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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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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). -
Dispensing of Vitamin Products by Retail Pharmacies in South Africa: Implications for Dietitians
South African Journal of Clinical Nutrition 2016; 29(4):133–138 http://dx.doi.org/10.1080/16070658.2016.1219468 SAJCN ISSN 1607-0658 EISSN 2221-1268 Open Access article distributed under the terms of the © 2016 The Author(s) Creative Commons License [CC BY-NC 3.0] http://creativecommons.org/licenses/by-nc/3.0 RESEARCH Dispensing of vitamin products by retail pharmacies in South Africa: Implications for dietitians Ilse Trutera* and Liana Steenkampb a Department of Pharmacy, Drug Utilisation Research Unit (DURU), Nelson Mandela Metropolitan University, Port Elizabeth, South Africa b HIV & AIDS Research Unit, Nelson Mandela Metropolitan University, Port Elizabeth, South Africa *Corresponding author, email: [email protected] Objective: The objective of this study was to analyse the dispensing patterns of vitamins (Anatomical Therapeutic Chemical (ATC) group A11) over a one-year period in a group of community pharmacies in South Africa. Design and setting: A retrospective drug utilisation study was conducted on community pharmacy electronic dispensing records in South Africa recorded in 2013. Outcome measures: All products for ATC subgroup A11 were extracted and analysed. Results: A total of 164 233 vitamin products were dispensed to 84 805 patients (62.64% female patients). Males received on average 2.09 (SD = 2.63) vitamin products per year, compared to 1.84 (SD = 2.13) products for females. Ergocalciferol (A11CC01) was the most often dispensed (37.48% of all vitamin products), followed by plain Vitamin B-complex products (A11EA00) accounting for 32.77%. Ergocalciferol (vitamin D2) is only available on prescription (50 000 IU tablets or 50 000 IU/ml oily drops) in South Africa. -
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. -
Folic Acid, Pyridoxine, and Cyanocobalamin Combination
ORIGINAL INVESTIGATION Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women The Women’s Antioxidant and Folic Acid Cardiovascular Study William G. Christen, ScD; Robert J. Glynn, ScD; Emily Y. Chew, MD; Christine M. Albert, MD; JoAnn E. Manson, MD Background: Observational epidemiologic studies indi- and visually significant AMD, defined as confirmed in- cate a direct association between homocysteine concentra- cident AMD with visual acuity of 20/30 or worse attrib- tion in the blood and the risk of age-related macular degen- utable to this condition. eration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are Results:Afteranaverageof7.3yearsoftreatmentandfollow- lacking. Our objective was to examine the incidence of AMD up, there were 55 cases of AMD in the combination treat- in a trial of combined folic acid, pyridoxine hydrochloride ment group and 82 in the placebo group (relative risk, 0.66; (vitamin B6), and cyanocobalamin (vitamin B12) therapy. 95% confidence interval, 0.47-0.93 [P=.02]). For visually significant AMD, there were 26 cases in the combination Methods: We conducted a randomized, double-blind, treatment group and 44 in the placebo group (relative risk, placebo-controlled trial including 5442 female health care 0.59; 95% confidence interval, 0.36-0.95 [P=.03]). professionals 40 years or older with preexisting cardio- vascular disease or 3 or more cardiovascular disease risk Conclusions: These randomized trial data from a large factors. A total of 5205 of these women did not have a cohort of women at high risk of cardiovascular disease diagnosis of AMD at baseline and were included in this indicate that daily supplementation with folic acid, pyri- analysis. -
IV-23 N. Hydroxocobalamin (Cyanokit®)
N. Hydroxocobalamin (Cyanokit®) I. Classification •Cyanide antidote II. Actions •Binds cyanide ions with more affinity than hemoglobin molecule •Cyanide ion and hydroxocobalamin form cyanocobalamin (Vitamin B12) which is then excreted in the urine. III. Indications •Known or suspected cyanide poisoning - patients at high risk (industrial accidents, fire victims with smoke inhalation, known overdose, etc) with one more more of the following symptoms: - Altered mental status, confusion, seizures, coma - Headache - Chest pain or tightness - Shortness of breath, bradypnea, tachypnea - Hypertension (early), hypotension (late), cardiovascular collapse - Nausea, vomiting - Cardiac arrest - Mydriasis (dilated pupils) IV. Contraindications •Known allergic reaction to hydroxocobalamin or cyanocobalamin V. Adverse effects A. Cardiovascular •Ventricular extrasystoles •Tachycardia •Transient hypertension B. Neurological •Memory impairment •Dizziness •Restlessness C. Respiratory •Dyspnea •Dry Throat •Throat tightness D. Gastrointestinal •Abdominal discomfort •Dysphagia •Vomiting, diarrhea •Hematochezia E. General •Allergic reaction, pruritis, anaphylaxis •Hot flush SUBJECT : PATIENT CARE GUIDELINES AND STANDING ORDERS FOR BLS AND ALS UNITS REFERENCE NO. III-01 PUBLICATION : 1/11/21 IV-23 VI. Administration A. Do not administer hydroxocobalamin through the same IV site/set as the following medications: dopamine, fentanyl, dobutamine, diazepam, nitroglycerin, pentobarbital, propofol, thiopental, sodium thiosulfate, sodium nitrite and ascorbic acid. You must start a second IV to administer hydroxocobalamin in patient’s receiving these medications. B. Adult: •5 grams IV/IO over 15 minutes (Stocked as single 5gm bottle, or two 2.5 gm bottles) -Single 5 gm Bottle - Reconstituted with 200 ml Normal Saline. -Two 2.5 gm Bottles, give over 7.5 minutes each. - Each vial reconstituted with 100 ml Normal Saline. C. Pediatric •100 mg/kg IV/IO of hydroxocobalamin (reconstituted with Normal Saline the same as adults) over 15 minutes. -
Vitamins Minerals Nutrients
vitamins minerals nutrients Vitamin B12 (Cyanocobalamin) Snapshot Monograph Vitamin B12 Nutrient name(s): (Cyanocobalamin) Vitamin B12 Most Frequent Reported Uses: Cyanocobalamin • Homocysteine regulation Methylcobalamin • Neurological health, including Adenosylcobalamin (Cobamamide) diabetic neuropathy, cognitive Hydroxycobalamin (European) function, vascular dementia, stroke prevention • Anemias, including pernicious and megaloblastic • Sulfite sensitivity Cyanocobalamin Introduction: Vitamin B12 was isolated from liver extract in 1948 and reported to control pernicious anemia. Cobalamin is the generic name of vitamin B12 because it contains the heavy metal cobalt, which gives this water-soluble vitamin its red color. Vitamin B12 is an essential growth factor and plays a role in the metabolism of cells, especially those of the gastrointestinal tract, bone marrow, and nervous tissue. Several different cobalamin compounds exhibit vitamin B12 activity. The most stable form is cyanocobalamin, which contains a cyanide group that is well below toxic levels. To become active in the body, cyanocobalamin must be converted to either methylcobalamin or adenosylcobalamin. Adenosylcobalamin is the primary form of vitamin B12 in the liver. © Copyright 2013, Integrative Health Resources, LLC | www.metaboliccode.com A protein in gastric secretions called intrinsic factor binds to vitamin B12 and facilitates its absorption. Without intrinsic factor, only a small percentage of vitamin B12 is absorbed. Once absorbed, relatively large amounts of vitamin B12 can be stored in the liver. The body actually reabsorbs vitamin B12 in the intestines and returns much of it to the liver, allowing for very little to be excreted from the body. However, when there are problems in the intestines, such as the microflora being imbalanced resulting in gastrointestinal inflammation, then vitamin B12 deficiencies can occur. -
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. -
Self-Administering a Vitamin B12 Injection
Self-administering a Vitamin B12 injection This is usually given as an intramuscular injection, every 2-3 months. Alternatives to an intramuscular injection are: Oral Vitamin B12 at a dose of at least 1000mcg per day. • Available as tablets or a spray. They can be bought over the counter and available at most health food stores and pharmacies. • Oral Vitamin B12 is not recommended if: - If you have a bowel condition such as inflammatory bowel disease, Coeliac disease, small bowel overgrowth, bile acid malabsorption and short bowel (you will require injections) - You require an initial loading of B12 (soon after diagnosis) It is important to monitor your symptoms if you change to oral B12. If symptoms return, then the oral/sublingual dose can be increased to 2000mcg or you may need to consider starting back on injections. https://www.hollandandbarrett.com/shop/product/betteryou-pure-energy-b12-boost-oral-spray-60099160?skuid=099160 https://www.hollandandbarrett.com/search?query=%20Vitamin%20B12%20Tablets&utm_medium=cpc&utm_source=google&isSearch=true# gclid=EAIaIQobChMIh5nLgOH26AIVxLTtCh0JIA_GEAAYASAAEgJL-fD_BwE&gclsrc=aw.ds Subcutaneous (SC) injection; this is off-licence but still effective. It is considered an easier method of administration. It is how insulin and blood thinning medication are usually self-administered. Equipment needed to self-inject - Prescribed medicine - 1 syringe (2 ml) - 2 needles (1 for drawing up the drug and 1 for administration – you can use the same size needle for both). o For an IM injection; the needle gauge should be 19-25. The needle length is 1- 1 ½ inches (up to 3 inches for larger adults) o For a SC injection; the needle gauge should be 25-27. -
Guidelines on Food Fortification with Micronutrients
GUIDELINES ON FOOD FORTIFICATION FORTIFICATION FOOD ON GUIDELINES Interest in micronutrient malnutrition has increased greatly over the last few MICRONUTRIENTS WITH years. One of the main reasons is the realization that micronutrient malnutrition contributes substantially to the global burden of disease. Furthermore, although micronutrient malnutrition is more frequent and severe in the developing world and among disadvantaged populations, it also represents a public health problem in some industrialized countries. Measures to correct micronutrient deficiencies aim at ensuring consumption of a balanced diet that is adequate in every nutrient. Unfortunately, this is far from being achieved everywhere since it requires universal access to adequate food and appropriate dietary habits. Food fortification has the dual advantage of being able to deliver nutrients to large segments of the population without requiring radical changes in food consumption patterns. Drawing on several recent high quality publications and programme experience on the subject, information on food fortification has been critically analysed and then translated into scientifically sound guidelines for application in the field. The main purpose of these guidelines is to assist countries in the design and implementation of appropriate food fortification programmes. They are intended to be a resource for governments and agencies that are currently implementing or considering food fortification, and a source of information for scientists, technologists and the food industry. The guidelines are written from a nutrition and public health perspective, to provide practical guidance on how food fortification should be implemented, monitored and evaluated. They are primarily intended for nutrition-related public health programme managers, but should also be useful to all those working to control micronutrient malnutrition, including the food industry. -
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]. -
Dietary Reference Intakes (Dris): Recommended Dietary Allowances and Adequate Intakes, Vitamins Food and Nutrition Board, Institute of Medicine, National Academies
Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes, Vitamins Food and Nutrition Board, Institute of Medicine, National Academies Life Stage Vitamin A Vitamin C Vitamin D Vitamin E Vitamin K Thiamin Riboflavin Niacin Vitamin B6 Folate Vitamin B12 Pantothenic Biotin Choline Group (µg/d)a (mg/d) (µg/d)b,c (mg/d) d (µg/d) (mg/d) (mg/d) (mg/d)e (mg/d) (µg/d)f (µg/d) Acid (mg/d) (µg/d) (mg/d)g Infants 0 to 6 mo 400* 40* 10 4* 2.0* 0.2* 0.3* 2* 0.1* 65* 0.4* 1.7* 5* 125* 6 to 12 mo 500* 50* 10 5* 2.5* 0.3* 0.4* 4* 0.3* 80* 0.5* 1.8* 6* 150* Children 1–3 y 300 15 15 6 30* 0.5 0.5 6 0.5 150 0.9 2* 8* 200* 4–8 y 400 25 15 7 55* 0.6 0.6 8 0.6 200 1.2 3* 12* 250* Males 9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375* 14–18 y 900 75 15 15 75* 1.2 1.3 16 1.3 400 2.4 5* 25* 550* 19–30 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550* 31–50 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550* 51–70 y 900 90 15 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550* > 70 y 900 90 20 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550* Females 9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375* 14–18 y 700 65 15 15 75* 1.0 1.0 14 1.2 400i 2.4 5* 25* 400* 19–30 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425* 31–50 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425* 51–70 y 700 75 15 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425* > 70 y 700 75 20 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425* Pregnancy 14–18 y 750 80 15 15 75* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450* 19–30 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450* 31–50 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450* Lactation 14–18 y 1,200 115 15 19 75* 1.4 1.6 17 2.0 500 2.8 7* 35* 550* 19–30 y 1,300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550* 31–50 y 1,300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550* NOTE: This table (taken from the DRI reports, see www.nap.edu) presents Recommended Dietary Allowances (RDAs) in bold type and Adequate Intakes (AIs) in ordinary type followed by an asterisk (*). -
Vitamin B12 Vitamin D Iodine and Selenium
Frequently Asked Questions for VEG 1 General 1. Why has VEG 1 been developed? VEG 1 was developed to provide a convenient way of avoiding the most common weak points in a varied vegan diet: vitamin B12, iodine, vitamin D and selenium. Vitamin B12 Vitamin B12 is almost entirely absent from modern plant foods which are not contaminated by bacteria and insects. Even unwashed, organically grown plants do not contain a significant amount of B12. Vegans often have intakes of vitamin B12 well below recommended intakes. Low vitamin B12 intake by vegans routinely leads to reduced activity of some important enzymes and increased levels of homocysteine and methylmalonic acid (MMA). Even moderately elevated homocysteine is associated with increased risk of death, depression, stroke, dementia and birth defects, though it remains unclear how many of these associations reflect true cause and effect. Vegans who do not get vitamin B12 from fortified food or supplements are at increased risk of clinical deficiency symptoms such as anaemia and nervous system damage. The most common early symptoms of vitamin B12 deficiency are tiredness (from anaemia), numbness and tingling (from nervous system damage) and sore tongue. VEG 1 is designed to provide sufficient absorbed vitamin B12 to match national and international recommended intakes. It is designed to be chewed as this increases the reliability of vitamin B12 absorption by dispersing and dissolving the tablet. Vitamin D In the winter – whenever our shadows at midday are more than twice as long as we are – our skin cannot produce vitamin D effectively and even small dietary intakes may become important to avoid deficiency.