Medical Lecture: Water Soluble Vitamins - Thiamine, Riboflavin, Niacin PDF

Water Soluble Vitamins Dr. J. Mahinthan FHCS  Vitamin B Vitamin B1 (Thiamine) Vitamin B2 (Riboflavin) Vitamin B3 or (Niacin) Energy- releasing Vitamin B5 (Pantothenic acid) Vitamin B7 or Vitamin H (Bi...

Water Soluble Vitamins Dr. J. Mahinthan FHCS  Vitamin B Vitamin B1 (Thiamine) Vitamin B2 (Riboflavin) Vitamin B3 or (Niacin) Energy- releasing Vitamin B5 (Pantothenic acid) Vitamin B7 or Vitamin H (Biotin) Vitamin B6 (Pyridoxine) 4,8 & 10,11 Vitamin B9 (Folic acid) Vitamin B12 (Cyanocobalamin) Hemato poietic Vitamin B1: Thiamine 3  Structure Composed of a substituted pyrimidine and thiazole ring linked by a methylene bridge The pyrophosphate moiety is donated by ATP catalysed by the enzyme thiamine pyrophosphate kinase. Active form is thiamin pyrophosphate (TPP) serves as a coenzyme in several metabolic pathways.  Requirement & Dietary sources animal tissues- 90% is phosphorylated, thiaminTPP Plant- non-phosphorylated thiamin. Thiamine is related to energy metabolism, dietary requirement depends on the caloric intake Rich: yeast & yeast extract, cereal bran, oatmeal, whole-grain cereals, pulses, nuts, lean pork, heart, kidney and liver. Moderate: Beef, lamb, chicken, eggs, vegetables and fruits Poor: milk , white flour, polished rice  Absorption Absorbed from jejunum & proximal ileum. Absorption by 2 mechanism 1. levels > 5 mg/day- active, ATP-dependent 2. levels < 5 mg/day- passive diffusion. Ethanol inhibits active transport of thiamine converted to thiamine pyrophosphate (TPP) in enterocytes & released as thiamine Transported to tissue bound to albumin& After cellular uptake it is converted into TPP  Function TPP is a coenzyme for 1.Oxidative-decarboxylation: Pyruvate dehydrogenase -ketoglutarate dehydrogenase.  Function 2.Transketolase reactions coenzyme for the transketolase, in the pentose phosphate pathway. generates ribose sugars and supplies NADPH necessary for a wide variety of redox and biosynthetic reactions.  Function 3. Decarboxylation reactions in the metabolism of branched chain amino acids. Maple syrup disease may be ttreated with large doses of thiamine.  Function Another thiamine derivative, thiamine trisphosphate, is known to be involved in nerve conduction required for acetylcholine synthesis and the ion translocation of neural tissue.  Function Functions Coenzyme in energy metabolism – TPP is a coenzyme for: Pyruvate dehydrogenase. α-ketoglutarate dehydrogenase Transketolase Helps synthesize neurotransmitters Function 12  Deficiency Malnutrition. areas where polished rice is the major component of the diet. A diet high in thiaminase-rich food (raw freshwater fish, raw shellfish, ferns) Foods high in anti-thiamine factors (tea, coffee, nuts). Chronic consumption of alcohol (ethanol inhibit the active transport of thiamine). Use of tobacco products, or carbonate and citrate food additives can impair thiamine absorption.  Deficiency Beriberi Dry - poor appetite, peripheral neuropathy, fatigue, constipation, muscle weakness, muscle spasms neuromuscular symptoms predominate Wet – neurological manifestation, cardiovascular symptoms and odema Cerebral (Wernicke-Korsakoff Syndrome)- characterized by apathy, loss of memory, and a rhythmical to-and-fro motion of the eyeballs. Chronic alcoholism - due to dietary insufficiency or impaired intestinal absorption of the vitamin. infantile- low thiamine in breast milk Tachycardia , anorexia, vomiting  RDA Thiamine is related to energy metabolism, therefore its dietary requirement depends on the caloric intake It is about 0.4 mg/1000 calories.  Stability Thiamine is liable to heat in neutral or alkaline medium Stable in acidic medium at less than 100ºC Assessment of Thiamine status A diagnosis test for B1 deficiency can be determined by measuring transketolase levels of erythrocyte Thiamine status is evaluated by estimating urinary thiamine excretion plasma levels of pyruvate and lactate, particularly after an oral glucose load Determination of erythrocyte transketolase activity, which requires TPP as a coenzyme & confi rm the deficiency  Toxicity rare Vitamin B2: Riboflavin 19  structure CH2OH Ribose moiety (HO-C-H) 3 CH2 N N Me O Isoalloxazine moiety NH Me N O Vit B2 = Riboflavin It chemically has a three rings structure (isoalloxazine) linked to ribitol moiety. Riboflavin is a yellow compound  Requirement & Dietary sources Rich: milk , milk product, egg liver meat Moderate: vegetables and fruits Poor: cereals  Absorption B2 is ingested in form of flavoproteins. The FAD & FMN components are released from the protein complex in the stomach, and free ribofl avin is released in the intestine, absorbed by an active ATPdependent process. The activation of riboflavin via an ATPdependent enzyme.  Function Riboflavin is converted to the active forms: Flavin-Mononucleotide (FMN). Flavin-Adenine Dinucleotide (FAD). The Active forms work as co-enzymes for about 150 oxidation-reduction reactions involved in: Carbohydrate, Proteins and fat metabolism Activation of vitamin B12 and folate. Protection of erythrocytes and other cells from oxidative stress. e.g. D-amino acid oxidase, succinate dehydrogenase, acyl CoA dehydrogenase, glycerol 3-phosphate dehydrogenase,  Function xanthine oxidase, pyruvate dehydrogenase, - ketoglutarate dehydrogenase, etc. During oxidation process, FAD/ FMN accepts 2 hydrogen atoms from substrate and gets reduced to FADH2 or FMNH2.  Deficiency Deficiency of riboflavin is rare (Dietary requirement is low / intestinal flora synthesizes it) Disorder- Avitaminosis It is generally combined with other deficiencies, such as beriberi, pellagra and kwashiorkor. Symptoms of riboflavin deficiency: Angular stomatitis (inflamation of mouth) cheilosis (fissures at the lips) Glossitis (tongue smooth and purplish) Dermatitis Vascularisation of cornea  Required Daily Amount 1.3- 1.6 mg/day. Stability Vitamin B2 is unstable to light in both acidic and basic medium. Under acidic condition light produce lumichrome. In alkaline PH light produce lumiflavin. Both are inactive biologically Phototherapy for physiological jaundice may induce transient riboflavin deficiency in infants.  Diagnostic Testing of B2 Deficiency Riboflavin assay: serum riboflavin by measuring glutathione reductase levels of erythrocytes. Vitamin B3: Niacin 28  Structure COOH CONH2 N N Nicotinic acid Nicotinamide Niacin is a general name of nicotinic acid & nicotinamide. It is also called as Pellagra preventing factor. Both are act as a source of vitamin in diet. Niacinamide, the form present in tissues. Derivative of pyridine, chemically related to nicotine functionally different.  Requirement & Dietary sources yeast extract. Liver, poultry , legumes, milk, egg Cereals present as bound form. obtained from tryptophan metabolism. but the synthesis is extremely slow and requires vitamin B6. (60 mg of Tryptophan= 1mg of niacin). Bacteria in the gut also synthesize but are inefficient.  Active form nicotinamide adenine dinucleotide (NAD+) nicotinamide adenine dinucleotide phosphate (NADP+)  Function It is act as co-enzyme in oxidation-reduction reactions dehydrogenase or reductase enzymes. Oxidative catabolic reactions: NAD+/NADH-TCA, Glycolysis Reductive anabolic reactions: NADP+/NADPH-HMP, Cholesterol, FA synthesis NAD play a role in DNA repair & other cellular response to damage DNA  Deficiency Pellagra –disorder in skin, GIT & CNS Symptoms: Dermatitis (scaly), Diarrhoea, Dementia, death 3D Pellagra commonly seen in population consuming maize/sorghum as the staple food Maize Low tryptophan Presence of Trp analogs Niacin bound in ester form (niacytin) Fermentation, liming hydrolyze niacytin  Deficiency Sorghum High content of leucine Inhibit quinolinate phosphoribosyl transferase (key enzyme in niacin synthesis from trp) Hartnup disease-unable to absorb or transport trp Deficiency of Vit B6- as a coenzyme in the pathway of niacin synthesis from tryptophan Pellagra 35  Therapeutic use of Niacin Nicotinic acid (not amide) at high dose (1g/day) produce Vasodilatation lowering serum lipid/ lowering lipoprotein Inhibition of adipocyte lipolysis Inhibition of synthesis & secretion of VLDL Lowering serum levels of lipoprotein (a)- a variant of LDL Increase serum level of HDL Inhibition of cholesterol biosynthesis  Toxicity Nicotinic acid in doses 3-4 x RDA can cause “Niacin flush;” dilates capillaries and causes fatty liver. RDA 13- 20 mg/day Vitamin B5: Pantothenic acid 38  Vit B5: Structure Pantoic acid CH3 OH -Alanine O HO CH2 C CH C NH CH2 CH2 COOH CH3 Pantothenic Acid CH3 OH O HO CH2 C CH C NH CH2 CH2 CH2OH CH3 Pantothenol composed of Pantoic acid and b-Alanine. Active forms are Coenzyme-A (CoA-SH)- 80% Acyl carrier protein - Phosphopantetheine & phosphopantethenate  Requirement & Dietary sources Egg, liver, yeast extract, wheat germs, cereals widely distributed No RDA has been established  Function It is a part of Coenzyme A that assists the following reactions: – TCA cycle – Synthesis of cholesterol – Formation of Sterols (Cholesterol and 7- Dehydrocholesterol). – Oxidation & Formation of Fatty acids (ACP). – Utilisation of Keto acids  Deficiency Rare. When occur it leads to Paresthesias (is a sensation of tingling, pricking, or numbness of a person's skin). Vitamin B6: Pyridoxin 43 Vit B6 (pyridoxine): Structure Pyridine derivatives : Pyridoxal, pyridoxine, pyridoxamine Can be interconverted. Active form is pridoxal phosphate (PLP) heat-stable, but decomposes in the light or in alkaline solutions.  Requirement & Dietary sources Major: Meat, poultry. Fish, Poor: dairy product & grain pyridoxine- mainly in palnt pyridoxamine & pyridoxal – present in animal  Absorption is rapidly absorbed by passive diffusion. Phosphorylated pyridoxine vitamers are hydrolyzed by intestinal membrane alkaline phosphatase and dephosphorylated forms are absorbed. cytosolic FMN-dependent oxidase enzyme convert pyridoxine phosphte & pyridoxamine phosphate to PLP PLP is the major circulating form Most of the body stores of pyridoxine are associated with the enzyme glycogen phosphorylase in the skeletal muscle. As a coenzyme.  Function B6 is high in the brain, liver and muscle. Pyridoxal phosphate is required as coenzyme in the reactions involved amino acid metabolism for the enzymes like Transaminases Decarboxylases Kynureninase Cystathionine α-synthase Cystathionine gamma-lyase and ALA synthase. 48  Deficiency Hypochromic microcytic anemia Glossitis Pigmented scaly dermatitis similar to pellagra Numbness and tingling sensations in the extremities Irritability, depression and convulsive seizures. Tuberculous patients on antituberculosis drug Isoniazid (isonicotinic acid hydrazide (INH) )suffer from B6 deficiency. ( drug has a structure similar to B6 ) along with INH, they have to be given large doses of B6.  Required Daily Amount Vitamin B-6 Recommendations – RDA: 1.3 mg/day adults; Upper limit: 100 mg/day 50 Vitamin B7: Biotin 51  Structure Sulfur containing vitamin, consists of two fused rings,with imidazole. The intestinal bacteria also synthesize biotin to some extent. Food sources: Egg yolk, Organ meats (liver, kidney), Milk. Legumes, Nuts. RDA: 5 mg/day adults The coenzyme form: Biotin itself acts as coenzyme  Function functions as a coenzyme in the reactions involving fixation of CO2.  Deficiency Avidin, a glycoprotein present in raw egg white when fed to animals can produce biotin deficiency Deficiency is rare, experimental animals shows the symptoms like anorexia, depression, insomnia, muscle pain and dermatitis. Vitamin B9: Folic acid 55  Folic Acid- BStructure 9 (Folate, Folacin) Pteridine p-Aminobenzoic acid Glutamic acid H2 N N N COOH N O N CH2 NH C NH CH OH CH2 CH2 COOH Composed pteridine ring attached to para amino benzoic acid (PABA) and conjugated with glutamic acid residues. Tetrahydrofolate (THF) is the active form Folate antagonist 57 Fresh green Vegetables Liver Whole grains Meat Legumes 58  Folate’s Absorption and Activation In foods, folate naturally occurs Spinach as polyglutamate. (Folate occurs as mono-glutamate in fortified foods and supplements.) Ring structure + Glutamate + CH3 Folate In the intestine, digestion breaks glutamates off… and adds a Intestine methyl group. Folate is absorbed and delivered to cells. -glutamyl hydrolases CH3 The major circulating In the cells, folate is trapped in its inactive form. Cell form is B12 methyltetrahydrofolate CH3 To activate folate, vitamin B12. Folic acid removes and keeps the methyl group, is not stored in tissues. which activates vitamin B12. B12 CH3 Both the folate coenzyme and the vitamin B12 coenzyme are now active DNA and available for DNA synthesis.  Role of Vitamin B9 Folic acid Dihydrofolate Dihydrofolic acid Tetrahydrofolate Folic Acid reductase (DHF) (THF) reductase THF act as Co-enzyme (actively involved in the one carbon metabolism) for: Leucopoiesis (Production of Leukocytes). Erythropoiesis (Production of Erythrocytes). Nucleic acid (DNA/RNA) synthesis. 61 62  Folate Deficiency – Megaloblastic anemia – Neural Tube Defects (Spina bifida) RDA: 200mg /day All women need 400 micrograms/day of folic acid Toxicity – Can mask vitamin B12 deficiency DNA synthesis indirectly requires folic acid because of its role in the synthesis of purines and in thymidylate synthesis Vitamin B12: Cobalamine 67 Vitamin B12(Cobalamine)  Structure Most chemically complex vitamins. Bear a corrin ring (similar to the Porphyrin ring found in Heme, Chlorophyll, and Cytochrome) linked to a central metal ion Co (cobalt) Synthesised only by microorganism Not present in plant Only in animal food Forms Cyanocobolamin Methylcobalamin (MeB12) Deoxyadenosyl cobalamin (AdoB12)  Vitamin B12 in food is bound to the glycoprotein. Pancreatic enzyme releases free vitamin B12. Once released vitamin B12 combines with a substance called intrinsic factor (IF). This complex can then be absorbed by the intestinal tract (distal ileum). Converted into methycobalamine Stored in liver Transported in the blood bound to transcobalamine II & Transcobalamine I  Functions – Needed for normal folate function DNA and red blood cell synthesis – Maintains myelin sheath around nerves – Synthesis of methionine from homocysteine Deficiency – Pernicious anemia Megaloblastic anemia + nerve damage – Most due to inadequate absorption due to lack of hydrochloric acid or lack of intrinsic factor – Atrophic gastritis – Vegetarian diets  Red Blood Cells Normal Pernicious Anemia Impaired DNS synthesis Impaired purine pyrimidine synthesis Megaloblastic blood cells are slightly larger than normal red blood cells, and their shapes are irregular.  Vitamin B-12: Recommendations: – RDA: 3 µg/day adults 4 µg/day pregnancy and lactation 76 77 Vitamin C: Ascorbic acid 78  Structure Vitamin C Ascorbic acid Six carbon sugar derivatives Cannot be synthesized in human Sensitive to o2, metal ions, alkaline conditions Most liable nutrient in the diet  Active form of Vitamin C 2H+ L-Dehydro ascorbic acid 2H+ L-Ascorbic acid 2,3 Diketo-L- Gluconic acid (inactive form)  Functions Reducing agent in many metabolic processes Collagen synthesis Bone formation Hormones synthesis Carnitine synthesis Bile acids formation Folate metabolism Absorption of iron Immunity Antioxidant Atherosclerosis (prevent LDL oxidation) Prevention of cancer  Deficiency Scurvy (inadequate collagen synthesis) gums bleeding, muscles weakness, soft swollen gums Formation of petechiae Poor wound healing Deficiency in bone matrix causing osteoporosis and fractures Anemia Vitamin C Recommendations – To prevent scurvy:10 mg/day; RDA: – 90 mg/day--men; – 75 mg/day women; – pregnancy=85 mg; – lactation=120 mg – tolerable upper limit: 2000 mg/day Toxicity – nausea, abdominal cramps, diarrhea Scurvy Petechiae  Water-soluble Vit. Small Group Questions 1. Match the B vitamin with its coenzyme 2. Name the deficiency disease of thiamin? niacin? Riboflavin? Vitamin B-6? Folate? Vitamin B-12? Vitamin C? 3. What B vitamins are associated with lowering homocysteine levels? Why may high levels of homocysteine be bad? 4. List food sources of folate. Who needs to make sure they intake enough folate? 5. What foods contain vitamin B-12? Who is at risk for B-12 deficiency? 6. What are the functions of vitamin C? 86  B-Vitamins Do not provide the body with fuel for energy Help the body to use fuel Many form part of the coenzymes – coenzyme: small organic molecule that associates closely with certain enzymes – thiamin, riboflavin, niacin, panthothenic acid, biotin Some play roles in metabolism – B6 assists enzymes that metabolize a.a. – folate, B12 help RBC & GI cells multiply 87  Functions – Coenzyme in protein and amino acid metabolism; PLP: pyridoxal phosphate – Supports immune system Food sources – Meat, fish, poultry, liver – Potatoes, bananas, watermelon, sunflower seeds Deficiency – Microcytic hypochromic anemia Toxicity – Can cause permanent nerve damage in high doses 88