Vitamin B1 (2) Water-Soluble Vitamins
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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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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). -
L-Carnitine, Mecobalamin and Folic Acid Tablets) TRINERVE-LC
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only (L-Carnitine, Mecobalamin and Folic acid Tablets) TRINERVE-LC 1. Name of the medicinal product Trinerve-LC Tablets 2. Qualitative and quantitative composition Each film- coated tablets contains L-Carnitine…………………….500 mg Mecobalamin……………….1500 mcg Folic acid IP…………………..1.5mg 3. Pharmaceutical form Film- coated tablets 4. Clinical particulars 4.1 Therapeutic indications Vitamin and micronutrient supplementation in the management of chronic disease. 4.2 Posology and method of administration For oral administration only. One tablet daily or as directed by physician. 4.3 Contraindications Hypersensitivity to any constituent of the product. 4.4 Special warnings and precautions for use L-Carnitine The safety and efficacy of oral L-Carnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral L-Carnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. Mecobalamin Should be given with caution in patients suffering from folate deficiency. The following warnings and precautions suggested with parent form – vitamin B12 The treatment of vitamin B12 deficiency can unmask the symptoms of polycythemia vera. Megaloblastic anemia is sometimes corrected by treatment with vitamin B12. But this can have very serious side effects. Don’t attempt vitamin B12 therapy without close supervision by healthcare provider. Do not take vitamin B12 if Leber’s disease, a hereditary eye disease. -
An Overview of Biosynthesis Pathways – Inspiration for Pharmaceutical and Agrochemical Discovery
An Overview of Biosynthesis Pathways – Inspiration for Pharmaceutical and Agrochemical Discovery Alan C. Spivey [email protected] 19th Oct 2019 Lessons in Synthesis - Azadirachtin • Azadirachtin is a potent insect anti-feedant from the Indian neem tree: – exact biogenesis unknown but certainly via steroid modification: O MeO C OAc O 2 H O OH O H O OH 12 O O C 11 O 14 OH oxidative 8 O H 7 cleavage highly hindered C-C bond HO OH AcO OH AcO OH for synthesis! H H of C ring H MeO2C O AcO H tirucallol azadirachtanin A azadirachtin (cf. lanosterol) (a limanoid = tetra-nor-triterpenoid) – Intense synhtetic efforts by the groups of Nicolaou, Watanabe, Ley and others since structural elucidation in 1987. –1st total synthesis achieved in 2007 by Ley following 22 yrs of effort – ~40 researchers and over 100 person-years of research! – 64-step synthesis – Veitch Angew. Chem. Int. Ed. 2007, 46, 7629 (DOI) & Veitch Angew. Chem. Int. Ed. 2007, 46, 7633 (DOI) – Review ‘The azadirachtin story’ see: Veitch Angew. Chem. Int. Ed. 2008, 47, 9402 (DOI) Format & Scope of Presentation • Metabolism & Biosynthesis – some definitions, 1° & 2° metabolites • Shikimate Metabolites – photosynthesis & glycolysis → shikimate formation → shikimate metabolites – Glyphosate – a non-selective herbicide • Alkaloids – acetylCoA & the citric acid cycle → -amino acids → alkaloids – Opioids – powerful pain killers • Fatty Acids and Polyketides –acetylCoA → malonylCoA → fatty acids, prostaglandins, polyketides, macrolide antibiotics – NSAIDs – anti-inflammatory’s • Isoprenoids/terpenes -
The Effect of Vitamin Supplementation on Subclinical
molecules Review The Effect of Vitamin Supplementation on Subclinical Atherosclerosis in Patients without Manifest Cardiovascular Diseases: Never-ending Hope or Underestimated Effect? Ovidiu Mitu 1,2,* , Ioana Alexandra Cirneala 1,*, Andrada Ioana Lupsan 3, Mircea Iurciuc 4 , 5 5 2, Ivona Mitu , Daniela Cristina Dimitriu , Alexandru Dan Costache y , Antoniu Octavian Petris 1,2 and Irina Iuliana Costache 1,2 1 Department of Cardiology, Clinical Emergency Hospital “Sf. Spiridon”, 700111 Iasi, Romania 2 1st Medical Department, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania 3 Department of Cardiology, University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania 4 Department of Cardiology, University of Medicine and Pharmacy “Victor Babes”, 300041 Timisoara, Romania 5 2nd Morpho-Functional Department, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania * Correspondence: [email protected] (O.M.); [email protected] (I.A.C.); Tel.: +40-745-279-714 (O.M.) Medical Student, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania. y Academic Editors: Raluca Maria Pop, Ada Popolo and Stefan Cristian Vesa Received: 25 March 2020; Accepted: 7 April 2020; Published: 9 April 2020 Abstract: Micronutrients, especially vitamins, play an important role in the evolution of cardiovascular diseases (CVD). It has been speculated that additional intake of vitamins may reduce the CVD burden by acting on the inflammatory and oxidative response starting from early stages of atherosclerosis, when the vascular impairment might still be reversible or, at least, slowed down. The current review assesses the role of major vitamins on subclinical atherosclerosis process and the potential clinical implications in patients without CVD. -
Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues
Published OnlineFirst September 8, 2009; DOI: 10.1158/0008-5472.CAN-09-1927 Experimental Therapeutics, Molecular Targets, and Chemical Biology Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues Dong Wu,1 Yang Li,1 Gaojie Song,1 Chongyun Cheng,1 Rongguang Zhang,2 Andrzej Joachimiak,2 NeilShaw, 1 and Zhi-Jie Liu1 1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China and 2Structural Biology Center, Argonne National Laboratory, Argonne, Illinois Abstract of the one-carbon metabolic network, dihydrofolate reductase, 5,10-Methenyltetrahydrofolate synthetase (MTHFS) regulates which catalyzes the conversion of dihydrofolate to tetrahydrofolate. the flow of carbon through the one-carbon metabolic network, Similarly, colorectal and pancreatic cancers are routinely treated by which supplies essential components for the growth and administration of the pyrimidine analogue 5-fluorouracil (5-FU), proliferation of cells. Inhibition of MTHFS in human MCF-7 which inhibits thymidylate synthase (TS; ref. 6). TS converts breast cancer cells has been shown to arrest the growth of deoxyuridylate to deoxythymidylate using a carbon donated by cells. Absence of the three-dimensional structure of human 5,10-methylenetetrahydrofolate (Fig. 1). This conversion is essential MTHFS (hMTHFS) has hampered the rational design and for DNA synthesis (7). To increase the clinical efficiency of the optimization of drug candidates. Here, we report the treatment, 5-formyltetrahydrofolate is often coadministered along structures of native hMTHFS, a binary complex of hMTHFS with 5-FU. The beneficial effect of administering 5-formyltetrahy- with ADP, hMTHFS bound with the N5-iminium phosphate drofolate during the therapy with 5-FU is a consequence of the reaction intermediate, and an enzyme-product complex of 5,10-methenyltetrahydrofolate synthetase (MTHFS)–catalyzed hMTHFS. -
PC22 Doc. 22.1 Annex (In English Only / Únicamente En Inglés / Seulement En Anglais)
Original language: English PC22 Doc. 22.1 Annex (in English only / únicamente en inglés / seulement en anglais) Quick scan of Orchidaceae species in European commerce as components of cosmetic, food and medicinal products Prepared by Josef A. Brinckmann Sebastopol, California, 95472 USA Commissioned by Federal Food Safety and Veterinary Office FSVO CITES Management Authorithy of Switzerland and Lichtenstein 2014 PC22 Doc 22.1 – p. 1 Contents Abbreviations and Acronyms ........................................................................................................................ 7 Executive Summary ...................................................................................................................................... 8 Information about the Databases Used ...................................................................................................... 11 1. Anoectochilus formosanus .................................................................................................................. 13 1.1. Countries of origin ................................................................................................................. 13 1.2. Commercially traded forms ................................................................................................... 13 1.2.1. Anoectochilus Formosanus Cell Culture Extract (CosIng) ............................................ 13 1.2.2. Anoectochilus Formosanus Extract (CosIng) ................................................................ 13 1.3. Selected finished -
Structural and Functional Characterization O
Julius-Maximilians-Universität Würzburg Approaching antimicrobial resistance – Structural and functional characterization of the fungal transcription factor Mrr1 from Candida albicans and the bacterial ß-ketoacyl-CoA thiolase FadA5 from Mycobacterium tuberculosis Auf den Spuren der antimikrobiellen Resistenz – Strukturelle und funktionelle Charakterisierung des Transkriptionsfaktors Mrr1 aus Candida albicans und der bakteriellen β-ketoacyl-CoA thiolase FadA5 aus Mykobakterium tuberculosis Dissertation for a doctoral degree at the Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg, Section Biomedicine submitted by Christin Marliese Schäfer from Miltenberg am Main Würzburg, November 2014 Submitted on: ………………………………………………………..…… Office stamp Members of the Promotionskomitee: Chairperson: Ulrike Holzgrabe Primary Supervisor: Caroline Kisker Supervisor (Second): Joachim Morschhäuser Supervisor (Third): Nicole Sampson Date of Public Defence: …………………………………………….… Date of Receipt of Certificates: ……………………………………… Table of content Table of content Table of content ....................................................................................................................................... I Summary ................................................................................................................................................. 1 Zusammenfassung ................................................................................................................................... 4 1 Introduction .................................................................................................................................... -
Considerations for Crop Biofortification
fpls-09-00443 April 4, 2018 Time: 16:15 # 1 REVIEW published: 06 April 2018 doi: 10.3389/fpls.2018.00443 Toward Eradication of B-Vitamin Deficiencies: Considerations for Crop Biofortification Simon Strobbe and Dominique Van Der Straeten* Laboratory of Functional Plant Biology, Department of Biology, Ghent University, Ghent, Belgium ‘Hidden hunger’ involves insufficient intake of micronutrients and is estimated to affect over two billion people on a global scale. Malnutrition of vitamins and minerals is known to cause an alarming number of casualties, even in the developed world. Many staple crops, although serving as the main dietary component for large population groups, deliver inadequate amounts of micronutrients. Biofortification, the augmentation of natural micronutrient levels in crop products through breeding or genetic engineering, is a pivotal tool in the fight against micronutrient malnutrition (MNM). Although these approaches have shown to be successful in several species, a more extensive knowledge of plant metabolism and function of these micronutrients is required to refine and improve biofortification strategies. This review focuses on the relevant B-vitamins Edited by: (B1, B6, and B9). First, the role of these vitamins in plant physiology is elaborated, Alexander Arthur Theodore Johnson, as well their biosynthesis. Second, the rationale behind vitamin biofortification is University of Melbourne, Australia illustrated in view of pathophysiology and epidemiology of the deficiency. Furthermore, Reviewed by: advances in biofortification, via metabolic engineering or breeding, are presented. Finally, Francesco Di Gioia, University of Florida, United States considerations on B-vitamin multi-biofortified crops are raised, comprising the possible Aymeric Goyer, interplay of these vitamins in planta. -
Recombinant Human Dihydrofolate Reductase/DHFR
Recombinant Human Dihydrofolate Reductase/DHFR Catalog Number: 8456-DR DESCRIPTION Source E. coliderived Met1Asp187, with a Cterminal 6His tag Accession # P00374 Nterminal Sequence Met1 & Val2 Analysis Predicted Molecular 22 kDa Mass SPECIFICATIONS SDSPAGE 23 kDa, reducing conditions Activity Measured by the reduction of dihydrofolic acid (DHF). The specific activity is >5,500 pmol/min/μg, as measured under the described conditions. Endotoxin Level <1.0 EU per 1 μg of the protein by the LAL method. Purity >95%, by SDSPAGE under reducing conditions and visualized by Colloidal Coomassie® Blue stain at 5 μg per lane. Formulation Supplied as a 0.2 μm filtered solution in Tris, NaCl, Glycerol, Brij35 and DTT. See Certificate of Analysis for details. Activity Assay Protocol Materials l Assay Buffer: 50 mM MES, 25 mM Tris, 100 mM NaCl, 25 mM Ethanolamine, 2 mM DTT l Recombinant Dihydrofolate Reductase/DHFR (rhDHFR) (Catalog # 8456DR) l βNicotinamide adenine dinucleotide phosphate reduced, tetrasodium salt (βNADPH) (Sigma, Catalog # N7505), 10 mM stock in deionized water l Dihydrofolic acid (DHF) (Sigma, Catalog # D7006), 10 mM stock in Assay Buffer + 4.5 mM NaOH l 96well Clear Plate (Catalog # DY990) l Plate Reader (Model: SpectraMax Plus by Molecular Devices) or equivalent Assay 1. Dilute rhDHFR to 1 μg/mL in Assay Buffer. 2. Prepare a Substrate Mixture containing 0.2 mM DHF and 0.25 mM βNADPH in Assay Buffer. 3. Load 50 μL of 1 μg/mL rhDHFR into a plate, and start the reaction by adding 50 μL of Substrate Mixture. -
Oral Immunosuppressive Drugs in the Treatment of Atopic Dermatitis
Oral immunosuppressive drugs in the treatment of atopic dermatitis IMPROVING PERFORMANCE AND SAFETY FLOOR M. GARRITSEN Colofon Oral immunosuppressive drugs in the treatment of atopic dermatitis Improving performance and safety Thesis with a summary in Dutch, Utrecht University, the Netherlands © Floor Garritsen, 2018 No part of this thesis may be reproduced, stored or transmitted, in any form or by any means, without prior permission of the author. ISBN: 978-90-393-6931-9 Cover design and layout: Die Jongens Printed and published by: Proefschriftmaken.nl Oral immunosuppressive drugs in the treatment of atopic dermatitis: improving performance and safety Orale immunosuppressiva bij de behandeling van constitutioneel eczeem: het verbeteren van effectiviteit en veiligheid (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 8 februari 2018 des middags te 2.30 uur door Floralie Maria Garritsen geboren op 22 oktober 1986 te Beek en Donk Promotor: Prof. dr. C.A.F.M. Bruijnzeel-Koomen Copromotoren: Dr. M.S. de Bruin-Weller Dr. M.P.H. van den Broek Table of contents Chapter 1 General introduction 7 Part I – Qualitative and quantitative exploration of oral immunosuppressive drug use in the Netherlands Chapter 2 Ten years experience with oral immunosuppressive treatment 23 in adult patients with atopic dermatitis in two -
Cheminformatics for Genome-Scale Metabolic Reconstructions
CHEMINFORMATICS FOR GENOME-SCALE METABOLIC RECONSTRUCTIONS John W. May European Molecular Biology Laboratory European Bioinformatics Institute University of Cambridge Homerton College A thesis submitted for the degree of Doctor of Philosophy June 2014 Declaration This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration except where specifically indicated in the text. This dissertation is not substantially the same as any I have submitted for a degree, diploma or other qualification at any other university, and no part has already been, or is currently being submitted for any degree, diploma or other qualification. This dissertation does not exceed the specified length limit of 60,000 words as defined by the Biology Degree Committee. This dissertation has been typeset using LATEX in 11 pt Palatino, one and half spaced, according to the specifications defined by the Board of Graduate Studies and the Biology Degree Committee. June 2014 John W. May to Róisín Acknowledgements This work was carried out in the Cheminformatics and Metabolism Group at the European Bioinformatics Institute (EMBL-EBI). The project was fund- ed by Unilever, the Biotechnology and Biological Sciences Research Coun- cil [BB/I532153/1], and the European Molecular Biology Laboratory. I would like to thank my supervisor, Christoph Steinbeck for his guidance and providing intellectual freedom. I am also thankful to each member of my thesis advisory committee: Gordon James, Julio Saez-Rodriguez, Kiran Patil, and Gos Micklem who gave their time, advice, and guidance. I am thankful to all members of the Cheminformatics and Metabolism Group. -
BIOPAR DELTA-FORTE- 1 Nf Units, 50 Mcg Cbl, 2.5 Mg F-Thf, 1
BIOPAR DELTA-FORTE- 1 nf units, 50 mcg cbl, 2.5 mg f-thf, 1 mg pteglu-, 7 mg me- thf capsule Jaymac Pharmacueticals LLC Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA. For further information about unapproved drugs, click here. ---------- BioparTM delta-FORTE DESCRIPTION [1 NF Units] [50 mcg CBl] [2.5 mg F-THf] [1 mg PteGlu-] [7 mg Me-THf] Prescription Hematopoietic Preparation For Therapeutic Use Multiphasic Softgels (30ct carton) NDC 64661-793-30 Rx ONLY BioparTMdelta-FORTE is an orally administered prescription hematopoietic preparation for therapeutic use formulated for adult macrocytic anemia patients – specifically including pernicious anemia patients, ages 12 and up, who are under specific direction and monitoring of cobalamin and folate status by a physician. A recent study+ suggested that BioparTM delta-FORTE was effective in lowering homocysteine levels in patients that are positive for MTHFR (methylenetetrahydrofolate reductase polymorphism). BioparTM delta-FORTE may be taken by women of childbearing age. BioparTM delta- FORTE may be taken by geriatric patients where compliance is an issue. + ClinicalTrials.gov identifier: NCT02709668, Correlation of Clinical Response With Homocysteine Reduction During Therapy With Reduced B Vitamins in Patients with MDD Who Are Positive for MTHFR C677T or A1298C Polymorphism. INGREDIENTS Cobalamin-intrinsic factor concentrate (non-inhibitory)1 .............................................................................................