VITAMIN METABOLISM. and nutritional importancepptx

NUTRITION IN THE body

1. Vitamin metabolism

2. Vitamin metabolism Vitamins are defined as organic compounds occurring in small quantities in different natural foods and necessary for growth and maintenance of good health The vitamins are mainly classified into two The fat soluble vitamins are A, D, E and K Water soluble vitamins are named as B complex and C.

3. Water Soluble Vitamins Consists of the B complex and vitamin c Thiamine (Vitamin B1) Riboflavin (Vitamin B2) Niacin Pyridoxine (Vitamin B6) Pantothenic acid Biotin Folic acid Vitamin B12 Ascorbic acid (Vitamin C)

4. B complex group of vitamins They are chemically not related to one another They are grouped together because all of them function in the cells as co-enzymes Thiamine (vitamin B1) Sources Aleurone layer of cereals (food grains) Therefore whole wheat flour and unpolished hand-pound rice Yeast is also a very good source Thymine is the base present in DNA

5. Thiamine (vitamin B1) Structure of Thiamine Contains a substituted pyrimidine ring connected to a substituted thiazole ring by means of methylene bridge The vitamin is then converted to its active co-enzyme form by addition of two phosphate groups, with the help of ATP It is catalyzed by thiamine pyrophosphotransferase

6. Thiamine (vitamin B1) Physiological Role of Thiamine Pyruvate dehydrogenase It is used in oxidative decarboxylation of alpha keto acids, e.g. pyruvate dehydrogenase catalyzes the breakdown of pyruvate, to acetyl CoA and carbon dioxide The co-enzyme is thiamine pyrophosphate (TPP).

7. Thiamine (vitamin B1) Alpha ketoglutarate dehydrogenase An analogous biochemical reaction that requires TPP is the oxidative decarboxylation of alpha ketoglutarate to succinyl CoA and CO2 Transketolase Uses TPP as co-enzyme in the hexose monophosphate shunt pathway of glucose The main role of thiamine (TPP) is in carbohydrate metabolism . So, the requirement of thiamine is increased along with higher intake of carbohydrates

8. Thiamine (vitamin B1) Deficiency Manifestations of Thiamine Beriberi Deficiency of thiamine leads to beriberi. It is a Singhalese word, meaning "weakness“ The early symptoms are anorexia, dyspepsia, heaviness and weakness and get easily exhausted. Thiamine is useful in the treatment of beriberi, alcoholic polyneuritis, neuritis of pregnancy and neuritis of old age

9. Riboflavin (vitamin B2) Dietary Sources of Riboflavin Rich sources are liver, dried yeast, egg and whole milk. Good sources are fish, whole cereals, legumes and green leafy vegetables Structure of Riboflavin Riboflavin has a dimethyl isoalloxazine ring to which a ribitol is attached Ribitol is the alcohol of ribose sugar. Riboflavin is converted to its active co-enzyme forms (FMN (flavin mono nucleotide) and FAD (flavin adenine dinucleotide) with the help of ATP Riboflavin is heat stable

10. Riboflavin (vitamin B2) Co-enzyme Activity of Riboflavin Riboflavin exists in tissues tightly bound (but not covalently) with enzymes. Enzymes containing riboflavin are called flavoproteins. The two coenzymes are FMN (flavin mono nucleotide) and FAD (flavin adenine dinucleotide)

11. Riboflavin (vitamin B2) FAD Accepts Hydrogen During the oxidation process, FAD accepts two hydrogen atoms from substrate. In turn, FAD is reduced to FADH2. The two nitrogen atoms of isoalloxazine nucleus accept the hydrogen atoms

12. Riboflavin (vitamin B2) FMN-dependent Enzymes During the amino acid oxidation , FMN is reduced. It is reoxidized by molecular oxygen to produce hydrogen peroxide In the respiratory chain reaction, the NADH dehydrogenase contains FMN. FAD-dependent Enzymes FADH2 when oxidized in the electron transport chain will generate 1 ½ ATP molecules

13. Riboflavin (vitamin B2) Manifestations of Riboflavin Deficiency Symptoms are confined to skin and mucous membranes Glossitis, Magenta colored tongue, Cheilosis (Greek, cheilos = lip) Angular stomatitis (inflammation at the corners of mouth) Circumcorneal vascularization, Proliferation of the bulbar conjunctival capillaries is the earliest sign of riboflavin deficiency.

14. Riboflavin (vitamin B2) Daily Requirement Riboflavin is concerned mainly in the metabolism of carbohydrates and requirement is related to calorie intake Adults on sedentary work require about 1.5 mg per day. During pregnancy, lactation and old age, additional 0.2 to 0.4 mg /day are required

15. Niacin (vitamin B3) Niacin is pyridine-3-carboxylic acid. Niacinamide is the acid amide The co-enzyme is bound to the apo-enzyme (protein part of enzyme)

16. Niacin Dietary Sources of Niacin The richest natural sources of niacin are dried yeast, rice polishing, liver, peanut, whole cereals, legumes, meat and fish. About half of the requirement is met by the conversion of tryptophan to niacin About 60 mg of tryptophan will yield 1 mg of niacin

17. Niacin Co-enzyme Forms of Niacin Niacin is converted to its co-enzyme forms, Nicotinamide adenine dinucleotide (NAD+) and Nicotinamide adenine dinucleotide phosphate (NADP+). The niacin is attached to a ribose phosphate to form a mononucleotide. It is then attached to AMP, to form the dinucleotide The nitrogen atom of niacinamide contains one positive charge. The structure is abbreviated as NAD+. (The + ve sign is always shown) In the case of NADP+, one more phosphoric acid is attached to the ribose of the AMP

18. Niacin One Hydrogen Atom and One Electron In the oxidized form, nitrogen of the nicotinamide residue has a positive charge. Hence the oxidized form of co-enzyme is usually written as NAD+ In the process of reduction , NAD+ accepts one hydrogen atom fully. The other hydrogen is ionized. Only the electron is accepted Thus NAD+ accepts one H atom and one e- (electron), to form NADH. The hydrogen ion (H+) is released into the surrounding medium. During the oxidation of NADH, the reaction is reversed

19. Niacin NAD+ Dependent Enzymes One NADH molecule is oxidized in the respiratory chain to generate 2½ ATPs But NADPH is used almost exclusively for reductive biosynthetic reactions. NADPH Dependent Reactions Some enzymes can use either NAD+ or NADP+ as coenzyme, e.g. glutamate dehydrogenase In addition to this co-enzyme role, NAD+ is the source of ADP-ribose for the ADP-ribosylation of proteins and poly-ADP-ribosylation of nucleoprotein

20. Niacin Niacin Deficiency A. Pellagra Deficiency of niacin leads to the clinical condition called pellagra. Symptoms include dermatitis, diarrhea, and dementia

21. Vitamin B6 Co-enzyme Form Vitamin B6 is the term applied to a family of 3 related pyridine derivatives; pyridoxine (alcohol), pyridoxal (aldehyde) and pyridoxamine Active form of pyridoxine is pyridoxal phosphate (PLP) It is synthesized by pyridoxal kinase, utilizing ATP Main supply of B6 compounds in food is in the form of pyridoxine which can be readily converted to pyridoxal and pyridoxamine in the body Dietary Sources of Vitamin B6 Rich sources are yeast, rice polishing, wheat germs, cereals, legumes (pulses), oil seeds, egg, milk, meat, fish and green leafy vegetables

22. Vitamin B6 Functions of Pyridoxal Phosphate The pyridoxal phosphate (PLP) acts as co-enzyme for many reactions in amino acid metabolism Transamination These reactions are catalyzed by amino transferases (transaminases) which employ PLP as the co-enzyme For example: Alanine + Alpha keto glutarate → Pyruvate + Glutamic acid (Enzyme Alanine transaminase).

23. Vitamin B6 Decarboxylation All decarboxylation reactions of amino acids require PLP as co-enzyme. A few examples are given below Glutamate → GABA (gamma amino butyric acid) GABA is an inhibitory neurotransmitter, and hence in B6 deficiency, especially in children, convulsions may occur Histidine → histamine, which is the mediator of allergy and anaphylaxis 5-hydroxy tryptophan → serotonin Cysteine → taurine Serine → ethanol amine

24. Vitamin B6 Sulfur Containing Amino Acids PLP plays an important role in methionine and cysteine metabolism. Homocysteine + Serine → Cystathionine. (Enzyme Cystathionine synthase) Cystathionine → Homoserine + Cysteine (Enzyme Cystathionase) Both these reactions require PLP. Hence in vitamin B6 deficiency homocysteine in blood is increased Homocysteine level is correlated with myocardial infarction. Therefore, pyridoxine is used to prevent homocysteinemia

25. Vitamin B6 Heme Synthesis ALA synthase (Aminolevulinic acid ) is a PLP dependent enzyme. This is the rate limiting step in heme biosynthesis So, in B6 deficiency, anemia develops

26. Vitamin B6 Production of Niacin Pyridoxal phosphate is required for the synthesis of niacin from tryptophan (one vitamin is necessary for synthesis of another vitamin) 3-hydroxy kynurenine → 3-hydroxy anthranilic acid (Enzyme Kynureninase). Kynureninase is a PLP dependent enzyme. Hence in vitamin B6 deficiency niacin production is less. Moreover kynurenine cannot be converted further, which is metabolized to xanthurenic acid and excreted through urine

27. Vitamin B6 Glycogenolysis Phosphorylase enzyme (glycogen to glucose-1- phosphate) requires PLP. In fact, more than 70% of total PLP content of the body is in muscles, where it is a part of the phosphorylase enzyme.

28. Vitamin B6 Deficiency Manifestations of Pyridoxine Neurological Manifestations- In children, B6 deficiency leads to convulsions due to decreased formation of GABA Dermatological Manifestations- B6 deficiency in turn leads to niacin deficiency which is manifested as pellagra. Hematological Manifestations In adults hypochromic microcytic anemia may occur

29. Pantothenic acid (vitamin B5) The Greek word “pantos” means everywhere. As the name suggests, it is widely distributed in nature Pantothenic acid contains beta alanine and D- pantoic acid in amide linkage

30. Pantothenic acid Sources of Pantothenic Acid It is synthesized by the normal bacterial flora in intestines. Therefore, deficiency is very rare. Yeast, liver and eggs are good sources

31. Pantothenic acid Synthesis of Acetyl- COA It needs the expenditure of 4 high energy bonds. Pantothenic acid and beta mercaptoethanol amine are parts of co-enzyme A

32. Pantothenic acid Co-enzyme Activity of Pantothenic Acid a)The beta mercaptoethanol amine (NH2-CH2- CH2-SH) contains one thiol or sulfhydryl (-SH) group It is the active site where acyl groups are carried It requires pantothenic acid Therefore the co-enzyme A is sometimes abbreviated as CoA-SH to denote this active site.

33. Pantothenic acid b) The thio ester bond in acyl-CoA These acyl groups are transferred to other acceptors, for example: Acetyl CoA + Choline → Acetyl choline + CoA (enzyme is acetyl choline synthase) c) Acyl groups are also accepted by the CoA molecule during the metabolism of other substrates for example: Pyruvate+CoA+NAD+ → AcetylCoA+CO2+NADH (Enzyme is pyruvate dehydrogenase). d) Co-enzyme A is an important component of fatty acid synthase complex. The ACP (acyl carrier protein) also contains pantothenic acid

34. Pantothenic acid Deficiency of Pantothenic Acid Gopalan's Burning Foot Syndrome Is manifested as paresthesia (burning, lightning pain) in lower extremities, staggering gait due to impaired coordination and sleep disturbances. Requirement of Pantothenic Acid RDA is assumed to be about 10 mg/day

35. Biotin (vitamin B7) It consists of an imidazole ring fused with a thiophene ring with a valeric acid side chain The carboxyl group forms an amide linkage with the epsilon nitrogen of a lysine residue in the apo-enzyme

36. Biotin Sources of Biotin Normal bacterial flora of the gut will provide adequate quantities of biotin. Moreover, it is distributed ubiquitously in plant and animal tissues. Liver, yeast, peanut, soybean, milk and egg yolk are rich sources.

37. Biotin Co-enzyme Activity of Biotin Biotin acts as co-enzyme for carboxylation reactions. Biotin captures a molecule of CO2 which is attached to nitrogen of the biotin molecule The energy required for this reaction is provided by ATP Then the activated carboxyl group is transferred to the substrate.

38. Biotin 1. Acetyl CoA carboxylase This enzyme adds CO2 to acetyl CoA to form malonyl CoA. This is the rate limiting reaction in biosynthesis of fatty acids Acetyl CoA +CO2+ATP→ Malonyl CoA + ADP+Pi

39. Biotin Propionyl CoA carboxylase Propionyl CoA +CO2+ATP→ Methyl malonyl CoA +ADP+Pi Pyruvate carboxylase Pyruvate + CO2 +ATP→ Oxaloacetate +ADP +Pi This is important in two aspects. One, it provides the oxaloacetate, which is the catalyst for TCA cycle. Second, it is an important enzyme in the gluconeogenic pathway.

40. Biotin Biotin-Independent Carboxylation Reactions Carbamoyl phosphate synthetase, which is the stepping stone for urea and pyrimidine synthesis Addition of CO2 to form C6 in purine ring Malic enzyme, converting pyruvate to malate.

41. Biotin Deficiency of Biotin Prolonged use of antibacterial drugs Biotin deficiency symptoms include dermatitis, atrophic glossitis, hyperesthesia, muscle pain, anorexia and hallucinations. Injection of biotin 100-300 mg will bring about rapid cure of these symptoms. Requirement of Biotin About 200-300 mg will meet the daily requirements.

42. Folic acid The Latin word folium means leaf of vegetable Folic acid is abundant in vegetables It is composed of three constituents The pteridine group linked with para amino benzoic acid (PABA) is called pteroic acid. It is then attached to glutamic acid to form pteroyl glutamic acid or folic acid Folacin is the generic name for such folic acid related compounds. Folic acid is soluble in water. When exposed to light, it is rapidly destroyed.

43. Folic acid Sources of Folic Acid Rich sources of folate are yeast, green leafy vegetables Moderate sources are cereals, pulses, oil seeds and egg Milk is a poor source for folic acid. Absorption of Folic Acid Folic acid is readily absorbed by the upper part of jejunum In the blood, it is transported by beta globulins It is taken up by the liver where the coenzymes are produced Folic acid is not stored in tissues

44. Folic acid Co-enzyme Functions of Folic Acid The folic acid is first reduced to 7,8-dihydrofolic acid and further reduced to 5,6,7,8-tetrahydrofolic acid (THFA) Both reactions are catalyzed by NADPH dependent folate reductase. The THFA is the carrier of one-carbon groups One carbon compound is an organic molecule that contains only a single carbon atom.

45. Folic acid The following groups are one carbon compounds: Formyl (-CHO) Formimino (-CH=NH) Methenyl (-CH=) Methylene (-CH2–) Hydroxymethyl (-CH2OH) Methyl (-CH3).

46. Folic acid These one carbon compounds are attached either to the 5th or to the 10th or to both 5 and 10 nitrogen atoms Methyl group in N5-methyl THFA is used for synthesis of active methionine, which takes part in transmethylation reactions Such transmethylation reactions are required for synthesis of choline, epinephrine, creatine

47. 1= dihydrofolate reductase 

48. Folic acid Causes for Folate Deficiency Pregnancy, requirement is increased Defective absorption In sprue, celiac disease, gluten induced enteropathy, resection of jejunum and short-circuiting of jejunum in gastroileostomy, absorption is defective. Drugs, In the diet, folacins are mainly in polyglutamate form. Gastrointestinal enzymes in the gut remove the glutamate residues and only the mono-glutamate form of folic acid is absorbed. Anticonvulsant drugs (hydantoin, dilantin, phenytoin, phenobarbitone) will inhibit the intestinal enzyme, so that folate absorption is reduced

49. Folic acid Hemolytic anemias As requirement of folic acid becomes more, deficiency is manifested. Dietary deficiency, Absence of vegetables in food for prolonged periods may lead to deficiency Folate trap: The only way for regeneration of free THF is step No.1 in When B12 is deficient, this reaction cannot take place, leading to folate deficiency

50. Folic acid Deficiency Manifestations Reduced DNA synthesis Macrocytic Anemia Homocysteinemia Folic acid deficiency may cause increased homocysteine levels in blood. Plasma homocysteine levels above 15 micromoles / L is known to increase the risk of coronary artery diseases. Providing adequate doses of pyridoxine, B12 and folic acid may lower the homocysteine levels Birth Defects- neural tube defects Cancer- Folic acid is beneficial in prevention of cancer

51. Folic acid Recommended Daily Allowance (RDA) The requirement of free folate is 200 microgram/ day. In pregnancy the requirement is increased to 400 microgram/day and during lactation to 300 microgram/day

52. VITAMIN B12 Vitamin B12 is water soluble, heat stable and red in color It contains 4.35% cobalt by weight It contains one cobalt atom. Four pyrrole rings co-ordinated with a cobalt atom is called a Corrin ring The 5th valency of the cobalt is covalently linked to a substituted benzimidazole ring. This is then called cobalamin. The 6th valency of the cobalt is occupied by any of the following groups: cyanide, hydroxyl, adenosyl or methyl

53. VITAMIN B12 Vitamin B12 is not present in vegetables Liver is the richest source Curd is a good source, because lactobacillus can synthesize B12 Cyanocobalamin When cyanide is added at the R position, the molecule is called cyanocobalamin. During the isolation procedure, cyanide is added to get stable crystals. The CN group has no physiological function, it is only a laboratory artefact. Oral preparations are in this form Hydroxy cobalamin When hydroxyl group is attached at the R position, it is called hydroxy cobalamin or vitamin B12a. Injectable preparations are in this form

54. VITAMIN B12 Adenosyl cobalamin (Ado-B12 ) When taken up by the cells, these groups are removed and deoxy adenosyl cobalamin or AdoB12 is formed This is the major storage form, seen in liver Methyl cobalamin When the methyl group replaces adenosyl group, it is known as methyl cobalamin. This is the major form seen in blood circulation as well as in cytoplasm of cells. The Ado-B12 and methyl B12 are the functional co-enzymes in the body

55. VITAMIN B12 Functional Role of B12 Methyl Malonyl CoA Isomerase D-Methyl malonyl CoA is formed in the body from propionyl CoA. It is then converted to L form by a racemase and then isomerized by methyl malonyl CoA mutase (containing Ado–B12) to succinyl CoA, which enters into citric acid cycle In B12 deficiency, methyl malonyl CoA is excreted in urine (methyl malonic aciduria). The metabolism of odd chain fatty acids, valine, isoleucine, methionine and threonine leads to the production of methyl malonyl CoA

56. VITAMIN B12 Homocysteine Methyl Transferase Step 2 in Figure 34.19 is catalyzed by the enzyme methionine synthase or homocysteine methyl transferase. The steps marked as 1 and 2 in Figure 34.19 need the activity of vitamin B12 (methyl cobalamin).

57. VITAMIN B12 Methyl Folate Trap and Folate Deficiency The production of methyl THFA is an irreversible When B12 is deficient, this reaction cannot take place. This is called the methyl folate trap. This leads to the associated folic acid scarcity in B12 deficiency

58. VITAMIN B12 Deficiency Manifestations Vitamin B12 deficiency causes simultaneous folate deficiency due to the folate trap Megaloblastic anemia: In the peripheral blood, megaloblasts and immature RBCs are observed Abnormal homocysteine level: In vitamin B12 deficiency, step No. 2 (Fig. 34.19) is blocked, so that homocysteine is accumulated, leading to homocystinuria. Homocysteine level in blood has a positive correlation with myocardial infarction. So, B12 and folic acid are protective against ischemic heart disease Demyelination

59. VITAMIN B12 Requirement of Vitamin B12 Normal daily requirement is 1-2 microgram/day. During pregnancy and lactation, this is increased to 2 mg/day. Those who take folic acid, should also take vitamin B12. Elderly people are advised to take B12 supplementation. Many older adults are unable to absorb vitamin B-12 from food sources

60. Ascorbic acid (vitamin c) It is water soluble and is easily destroyed by heat, alkali and storage. In the process of cooking, 70% of vitamin C is lost. The structural formula of ascorbic acid closely resembles that of carbohydrates The strong reducing property of vitamin C depends on the double-bonded (enediol) carbons. Only L-ascorbic acid and dehydroascorbic acid have antiscorbutic activity. The D-ascorbic acid has no activity

61. Ascorbic acid (vitamin c) Biochemical Functions of Vitamin C 1. Reversible oxidation-reduction It can change between ascorbic acid and dehydroascorbic Hydroxylation of proline and lysine Ascorbic acid is necessary for the post-translational hydroxylation of proline and lysine residues Hydroxyproline and hydroxylysine are essential for the formation of cross links in the collagen, which gives the tensile strength to the fibers. This process is absolutely necessary for the normal production of supporting tissues such as osteoid, collagen and intercellular cement substance of capillaries

62. Ascorbic acid (vitamin c) Tryptophan metabolism Ascorbic acid is necessary for the hydroxylation of tryptophan to 5-hydroxy tryptophan. This is required for the formation of serotonin Tyrosine metabolism Vitamin C helps in the oxidation of parahydroxy phenyl pyruvate to homogentisic acid Iron metabolism Ascorbic acid enhances the iron absorption from the intestine Ascorbic acid reduces ferric iron to ferrous state, which is preferentially absorbed Deficiency : scurvy

63. References DM Vasudevan Textbook of biochemistry for medical students 6 th Edition Lehninger Principles Of Biochemistry 4 th Edition