Methionine Synthase Supports Tumor Tetrahydrofolate Pools
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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 -
The Vitamin B12 Coenzyme
THE VITAMIN B12 COENZYME D. DoLPHIN, A. W. JoHNSON, R. RoDRIGO and N. SHAW Department of Chemistry, University of Nottingham, U.K. INTRODUCTION In 19•58 Barker and his associatesl-3 recognized a new coenzyme which controlled the conversion of glutamate into ß-methylaspartate by Clostridium tetanomorpkim. The coenzyme was shown4 to be related to !f;-vitamin B12, i.e. contair ing an adenine nucleotide grouping in place of the 5,6-dimethyl benziminawle nucleotide of vitamin B12, although similar coenzymes con taining btnziminazole or 5,6-dimethylbenziminazole were produced by growing C. tetanomorphum in the presence of the a ppropriate base5. Other variations of the nucleotide base have been achieved using Propionibacterium arabinosum in the presence of other purines and benziminazoles6• The pres ence of;:he coenzymes in a wide variety of micro-organisms such as several species of Actinomycetes including Streptomyces olivaceus and S. griseus has been dem( mstrated by the glutamate isomerase assay7 or by isolation. I t appears thü Vitamin B12 and its analogues are always biosynthesized in the form of their coenzymes. Preliminary physical and chemical studies sug gested that in the 5,6-dimethylbenzirninazolyl cobamide coenzyme the cyanide gr )up of vitamin B12, cyanocobalamin, was replaced by an adenine nucleoside':, 5, 8 and the determination9 of the complete structure (I; R = 5'-de·)xyadenosyl) of the coenzyme by X-ray analysis revealed the existence c f an essentially covalent bond between the cobalt atom and the S'.. carbon üom of the additional 5'-deoxyadenosine group. The molecule Me CH 2• CO· NH2 In the vitamin 8 12 coenzyme R =5' - deoxyadenosyl = Me Me 539 D. -
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. -
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. -
The Potential Protective Role of Vitamin K in Diabetic Neuropathy
VITAMINS The potential protective role of vitamin K in diabetic neuropathy DILIP MEHTA Viridis Biopharma 6/10 Jogani Industrial Complex ew cases of diabetes are symptomatic pain relief (3-5). V. N. Purav Marg, Chunabhatti increasing worldwide at a rapid Mumbai 400022, India The etiopathology of peripheral pace, with the total number of neuropathy is poorly understood and many [email protected] people with diabetes was projected factors, including dietary deficiencies, may www.viridisbiopharma.com Nto rise from 171 million in 2000 to 366 million contribute to the clinical manifestation of the in 2030 – an increase of nearly 200 million in condition. Deficiency of vitamin B12 (also only three decades. There are more cases of known as cobalamin), which results in a lack diabetes in women and urban populations, of a related compound, methylcobalamin, is with diabetes in developing countries projected manifested by megaloblastic anemia, and to double in the coming years (1). has been associated with significant Based on reports from the Centers for neurological pathology, especially peripheral Disease Control and Prevention, type 2 neuropathy (6-8). Vitamin B12 is also diabetes dult onset diabetes affects associated with the onset of diabetic approximately 9.3% of the general neuropathy. In patients with diabetic population in the United States in contrast to neuropathy, vitamin B12 deficiency may be 25.9% among those 65 years or older (2). aggravated by the use of antidiabetic agents Diabetes mellitus accounts for 90% of the such as metformin (9-11). Even short-term cases of diabetes patients (3,4). treatment with metformin causes a decrease The prevalence of type 2 diabetes in serum cobalamin, folic acid and an increases with age, higher then 25 body increase in homocysteine, which leads to mass index and the presence of the disease peripheral neuropathy in patients with in family history. -
Potential Benefits of Methylcobalamin: a Review
Open Access Austin Journal of Pharmacology and Therapeutics Review Article Potential Benefits of Methylcobalamin: A Review Gupta JK* and Qureshi Shaiba Sana Department of Pharmacology, GLA University Mathura, Abstract India Methylcobalamin is an active form of vitamin B12 that helps in synthesis *Corresponding author: Jeetendra Kumar Gupta, of methionine and S-adenosylmethionine. It is required for integrity of myelin, Department of Pharmacology, Institute of Pharmaceutical neuronal function, proper red blood cell formation and DNA synthesis. The largest Research, GLA University Mathura, India group of vitamin B12 deficiency is found in typical vegetarians all over the world, which can be alleviated with its analogue Methylcobalamin. It is a beneficial Received: August 17, 2015; Accepted: September 30, drug to most of the common disorders like cardiovascular disorders, diabetes, 2015; Published: October 08, 2015 anemia, hyperhomocysteinemia and degenerative disorders. Methylcobalamin helps in the synthesis of neuronal lipids, regeneration of axonal nerves and has neuroprotective activity, which promote neurons to function in proper way and thus improves Alzheimer disease, Parkinsonism, Dementia and neuropathic syndromes. It is an approved treatment for peripheral neuropathy. Keywords: Mecobalamin; Neuropathy; Anemia; Nootropic; Dietary supplement Abbreviations essential for cell growth and replication. Sometimes the liver cannot convert cyanocobalamin into adequate amount of methylcobalamin SAMe: S-Adenosyl Methionine; ERK: Extracellular Signal- needed for proper neuronal functioning. Through enhanced Regulated Kinases; PKB: Protein Kinase B; B-globulin: Beta Globulin; methylation, it exerts its nerve cell protective effect and accelerates ENFD: Epidermal Nerve Fiber Density; DPN: Diabetic Peripheral its growth. A lot of energy is required for cyanocobalamin to remove Neuropathy; NSAIDs: Non Steroidal Anti Inflammatory Drugs; THF: its cyanide and replaces it with methyl group [3]. -
Vitamin and Mineral Requirements in Human Nutrition
P000i-00xx 3/12/05 8:54 PM Page i Vitamin and mineral requirements in human nutrition Second edition VITPR 3/12/05 16:50 Page ii WHO Library Cataloguing-in-Publication Data Joint FAO/WHO Expert Consultation on Human Vitamin and Mineral Requirements (1998 : Bangkok, Thailand). Vitamin and mineral requirements in human nutrition : report of a joint FAO/WHO expert consultation, Bangkok, Thailand, 21–30 September 1998. 1.Vitamins — standards 2.Micronutrients — standards 3.Trace elements — standards 4.Deficiency diseases — diet therapy 5.Nutritional requirements I.Title. ISBN 92 4 154612 3 (LC/NLM Classification: QU 145) © World Health Organization and Food and Agriculture Organization of the United Nations 2004 All rights reserved. Publications of the World Health Organization can be obtained from Market- ing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permis- sion to reproduce or translate WHO publications — whether for sale or for noncommercial distri- bution — should be addressed to Publications, at the above address (fax: +41 22 791 4806; e-mail: [email protected]), or to Chief, Publishing and Multimedia Service, Information Division, Food and Agriculture Organization of the United Nations, 00100 Rome, Italy. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization and the Food and Agriculture Organization of the United Nations concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. -
The Efficacy and Safety of Intramuscular Injections Of
Original Article Singapore Med J 2011; 52(12) : 868 The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial Chiu C K, Low T H, Tey Y S, Singh V A, Shong H K ABSTRACT both singly or in combination with other forms Introduction:Chronic, nonspecific low back of treatment. pain is a difficult ailment to treat and poses an economic burden in terms of medical Keywords: methylcobalamin, nonspecific low expenses and productivity loss. The aim of back pain, vitamin B12 this study was to determine the efficacy and Singapore Med J 2011; 52(12): 868-873 safety of intramuscular metylcobalamin in the treatment of chronic nonspecific low back INTRODUCTION pain. Low back pain (LBP) affects a substantial proportion of the population. Almost every person will encounter an Methods: This was a double-blinded, episode of back pain at some point in one’s life. Back randomised, controlled experimental study. pain does not discriminate based on gender, age, race or 60 patients were assigned to either the culture. It disables the working adult from performing his methylcobalamin group or the placebo group. duties and paralyses the society due to the cost incurred The former received intramuscular injections in terms of treatment and productivity loss. In 1988, a of 500 mcg parenteral methylcobalamin in 1 survey was conducted in a semirural area in Malaysia. Department of ml solution three times a week for two weeks, Orthopaedic A total of 2,594 individuals from a multi-racial (Malay, Surgery, and the placebo group received 1 ml normal Chinese, Indian) community were interviewed. -
Cyanocobalamin-A Case for Withdrawal
686 Journal of the Royal Society of Medicine Volume 85 November 1992 Cyanocobalamin- a case for withdrawal: discussion paper A G Freeman MD FRCP Meadow Rise, 3 Lakeside, Swindon SN3 IQE Keywords: anaemia, pernicious; optic neuropathies; chronic cyanide intoxication; hydroxocobalamin; cyanocobalamin It seems evident that controversy still surrounds the reduced ability to detoxify the cyanide in the tobacco- treatment of pernicious anaemia and other vitamin smoke to which they are exposed'0. B12 deficiency disorders. The long quest for the 'anti- Patients with tobacco amblyopia who have normal pernicious anaemia factor' in the liver seemed to serum vitamin B12 levels need not continue therapy have ended in 1948 when pure cyanocobalamin was with intramuscular hydroxocobalamin once their isolated. This was found to be very active thera- visual acuity and visual fields have returned to peutically when given by intramuscular injection and normal providing they abstain from further smoking. was non-toxic in extremely high doses'. However, those patients who have low serum vitamin Lederle, in a recent commentary2, advocates that B12 levels or evidence of -defective vitamin B12 patients with pernicious anaemia should now be absorption will need to continue-indefinitely with treated with oral cyanocobalamin. He is not without hydroxocobalamin irrespective of their smoking support in that 40% of patients with pernicious habits as will all patients with pernicious anaemia anaemia in Sweden are being similarly treated3. and other vitamin B12 deficiency disorders who are He further states that such!- treatment is cheap at risk of developing- optic neuropathy if they and effective, produces clinical and haematological are smokers. -
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. -
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............................................................................................................................. -
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.