ...................................................................................................................................... Matthew G. Vander Heiden Associate Professor of Biology Thesis Supervisor Accepted by...................................................................................................................................... Amy E. Keating Professor of Biology Co-Director, Biology Graduate Committee 1 2 Defining sources of nutrient limitation for tumors by Mark Robert Sullivan Submitted to the Department of Biology on April 30, 2019 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology ABSTRACT Tumor growth requires that cancer cells accumulate sufficient biomass to grow and divide. To accomplish this, tumor cells must acquire -
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. -
Involvements of Hyperhomocysteinemia in Neurological Disorders
H OH metabolites OH Review Involvements of Hyperhomocysteinemia in Neurological Disorders Marika Cordaro 1,† , Rosalba Siracusa 2,† , Roberta Fusco 2 , Salvatore Cuzzocrea 2,3,* , Rosanna Di Paola 2,* and Daniela Impellizzeri 2 1 Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; [email protected] 2 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy; [email protected] (R.S.); [email protected] (R.F.); [email protected] (D.I.) 3 Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA * Correspondence: [email protected] (S.C.); [email protected] (R.D.P.); Tel.: +39-090-6765208 (S.C. & R.D.P.) † The authors equally contributed to the review. Abstract: Homocysteine (HCY), a physiological amino acid formed when proteins break down, leads to a pathological condition called hyperhomocysteinemia (HHCY), when it is over a definite limit. It is well known that an increase in HCY levels in blood, can contribute to arterial damage and several cardiovascular disease, but the knowledge about the relationship between HCY and brain disorders is very poor. Recent studies demonstrated that an alteration in HCY metabolism or a deficiency in folate or vitamin B12 can cause altered methylation and/or redox potentials, that leads to a modification on calcium influx in cells, or into an accumulation in amyloid and/or tau protein involving a cascade of events that culminate in apoptosis, and, in the worst conditions, neuronal death. The present review will thus summarize how much is known about the possible role of HHCY in neurodegenerative disease. -
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. -
Recycling of Vitamin B12 and NAD+ Within the Pdu Microcompartment of Salmonella Enterica Shouqiang Cheng Iowa State University
Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2010 Recycling of vitamin B12 and NAD+ within the Pdu microcompartment of Salmonella enterica Shouqiang Cheng Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Biochemistry, Biophysics, and Structural Biology Commons Recommended Citation Cheng, Shouqiang, "Recycling of vitamin B12 and NAD+ within the Pdu microcompartment of Salmonella enterica" (2010). Graduate Theses and Dissertations. 11713. https://lib.dr.iastate.edu/etd/11713 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. + Recycling of vitamin B12 and NAD within the Pdu microcompartment of Salmonella enterica by Shouqiang Cheng A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Biochemistry Program of Study Committee: Thomas A. Bobik, Major Professor Alan DiSpirito Basil Nikolau Reuben Peters Gregory J. Phillips Iowa State University Ames, Iowa 2010 Copyright © Shouqiang Cheng, 2010. All rights reserved. ii Table of contents Abstract............................................................................................................................. -
S42003-019-0587-Z.Pdf
Corrected: Author Correction ARTICLE https://doi.org/10.1038/s42003-019-0587-z OPEN High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity Wen Zhu 1,10, Ashish Radadiya 1, Claudine Bisson2,10, Sabine Wenzel 3, Brian E. Nordin4,11, 1234567890():,; Francisco Martínez-Márquez3, Tsuyoshi Imasaki 3,5, Svetlana E. Sedelnikova2, Adriana Coricello 1,6,7, Patrick Baumann 1, Alexandria H. Berry8, Tyzoon K. Nomanbhoy4, John W. Kozarich 4, Yi Jin 1, David W. Rice 2, Yuichiro Takagi 3 & Nigel G.J. Richards 1,9 Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a bona fide drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 μM concentration in HCT- 116 cell lysates with almost no off-target binding. The high-resolution (1.85 Å) crystal structure of human ASNS has enabled us to identify a cluster of negatively charged side chains in the synthetase domain that plays a key role in inhibitor binding. Comparing this structure with those of evolutionarily related AMP-forming enzymes provides insights into intermolecular interactions that give rise to the observed binding selectivity. Our findings demonstrate the feasibility of developing second generation human ASNS inhibitors as lead compounds for the discovery of drugs against metastasis. 1 School of Chemistry, Cardiff University, Cardiff, UK. 2 Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK. -
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. -
Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk Susan E
University of South Carolina Scholar Commons Faculty Publications Epidemiology and Biostatistics 2008 Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk Susan E. Steck University of South Carolina - Columbia, [email protected] Temitope O. Keku Lesley M. Butler Joseph Galanko Beri Massa See next page for additional authors Follow this and additional works at: https://scholarcommons.sc.edu/ sph_epidemiology_biostatistics_facpub Part of the Public Health Commons Publication Info Postprint version. Published in Journal of Nutrigenetics and Nutrigenomics, Volume 1, Issue 4, 2008, pages 196-204. Steck, S. E., Keku, T., Butler, L. M., Galanko, J., Massa, B., Millikan, R. C., & Sandler, R. S. (2008). Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. Journal of Nutrigenetics and Nutrigenomics, 1(4), 196-204. DOI: 10.1159/000136651 © Journal of Nutrigenetics and Nutrigenomics, 2008, Karger http://content.karger.com/produktedb/produkte.asp?DOI=10.1159/000136651 This Article is brought to you by the Epidemiology and Biostatistics at Scholar Commons. It has been accepted for inclusion in Faculty Publications by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Author(s) Susan E. Steck, Temitope O. Keku, Lesley M. Butler, Joseph Galanko, Beri Massa, Robert C. Millikan, and Robert S. Sandler This article is available at Scholar Commons: https://scholarcommons.sc.edu/sph_epidemiology_biostatistics_facpub/303 NIH Public Access Author Manuscript J Nutrigenet Nutrigenomics. Author manuscript; available in PMC 2009 October 7. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Nutrigenet Nutrigenomics. -
Genome, Proteome and Physiology of the Thermophilic Bacterium Anoxybacillus Flavithermus
Open Access Research2008SawetVolume al. 9, Issue 11, Article R161 Encapsulated in silica: genome, proteome and physiology of the thermophilic bacterium Anoxybacillus flavithermus WK1 Jimmy H Saw¤*‡‡, Bruce W Mountain¤†, Lu Feng¤‡§¶, Marina V Omelchenko¤¥, Shaobin Hou¤#, Jennifer A Saito*, Matthew B Stott†, Dan Li‡§¶, Guang Zhao‡§¶, Junli Wu‡§¶, Michael Y Galperin¥, Eugene V Koonin¥, Kira S Makarova¥, Yuri I Wolf¥, Daniel J Rigden**, Peter F Dunfield††, Lei Wang‡§¶ and Maqsudul Alam*# Addresses: *Department of Microbiology, University of Hawai'i, 2538 The Mall, Honolulu, HI 96822, USA. †GNS Science, Extremophile Research Group, 3352 Taupo, New Zealand. ‡TEDA School of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, PR China. §Tianjin Research Center for Functional Genomics and Biochip, Tianjin 300457, PR China. ¶Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Tianjin 300457, PR China. ¥National Center for Biotechnology Information, NLM, National Institutes of Health, Bethesda, MD 20894, USA. #Advance Studies in Genomics, Proteomics and Bioinformatics, College of Natural Sciences, University of Hawai'i, Honolulu, HI 96822, USA. **School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK. ††Department of Biological Sciences, University of Calgary, 2500 University Dr. NW, Calgary, Alberta T2N 1N4, Canada. ‡‡Current address: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. ¤ These authors contributed equally to this work. Correspondence: Lei Wang. Email: [email protected]. Maqsudul Alam. Email: [email protected] Published: 17 November 2008 Received: 12 June 2008 Revised: 8 October 2008 Genome Biology 2008, 9:R161 (doi:10.1186/gb-2008-9-11-r161) Accepted: 17 November 2008 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2008/9/11/R161 © 2008 Saw et al.; licensee BioMed Central Ltd.