Más contenido relacionado


B and C.ppt

  1. The B Complex Vitamins
  2. Overview of Water-Soluble Vitamins • Dissolve in water • Generally readily excreted • Subject to cooking losses • Function as a coenzyme • Participate in energy metabolism • Marginal deficiency more common
  3. B Complex Primary Functions • Energy metabolism – Thiamin (B-1), Riboflavin (B-2), Niacin (B-3), Pyridoxine (B-6), Biotin, Pantothenic Acid • Red blood cell synthesis – Folate, B12 • Homocysteine metabolism – Folate, B12, B6
  4. VITAMIN B-COMPLEX B1- Thiamine B7 – Biotin B2- Riboflavin Panthothenic acid B3- Niacin B9 – Folic acid B6 – Pyridoxin B12- Cobalamin VITAMIN-B1(Thiamine): • it is anti beri beri or antineuritic vitamin • Active or Co enzyme form: Thiamine Pyro Phosphate(TPP) • Source: Aleurone layer of cereals (protein rich layer) is a rich source of Thiamine. • Whole wheat flour, unpolished handpound rice have a better nutritive value than completely polished rice. Yeast is also a good source of Thiamine.
  5. Chemistry of Thiamine(Pyrimidine + methylene bridge+Thiazole): • It contains a pyrimidine ring connected to a thiazole ring by means of methylene bridge. (pyrimidine – methylene bridge – Thiazole) • The Vitamin is converted to its active co-enzyme form by addition of two phosphate groups with the help of ATP. This is catalyzed by Thiamine pyrophospho transferase. ( Thiamine + PP ) TPP transferase Thiamine pyro phosphate (TPP)
  6. Physiological role of Thiamine: 1. The co-enzyme form of Thiamine is thiamine pyro phosphate is essential for activation of Pyruvate DeHydroganase PDH, TPP Eg: Pyruvate -------------- Acetyl CoA + CO2 2. TPP is used as co-enzyme in the oxidative decarboxylation of alpha keto glutarate to succinyl CoA and CO2(steps in TCA cycle).
  7. 3. For the activation of Transketolase (enzyme of HMP shunt) 4. TPP has a main role in carbohydrate metabolism 5. TPP plays a important role in the transmission of nerve impulse – Provide energy to the brain. – Improve transmission of nerve impulses – Proper function of the heart muscles. – Healthy mucus membrane. – Maintenance of smooth and skeletal muscles. – Formation of RBC’s.
  8. • DEFICIENCY MANIFESTATION OF THIAMINE : BERI-BERI(Weakness): Symptoms: anorexia (loss of appetite),weakness, constipation, nausea, mental depression, peripheral neuropathy, pins and needles sensations complaints in legs . WET BERI-BERI: • Edema of legs, face, trunk and serous cavities • Cardio-vascular manifestations are prominent. • Palpitation, breathlessness • Distended neck veins • Abnormal BP • Finally death occurs due to heart failure. DRY BERI-BERI: • Peripheral neuritis with sensory disturbances leads to complete paralysis. • Edema is not seen. • Muscles become weak and Difficulty in Walking . • CNS manifestations are the main features. • It is otherwise called mixed beri beri
  9. INFANTILE BERI-BERI: This occurs in infants born to mothers suffering from thiamine deficiency. • Restlessness • Sleeplessness • Vomiting • Convulsions and death may occur suddenly due to cardiac failure. CEREBRAL BERI-BERI (WERNICKE- KORSAKOFF SYNDROME) this disorder mainly due to 1. chronic alcoholics. 2. Insufficient intake or 3. Impairment of absorption of thiamine will lead to this syndrome. It is characterized by loss of memory, apathy and fromotion of the eye ball
  10. • BIOCHEMICAL PARAMETERS: 1. Blood thiamine is reduced. 2. Pyruvate alpha KG and lactate are increased. 3. Erythrocyte trans ketolase activity is reduced. • RECOMMENDED DAILY ALLOWANCE: 1 to 1.5mg/day Antagonist: Pyrithiamine and oxythiamine
  11. VITAMIN B2 (Riboflavin) • It is a water soluble vitamine and takes part in variety of oxidation reduction reactions • Riboflavin is orange-yellow fluorescent compound • Source of Riboflavin : Milk, Liver, Dried yeast, Egg are rich sources. Fish, whole cereals, legumes and green leafy vegetables are good source. • STRUCTURE OF RIBOFLAVIN: It has 6,7 di-methyl iso-alloxazine ring( a hetero cyclic 3 ring structure) to which a ribitol is attached. Active form: FMN(Flavin Adenine Mononucleotide) FAD (Flavin Adenine Dinucleotide). Riboflavin FMN ATP ADP FMN FAD ATP PPi
  12. dimethylisoalloxazine ring system linked to ribose N N N N H3C H3C O C O H C H H C H OH C H2C H OH H OH OH RIBOFLAVIN
  13. coenzymes are involved: FMN, riboflavin phosphate (flavin mononucleotide)-coenzyme for Warburg yellow enzyme, Cytochrome C reductase & L a. a dehydrogenase.  flavin adenine dinucleotide (FAD) Contains 2 phosphate groups, adenine, ribose & ribitol. It is the prosthetic grp for diaphorase, D amino acid dehydrogenase, glycine oxidase, Xanthine oxidase, and Acyl coA dehydrogenase.
  14. Structures of FMN & FAD
  15. •Biochemical Functions ( involved nearly150 reaction) . • It is involved in the metabolism of carbohydrates, fats and proteins • Acts as a coenzyme for several enzyme systems involved in hydrogen transfer reactions- flavoproteins •It acts as hydrogen carriers in the respiratory chain(ETC) •Involve in many redox reactions ( oxidation – reduction reaction) • for the activation of B12 and folate •Protect RBC and other cells from oxidative stress •ENZYMES USING RIBOFLAVIN COENZYMES FAD :NADH dehydrogenase FMN : L amino acid oxidase Cytochrome reductase succinate dehydrogenase d -amino acid oxidase pyridoxine-5-phosphate oxidase glutathione reductase Xanthine oxidase
  16. • MANIFESTATION : Symptoms are confined to skin and mucous membrane. • Glossitis (tongue smooth and purplish) • Magenta colored tongue • Cheilosis (dry scalling of lips, espicially in the corner of mouth) • Angular stomatitis (generalised inflammation on oral mucosa), mouth ulcers • Circum corneal vascularization(invasion of new blood vessel into the cornea) • DAILY REQUIREMENT: Adults on sedentary work require about 1.5mg/day During pregnancy lactation and old age requirement is between and 1.7 and 2.1mg/day
  17. NIACIN (Vit.B3)- Pellagara Preventing Factor • Active form: NAD & NADP (Nictonamide Adenine Dinucleotide) and it is synthesized from tryptophan • SOURCES: Dried yeast, rice polishing, liver, peanut, whole cereals, legumes, meat and fish are rich sources. Tuna(fish) is one of the best source About half the requirement is met by the conversion of Tryptophan to Niacin. • CHEMISTRY OF NIACIN: Niacin is derivative of pyridine and it is pyridine 3 carboxylic acid. Niacin + Amide = Nictonamide • CO ENZYME FORMS OF NIACIN: Niacin is converted into its co-enzyme forms viz., NAD+ and NADP+.
  18. Biochemical functions • It mainly involved in oxidation reduction reaction • Essential for O2 transport in Electron Transport chain • 1. Lactate dehydrogenase requires NAD+ as coenzyme in the conversion of lactate to pyruvate (anaerobic Glycolysis). One NADH molecule is oxidized in the respiratory chain to generate 2.5 ATP’s. • Lactate pyruvate • NAD NADH2 • 2. Alpha Keto glutarate dehydrogenase also requires NAD+ as coenzyme in the conversion of Alpha Keto glutarate to succinyl CoA(TCA Cycle). (Both B1 and B3 are act as co enzyme for AKGDH) • αKG succinyl coA • NAD NADH2
  19. 3. Glucose-6-phosphate dehydrogenase requires NADPH as coenzyme in the conversion of Glucose-6- Phosphate  6-phospho-gluconolactone in HMP SHUNT 4. Malic enzyme also requires NADPH as coenzyme in the conversion of Malate to pyruvate in gluconeogensis.
  20. • NIACIN DEFICIENCY: Pellagra ( rough skin): • It is characterized by three symptoms. The symptoms of pellagara are commonly referred as 3D(Dermatitis, Diarrhoea and Dementia) 1.Dermatitis bright red erythema (redness of skin) occurs in feet, ankles and face in early stages. (b) Increased pigmentation around the neck occurs - casal’s necklace. 2. Diarrhoea may be mild or severe with blood and mucus resulting in weight loss. (b) Nausea and vomiting may also be present.
  21. 3. (a) Dementia – it is associate with degeneration of nerve tissue and the symptoms are anxiety, irritability, poor memory and sleepness(insomnia)
  22. • Factors causing Niacin deficiency: 1. Dietary deficiency of tryptophan Niacin is synthesized from tryptophan Pellagra is seen among people whose staple diet is maize and sorghum (jowar or guinea corn). sorghum contains leucine in high quantities which inhibits QPRT (Quinolinate Phospho Ribosyl Transferase) and hence Niacin cannot be converted to NAD+
  23. 2. Lack of synthesis Kynureninase, an important enzyme(pyridoxal phosphate dependant) in the pathway of tryptophan. Hence, conversion of tryptophan to niacin is not possible in pyridoxal deficiency. 3. Isoniazid- This anti-tuberculosis drug inhibits pyridoxal phosphate formation blocking the conversion of tryptophan to NAD+
  24. 4. HARTNUP DISEASE: It is an inherited disease. Absorption of tryptophan is defective. Hence, tryptophan is excreted through urine in large quantities. This leads to lack of tryptophan and consequently deficiency of nicotinamide. 5. CARCINOID SYNDROME: It is type of cancer in gastrointestinal tract and lungs In this disease the tumor utilizes major portion of available tryptophan for serotonin synthesis making tryptophan unavailable.
  25. • RECOMMENDED DAILY ALLOWANCE: Normal requirement is 20mg/day. During lactation requirement is 25mg/day • THERAPEUTIC USE OF NIACIN: (a) Nicotinic acid when given orally or parenterally produces vasodilatation of the cutaneous vessels and histamine release. The reaction is accompanied by itching, burning and tingling. (b) Nicotinic acid inhibits the mobilization of free fatty acids from adipose tissue thus reducing acetyl CoA pool. Hence, serum cholesterol is lowered.
  26. VITAMIN B6 (Pyridoxine) • CHEMISTRY: • Vitamin B 6 refers to • Pyridoxine ---------alcohol (mostly in vegetables) • Pyridoxal ----------aldehyde} mostly in animal products • Pyridoxamine -----amine } “ “ “ “ • Active form : pyridoxal phosphate synthesized from Pyridoxal by Pyridoxal kinase using ATP. • FUNCTIONS: PLP acts as co-enzyme for many reactions in amino acid metabolism.
  27. N CHO CH2OH HO H3C N CH2NH2 CH2OH HO H3C PYRIDOXAMINE PYRIXOXAL N CH2OH CH2OH HO H3C PYRIDOXINE Collectively, pyridoxine, pyridoxal and pyridoxamine and their phosphates are known as vitamin B6
  28. Pyridoxal phosphate Biochemical functions: 1. Decarboxylation of amino acids 2. Transaminase reactions 3. Synthesis of heme 4. Transulfuration reactions 5. Conversion of Tryptophan to niacin(B3) 6. Conversion of linoleic acid into arachidonic acid (prostaglandin precursor) 7. Formation of sphingolipids
  29. 1. Transamination: These reactions are catalyzed by amino transferases using PLP as coenzyme. Alanine transaminase Alanine + α KG -------------------- Pyruvate + Glutamate PLP Aspartate transaminse also require PLP as their coenzyme for its activity PLP involve in the conversion of aminoacid to keto acid • 2.Decarboxylation : All decarboxylation reactions of amino acids require PLP as coenzyme. Eg: Glutamate- GABA • GABA is an inhibitory neuro transmitter (inhibits the transmission of nerve impulse) and so responsible for many sedative and depressive action in brain. • Histidine -  Histamine Histamine is a mediator of allergy, vasodilator and lowers BP Tryptophan  Serotonin(neuro transmitter responsible for sleep, behavior, blood pressure etc..,
  30. • Synthesis of catecholamines require PLP (dopamine, norepinephrine and epinephrine) which involved in nerve regulation
  31. • Homocysteine is correlated with myocardial infarction. Therefore, pyridoxine is used in clinical practice to prevent CAD in homocysteinemia • 4. ALA(Amino Levolinic Acid) synthase is a PLP dependant enzyme. It catalyzes the rate limiting step in heme biosynthesis. Hence, in Vit B6 deficiency, anemia may be seen.
  32. • 5. PRODUCTION OF NIACIN: Pyridoxal phosphate is required for the synthesis of Niacin from Tryptophan.
  33. • 6. GLYCOGENOLYSIS: Phosphorylase enzyme which is involved in the breakdown of glycogen to glucose-1-phosphate requires PLP. In Vit B6 deficiency glycogen breakdown is inhibited.
  34. • DEFICIENCY MANIFESTATION OF PYRODOXINE: 1.NEUROLOGICAL MANIFESTATIONS: In Vit B6 deficiency, PLP dependant enzymes function poorly. Hence, serotonin, epinephrine, nor-adrenaline and GABA are produced poorly. Therefore neurological symptoms are quite common. In children Vit B6 deficiency leads to convulsions due to decreased formation of GABA.
  35. • PLP is also involved in the synthesis of sphingolipids. Therefore Vit B6 deficiency leads to demyelination of nerves and consequent peripheral neuritis.
  36. 2. DERMATOLOGICAL MANIFESTATIONS: Vit B6 deficiency leads to Niacin deficiency since niacin is synthesized from tryptophan require PLP. Hence, pellagra which is one of the dermatological manifestations of niacin deficiency occur in Vit B6 deficiency also. 3. HAEMATOLOGICAL MANIFESTATIONS: Hypo chromic microcytic anaemia may occur due to the inhibition of heme biosynthesis.(ALA is a rate regulating enzyme(PLP depend) of heme synthesis) The metabolic disorders which respond to Vit B6 therapy are xanthurenic aciduria.
  37. • EFFECT OF DRUGS: 1. IsoNiazid: It is an anti-tuberculosis drug and it inhibits pyridoxal kinase, reducing the formation of PLP. This results in Vit B6 deficiency. 2. Oral contraceptives: Mild Vit B6 deficiency may be seen in women taking oral contraceptive pills. 3. Ethanol: Ethanol is converted to acetaldehyde which inactivates PLP. Hence, Vit B6 deficiency leads to neuritis.
  38. • DIETARY SOURCE: Yeast, rice polishing, wheat germs, cereals, pulses, oily seeds, egg, milk, fish, meat and green leafy vegetables. • REQUIREMENT (RDA): 1 to 2 mg per day in normal adults. 2.5mg per day in pregnancy and lactation Vit B6 requirement is related to protein intake. • TOXICITY OF VIT B6: Doses over 100mg may lead to imbalance, numbness (sensation of burning pricking of skin ), muscle weakness and nerve damage.
  39. PANTOTHENIC ACID(B5) • The Greek word “Pantos” means every where i.e., it is widely distributed in nature. • CHEMISTRY: Pantothenic acid contains β-Alanine and D-Pantoic acid in amide linkage.
  40. • a yellow viscous oil (free acid) • stable to moist heat (not to dry heat) and to oxidizing and reducing agents Active forms • Activated form : coenzyme A or Co A (panthothenic acid+ cysteine +ADP) • COASH • acyl carrier protein (ACP) • Co A is essential for the metabolism of carbohydrates, fats and Protein. About 70 enzymes require Co A as co enzyme. • Co A combines with the metabolites at SH grp of Pantotheine(B5 analogue) through a high energy sulfur bond. • Acyl carrier protein: • Pantothenic acid combines with protein to form Acyl carrier protein. ACP is the coenzyme for fatty acid synthesis.
  41. Synthesis of co enzyme A
  42. • Physiological role of Coenzyme A ( CoA .SH) Coenzyme A + acetate  active acetate in the form of acetyl co A- Acetyl Co A is essential for the following metabolic reactions: • Acetyl Co A from fat, carb, and proteins combines with oxalo acetate to form Citric acid , which enters TCA for complete oxidation to CO2 and H2O. • Acetyl Co A combines with choline to form Acetyl choline a neurotransmitter in autonomic nervous system (cholinergic) and in the brain. • Detoxification of certain drugs like sulfonamide
  43. •Acetyl Co A is the precursor for synthesis of ketone bodies and cholesterol which forms steroid hormones. •CoA is also associated with succinate to form succinyl Co A + glycine to form Heme. • Fatty acids are activated to acyl CoA before oxidation • Acetyl Co A is the precursor for synthesis of bile salts • Activation of branched chain amino acids, Valine & iso Leucine.
  44. • DEFICIENCY OF PANTOTHENIC ACID: “Dr.Gopalan’s burning foot “syndrome is manifested as ‘ Parasthesia’ (burning, lightning pain) in lower extremities and sleep disturbances. • This syndrome is seen in chronic alcoholics and in some renal dialysis patients • Apathy (lack of intrest) • Fatigue • Improper synthesis of acetyl choline • Fatigueue (tiredness, fatig ue can be allleviated by periods of rest) • GIT disturbances • .
  45. • SOURCES : Widely distributed in plants and animals. Also synthesized by normal bacterial flora in the intestine. Yeast , liver and eggs are rich sources. Deficiency is very rare. • REQUIREMENT ( RDA): • Normal adult 7mg/day pregnant and lactation 8mg/day
  46. BIOTIN • Biotin is also known as ‘anti-egg white injury factor’. • An imidazole sulfur containing compound • referred to as vitamin B7 or vitamin H • CHEMISTRY: It consists of an imidazole ring fused with a thiophene ring with a valeric acid side chain. • Active form: carboxy biocytin enzyme complex • Biotin + enzyme biocytin + HCo3 carboxy biocytin • CO ENZYME ACTIVITY OF BIOTIN: • biochemical role: carbon dioxide fixation • two step process: 1. Binding of CO2 to biotin – N-carboxybiotin 2. Transfer of CO2 to a substrate – Activation of biotin requires enzyme, CO , ATP and Mg++
  47. Biotin N N S O H H H H (CH2)4-COOH BIOTIN Imidazole ring fused with thiophene ring with valeric acid side chain
  48. • BIOTIN REQUIRING CO2 FIXATION REACTIONS: 1. Acetyl CoA carboxylase: Biotin adds CO2 to Acetyl CoA to form malonyl CoA.This is the rate limiting reaction in the biosynthesis of fatty acids. Acetyl CoA + CO2+ ATP--- Melonyl CoA + ADP + PI 2. Pyruvate carboxylase: Pyruvate + CO2+ ATP --- Oxalo acetate + ADP + PI This reaction is important in two aspects. One, it provides oxalo acetate which is the catalyst for TCA cycle. Second, it is an important enzyme in the gluco neogenic pathway. 3. Propionyl co A carboxylase Propionyl co A methyl malonyl coA 4. Carbomyl phosphate synthase (Urea cycle)
  49. • BIOTIN ANTAGONIST: Avidin, a protein present in egg white has great affinity to Biotin and it tightly bound with biotin and prevent it absorption. Hence, intake of raw egg may cause Biotin deficiency. Avidin is heat labile and boiling of egg will neutralize the inhibitory activity. Egg yolk contains Biotin.
  50. • DEFICIENCY OF BIOTIN : Prolonged use of anti-bacterial drugs may result in Biotin deficiency. Biotin deficiency symptoms include dermatitis, atrophic glossitis (swelling of tongue), hyperesthesia(abnormal increase in sensitivity in skin ), muscle pain and anorexia( loss of appetite) hair loss (in some condition) intramuscular dysfunction.
  51. • REQUIREMENT OF BIOTIN: 200 to 300mg/day • SOURCES : Normal bacterial flora of the gut provides adequate quantities of Biotin. It is widely distributed in plant and animal tissues. Liver ,Yeast, peanut, soyabean, milk and egg yolk are rich sources.
  52. Biotin-dependent enzymes: Pyruvate carboxylase (synthesis of oxaloacetate for gluconeogenesis and replenishment of the citric acid cycle) Acetyl CoA carboxylase (fatty acid biosynthesis) Propionyl-CoA carboxylase b-methylcrotonyl-CoA carboxylase holocarboxylase synthase (multiple carboxylase) Biotin antagonist: Desthiobiotin, biotin sulphanilic acid Extra: intake raw eggs leads to iching dermatitis which is called raw egg white injury which prevent by Biotin
  53. FOLIC ACID(B9) • The term ‘FOLIUM’ (latin ) means leaf of vegetable. Folic acid is abundant in vegetables. • It also obtained by yeast • Other common name(s): folate, folacin, vitamin B9 vitamin M • Vitamin B9 (folic acid and folate) is essential for numerous bodily functions. Humans cannot synthesize folate de novo; therefore, folate has to be supplied through the diet to meet their daily requirements. • The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions.[7]It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cellsand prevent anemia.[8] • CHEMISTRY: Folic acid is composed of three constituents. Pteridine + PABA to form pteroic acid. This is attached to glutamic acid to form pteroyl glutamic acid or folic acid. Initially folic acid is in oxidised form. But reduced form is only active form • Active co enzyme form is 5,6.7,8 tetrahydrofolic acid
  54. • ABSORPTION OF FOLIC ACID: It is readily absorbed by upper part of jejunum it is transported by beta globulins. It is taken up by the liver where the co-enzymes are produced. • CO ENZYME FUNCTIONS OF FOLIC ACID: Folic acid is first reduced to 7,8 di-hydro folic acid and then to 5,6,7,8 tetra-hydro folic acid. Both reactions are catalyzed by NADPH dependant folate reductase.
  55. • BIOCHEMICAL FUNCTIONS: carrier of one carbon groups ( organic moles containing a single carbon) • It actively involved in one carbon metabolism • It acts as acceptor or donor of one carbon units in variety of reaction involving in protein and nucleic acid metabolism • These one carbon grp is attached to the 5th or 10 th or both 5th and 10 th nitrogen atom of THFA so it is otherwise folinic acid • N 5 methyl THFA is required for the synthesis of methionine which takes part in transmethylation reactions for synthesizing choline, epinephrine,creatin etc. • The following groups are one carbon compounds. 1. Methyl (-CH3) 2. Methylene( -CH2-) 3. Methenyl (-CH=) 4. Formyl (CHO 5.. Formimino (- CH = NH)
  56. • Biochemical functions – one carbon fragment transfer (formyl, methyl, hydroxymethyl) • conversion of homocysteine to methionine • conversion of serine to glycine • It also involved in synthesis of ethanolamine and choline • synthesis of thymidylic acid: the synthesis of dTMP (2'- deoxythymidine-5'-phosphate) from dUMP (2'- deoxyuridine-5'-phosphate). Which is essential for DNA repair and DNA synthesis • synthesis of purines (de novo) 2 & 8 C formation • Involve in proper synthesis of neural tube which is very essential for the formation of brain and spinal cord
  57. • DEFICIENCY MANIFESTATIONS: Common symptoms of folate deficiency include diarrhea, macrocytic anemia with weakness or shortness of breath, nerve damage with weakness and limb numbness (peripheral neuropathy),[11] pregnancy complications, mental confusion, forgetfulness or other cognitive declines, mental depression, sore or swollen tongue, peptic or mouth ulcers, headaches, heart palpitations, irritability, and behavioral disorders. And also.. 1. Reduced DNA synthesis and cell growth is reduced
  58. 2. Macrocytic Anaemia: Most characteristic feature of folate deficiency . (a) During RBC generation DNA synthesis is delayed and protein synthesis is continued. Thus haemoglobin accumulates in RBC hence it seen abnormally large in size (b) Reticulo cytosis is often seen. These abnormal RBC’s are destroyed in spleen. This haemolysis leads to reduction of life span of RBC. Reduced generation and increased destruction of RBC’s results in anaemia. (c ) Leucopenia (abnormal lowering WBC in circulating blood) and thrombocytopenia (decrease the number of platlets in blood) are also manifested.
  59. Histidine metabolism: Histidine is metabolised to FIGLU which is intermediate during conversion of histidine to glutamate. The formimino grp is transferred to THF to produce N5 formiminoTHF. But deficiency of folic acid, cause the accumulation of Formimino Glutamic acid. In folic acid deficiency FIGLU is excreted in urine. Hyper Homocystenemia: Elevated plasma levels of homocysteine are associated with increased risk of atherosclerosis, thrombosis and hypertension. This complication is mainly due to deficiency of folic acid which is essential for the conversion of homocysteine to methionine
  60. • 3.HYPER HOMOCYSTEINEMIA: Increased Homocysteine levels in blood is seen (>15µmols/l) which increases the risk of coronary artery disease. • 4. BIRTH DEFECTS: Folic acid deficiency during pregnancy leads to neural tube defects in the fetus. Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen in the first month of pregnancy, often before a woman even knows that she is pregnant. The two most common neural tube defects are spina bifida and anencephaly. In spina bifida, the fetal spinal column doesn't close completely. There is usually nerve damage that causes at least some paralysis of the legs. In anencephaly, most of the brain and skull do not develop. • 5. CANCER:
  61. • ASSESMENT OF FOLIC ACID DEFICIENCY : 1. Histidine load test or FIGLU excretion test. Folic acid is associated with Histidine metabolism and produce FIGLU (For Imino Glutamate) which essential for one carbon transfer. Incase of folate deficiency FIGLU is accumulated and excreted through urine. 2. AICAR (Amino Imidazole Carboxamide Ribosyl) excretion: In purine ring biosynthesis the last step is the addition of C2 with the help of N-Formyl THFA. When this is blocked the precursor amino imidazole carboxamide ribosyl-5- phosphate accumulates and is excreted in urine. 3. Peripheral blood picture: Macrocytic anaemia
  62. • SOURCES: Yeast, Green leafy vegetables are rich sources , cereals, pulses, oil seeds and egg are moderate sources. Milk is a poor source. • RDA: • adults: 400 - 500µg • Chidren – 100 -300µg • Lactation & pregnancy – 600 -800µg • Plasma level – 2 - 5µg/ day • FOLIC ACID THERAPY: Therapeutic dose is 1mg of folic acid per day Folic acid and Vit B12 are given in combination to patients =macrocytic anaemia Antagonist Aminopterine, amethopterine, trimethoprin and sulfanamide
  63. • FOLATE ANTAGONIST: 1. Sulphonamides: They are structurally similar to PABA. Hence, competitively inhibit the enzyme responsible for the incorporation of PABA into di-hydro-pteroic acid which is precursor of folic acid. Bacteria can synthesize folic acid from the components Pteridine, PABA and Glutamate.
  64. • When sulphonamides are given such micro organisms cannot synthesize folic acid and hence their growth is inhibited. As man cannot synthesize folic acid the entire molecule has to be supplied in the diet. Preformed folic acid also cannot enter the bacteria. Thus sulphonamides act as very good anti-bacterial agents.
  65. • 2. Pyrimethamine: This is an anti- folate agent used against plasmodial infections especially as anti-malarial drug. • 3. Aminopterine & Amethopterin: Aminopterine (4-amino folic acid) and Amethopterin (4-amino 10-methyl folic acid) are powerful inhibitors of folate reductase and THFA generation. These drugs inhibit DNA formation and cell division. They are widely used as anti- cancer drugs especially for leukemia.
  66. VITAMIN B 12 • Vitamin B12 is the general name for cobalamins and is found only in the foods of animal origin • It is otherwise called anti pernicious anemia vitamin • It is the only vitamin that possesses a metal ion (cobalt) as part of its structure Source: Present in foods such as liver, fish, eggs, milk • absent in vegetables and fruits
  67. Co enzymatic form of B12: Adenosylcobalamin methylcobalamin CHEMISTRY: It is a water soluble, heat stable and red colored vitamin. It contains 4% Cobalt by weight. 4 pyrrole rings coordinated with a cobalt atom is called as ‘corrin ring’. The fifth valency of cobalt is linked to a substituted benzimidazole ring. This is then called Cobalamine. The sixth valency is satisfied by one of the following groups cyanide, hydroxyl, adenosyl or methyl. (Cobalt + 4 pyrrole ring = corrin ring, Corrin ring + benzimidazole = cobalamine ) (cobalamine + cyanide = cyano cobalamine) (cobalamine + hydroxyl = hydroxy cobalamine)
  68. • CYANOCOBALAMINE: When cyanide is added at R position the molecule is called ‘cyanocobalamine’ it has not physiological functions. Oral preparations are in this form. • HYDROXY COBALAMINE: OH group is attached at the R position. Injectable preparations are in this form. • ADENOSYL COBALAMINE: When taken up by the cells these groups are removed and deoxy andenosyl cobalamine is formed. This is the major storage form seen in liver.
  69. • METHYL COBALAMINE: When methyl group replaces adenosyl group methyl cobalamine is formed. This is the major form seen in blood circulation and in cytoplasm of cells. • Nitrocobalamine • ADO –B12 & METHYL B12 are the functional co enzymes in the body.
  70. • ABSORPTION OF VIT B 12: Vit B12 combines with the intrinsic factor (a glycoprotein released by parietal cells) in stomach. Hence, B12 is otherwise known as Extrinsic factor (EF). Intrinsic factor, a glycoprotein of molecular weight 50,000 is secreted by the gastric parietal cells. One molecule of IF combines with 2 molecules of B12 and this complex is attached with specific receptors on the mucosal cells and internalized. B12 is absorbed from ileum where as folic acid from jejunum
  71. • TRANSPORT AND STORAGE: In blood methyl cobalamine is predominant. Trans cobalamine (TC1) a glycoprotein is a specific carrier. B12 is stored in liver cells as methyl cobalamine and then it convert in to deoxy adnosyl cobalamine • Whole liver contains 2mg of Vit B12 which is sufficient for 2 to 3 years. Hence, B12 deficiency is seen only years after gastrectomy.
  72. • FUNCTIONAL ROLE OF VIT B12: 1. Methyl malonyl CoA isomerase: Methyl malonyl CoA is converted to succinyl CoA by enzymes methyl malonyl CoA mutase which require Ado-B12 for its activation. succinyl coA which then enter to TCA cycle and it is also essential for the synthesis of heme In B12 deficiency methyl malonyl CoA does not undergo further changes and hence excreted in urine (methyl malonic aciduria)
  73. 2. Synthesis of methionine from homo cysteine The conversion of methyl THFA to THFA and the conversion of Homocysteine to methionine need the activity of Vit B12 (methyl cobalamine). Homocysteine methyl transferase Homocysteine Methionine B12 The above metabolic step signifies the interrelationship between B12 and folic acid apart from above, B12 require for conversion of Uracil to thymine aminoethanol to choline activation of amino acids for protein synthesis
  74. • METHYL FOLATE TRAP & FOLATE DEFICIENCY: The production of methyl THFA is an irreversible step and the only way for generation of free THFA is from methyl THFA. Therefore, when Vit B12 is deficient this reaction cannot take place and this is called ‘methyl folate trap’ and leads to cause deficiency of folic acid
  75. • CAUSES OF VITAMIN B12 DEFICIENCY: 1.NUTRITIONAL DEFICIENCY: It is common amongst vegetarians of low socio economic growth. Only source of Vit B12 in vegetarian diet is curd or milk & lower income group may not be able to afford it. 2. DECREASED ABSORPTION : Absorptive surface is reduced by gastrectomy, resection of ileum and malabsoprtion syndrome. 3. ADDISONIAN PERINICIOUS ANAEMIA: It is an auto immune disease with a strong familial back group in persons >40 years of age. Antibodies are generated against IF and its destroyed. so IF becomes deficient leading to defective absorption of Vit B12.
  76. • 4. GASTRIC ATROPHY: Atrophy of gastric epithelium leads to IF deficiency and decreased B12 absorption. In chronic iron deficiency anaemia there is generalized mucosal atrophy. In 40% of cases of iron deficiency anaemia super added gastric atrophy is seen. • 5. PREGNANCY: Increased requirement in pregnancy is another cause for Vit B12 deficiency. • 6. FISH TAPE WORM: it is common in Scandinavian countries where eating live fish is a delicacy. This fish has special affinity to B12 causing reduction in available vitamin B12.
  77. • DEFICIENCY MANIFESTATIONS: 1. FOLATE TRAP: Vit B12 deficiency causes simultaneous folate deficiency due to folate trap. Therefore, all manifestations of folate deficiency is also seen in Vit B12 deficiency. 2. MEGALOBLASTIC ANAEMIA: Megaloblast and immature RBC’s are observed in peripheral blood. 3. Pernicious anemia: most important disease associated with vitB12 deficiency is pernicious anemia. And It is an auto immune disease with a strong familial back group in persons >40 years of age. Antibodies are generated against IF and it got destroyed. so IF becomes deficient leading to defective absorption of Vit B12. .
  78. it is charecterized by low hemoglobin levels, decreased the number of erythrocytes and neurological manifestations • Auto immune destruction of gastric parietal cells 4. ABNORMAL HOMOCYSTEINE LEVELS: The conversion of Homocysteine to methionine requires Vit B12. In B12 deficiency this step is blocked leading to homocysteinemia. Homocysteine is related to myocardial infarction. Hence, B12 and folic acid are protective against ischemic heart disease
  79. • 4. DEMYELINATION OF NERVES : The conversion of S-adenosyl methionine to S-adenosyl homocysteine liberates methyl group. This methyl group is used for the methylation of phosphatidyl ethanolamine to phosphatidyl choline. In B12 deficiency liberation of methyl group is inhibited and hence phosphatidyl choline formation is suppressed. This leads to deficient formation of myelin sheath of nerves, demyelination and neurological lesions.
  80. • 5. SUBACUTE COMBINED DEGENERATION : Damage to nervous system is seen in Vit B12 deficiency but not in folate deficiency. There is demyelination affecting cerebral cortex and spinal cord. Since both sensory and motor tracts are affected it is named as ‘combined degeneration’. Altered reflexes , loss of position sense, unsteadiness in gait, positive Romberg’s sign( falling when eyes are closed) and positive Babinski’s sign (plantar reflex) are seen. • 6. ACHLORHYDRIA: Absence of acid in gastric juice is associated with Vit B12 deficiency.
  81. • ASSESMENT OF VIT B12 DEFICIENCY: 1. Serum B12. is quantitated by RIA or ELISA. 2. Schilling Test: Radioactive labelled Cobalt 60 Vit B12 1mcg is given orally in gastric atrophy there is no absorption and hence the entire radioactivity is excreted in faeces and radioactivity is not observed in liver. In nutritional deficiency there will be enhanced absorption and therefore radioactivity is noted in liver region with very little excreted in fasces.
  82. 3. Methyl malonicaciduria is present. 4. FIGLU excretion test 5. Peripheral smear- peripheral blood and bone marrow morphology shows magalobalstic anaemia. 6. Homocysteineuria.
  83. • TREATMENT : If magalobalstic anaemia is treated with folic acid alone anaemia may improve but associated nervous lesions are aggravated. Hence, all macrocytic anaemias are treated with folate and Vit B12.
  84. VITAMIN - C • CHEMISTRY: Vitamin C is water soluble, easily destroyed by heat, alkali and storage. 70% of Vit-C is lost by cooking. The structural formula closely resembles that of carbohydrates. The strong reducing property of this Vitamin depends on the double bonded carbons ( enediol form). Only L-Ascorbic acid and Dehydro ascorbic acid have anti-scorbutic activity. D-Ascorbic acid has no activity.
  85. • BIOSYNTHESIS: Most animals and plants can synthesize ascorbic acid from glucose. Man, higher primates, guinea pigs and bats are the only species which cannot synthesize ascorbic acid. Therefore, it should be supplied in the diet. • METABOLISM OF ASCORBIC ACID: 1. It is readily absorbed from GI tract. Since it is water soluble it is excreted in the urine. It is a strong reducing agent and reduces Benedict’s reagent. 2. Oxidation of ascorbic acid is dehydroascorbic acid which is oxidized to oxalic acid. Ascorbic acid is partly excreted unchanged and partly as oxalic acid.
  86. 3. Ascorbic acid levels varies between 0.4 to 1.5mg/100ml plasma. A low level in blood is noted in women taking contraceptive pills and also in chronic alcoholics. 4. Very high concentration of Vit C is observed locally in healing wounds. Vitamin C is essential for would healing.
  87. • BIOCHEMICAL FUNCTIONS: 1.REVERSIBLE OXIDATION REDUCTION: Vit C can change between ascorbic acid and dehydro ascorbic acid. Most of the physiological properties could be explained by this redox system. • 2. HYDROXYLATION OF PROLINE AND LYSINE: Hydroxy proline and Hydroxy lysine are essential for the formation of cross links in collagen which gives tensile strength to the fibers. This process is absolutely necessary for the production of supporting tissues such as osteoid, collagen and inter cellular cement substance.
  88. • 3. TRYPTOPHAN METABOLISM: Ascorbic acid is necessary for hydroxylation of Tryptophan to 5-hydroxy tryptophan. This is required for the formation of serotonin. 4. TYROSINE METABOLISM: 5. IRON METABOLISM: 6. HAEMOGLOBIN METABOLISM:
  90. • DEFICIENCY MANIFESTATIONS OF VITAMIN C 1. Scurvy 2. Infantile scurvy( Barlow’s disease) 3. Haemorrhagic tendency • abnormal collagen • Petechiae • Ecchymoses
  91. 4. Internal Haemorrhage: • Oral cavity- painful, swollen,spongy gums • Bones- Fractures easily, swelling of joints • Anemia- Microcytic, hypo chromic anemia Poikilocytosis and anisocytosis 1. Loss of blood 2. Decreased iron absorption 3. Decreased THF4 4. accumulation of meth Hb
  92. • Dietary source: 1. Amla, guava,lime,lemon,green leafy vegetables 2.Requirement( RDA ): 75 mg per day in normal adults 100 mg per day in pregnancy, lactation,and aged people. 3. Therapeutic use: Adjuvant in infections In the treatment of ulcer-trauma burns