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Haemopoietic Functions- Related Vitamins HMIM224.

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Presentation on theme: "Haemopoietic Functions- Related Vitamins HMIM224."— Presentation transcript:

1 Haemopoietic Functions- Related Vitamins HMIM224

2 Objectives of the Lectures 1.Introduction to the role of vitamins 2.Types of vitamins 3.Biochemistry of water soluble vitamins 4.Importance of water soluble vitamins in red blood cells formation 5.Biochemistry of the fat soluble vitamins 6.Role of vitamin K in blood coagulation

3 Vitamins Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans & therefore must be supplied by diet

4 Nutritional deficiency of many vitamins may lead to different types of anemia

5 Types of water-soluble vitamins: Types of water-soluble vitamins: Non B – Complex : Non B – Complex : Vitamin C Vitamin C B-Complex : B-Complex : cobalamin (B 12 ) & folic acid Thiamin (B 1 ), riboflavin (B 2 ), niacin (B 3 ), pantothenic acid (B 5 ), pyridoxine (B 6 ), biotin (B 7 ), cobalamin (B 12 ) & folic acid Water-soluble vitamins: Water-soluble vitamins: Not Not significantly stored in the body Must Must be supplied regularly in the diet excreted in urine Excess than need is excreted in urine. Water-soluble vitamins

6 B-Complex vitamins Available in small quantities in different types of food Important for growth & good health precursors of coenzymes Help in various biochemical processes in cell as many of them are precursors of coenzymes

7 Folic acid Folic acid Cobalamin (vitamin B12) Cobalamin (vitamin B12) Ascorbic Acid (vitamin C) Ascorbic Acid (vitamin C) Water-soluble vitamins related to the haemopoeitic system

8 Biochemistry of Folic Acid

9 Synthesized bynot synthesized Synthesized by: microorganisms (not synthesized by humans) Active form activation occurs in human cells Active form : Tetrahydrofolate (activation occurs in human cells) Function Function: Active form of folic acid receives one-carbon fragments from donors such as serine, glycine, and histidine & transfers them to intermediates purinesTMP This function is required in synthesis of purines & TMP. DNA synthesis Purines & TMP are required for DNA synthesis that is essential for cell division. So, folic acid is essential for cell division including haemopoetic cells (as RBCS) cells (as RBCS) Folic acid

10 Folic acid Folic acid is synthesized by microorganisms (as bacteria) not Humans can not synthesize folic acid. Humans obtain folic acid by diet & converts it to the active form tetrahydrofolate. Tetrahydrofolate Tetrahydrofolate is required for synthesis of purines & TMP Purines & TMP are required for DNA synthesis (required during cell division)

11 Inadequate serum levels of folic acid is caused by: increased demand increased demand (pregnancy & lactation) poor absorption poor absorption caused by pathology of the small intestine drugs drugs for example, methotrexate (inhibit activation of folic acid) rare A folate-free diet (rare) can cause a deficiency within a few weeks. Effect of folic acid deficiency: megaloblastic anemia A primary result of folic acid deficiency is megaloblastic anemia caused by diminished synthesis of purines & TMP (required for DNA molecules synthesis in the nucleus & hence no division of cells) Folic Acid & Anemia

12 evaluate the cause of the megaloblastic anemia It is important to evaluate the cause of the megaloblastic anemia prior to instituting therapy because also vitamin B12 deficiency indirectly causes symptoms of this disorder. neural tube defects Deficiency of folic acid leads to neural tube defects in fetus. Folic Acid & Anemia Folic Acid & Anemia (cont.)

13 Biochemistry of Vitamin B12 (Cobalamin)

14 Vitamin B12 (Cobalamin)

15 Cyanocobalamin (commercial preparation) Cyanocobalamin (commercial preparation) Hydroxycobalamin Hydroxycobalamin Adenosylcobalamin Adenosylcobalamin (major storage form in the liver) Methylcobalamin Methylcobalamin (mostly found in blood circulation) Forms of vitamin B12

16 Adenosylcobalamin Adenosylcobalamin Methylcobalamin Methylcobalamin Body can convert other forms of cobalamins into active coenzymes Coenzyme forms of B12

17 Not Vitamin B12 is Not synthesized in the body (synthesized only by microorganism) Humans obtain vitamin B12 Humans obtain vitamin B12: bacterial flora - performed by natural bacterial flora diet - or/ supplied in the diet (animal sources of diet – not in plants) Vitamin B12 binds to intrinsic factor and absorbed by intestine. Intrinsic factor is a protein secreted by cells in the stomach Sources & absorption of vitamin B12

18 Sources & absorption of vitamin B12 Sources & absorption of vitamin B12 (cont.)

19 Two reactions require B 12 Reaction 1: Conversion of methylmalonyl-CoA to succinyl-CoA Methylmalonyl CoA is produced during the degradation of fatty acids with odd numbers of carbon atoms. When vitamin B12 is deficient, abnormal fatty acids accumulate & become incorporated to cell membranes including those of nervous system neurological manifestations. leading to neurological manifestations. Functions of vitamin B12

20 Reaction 2: Conversion of homocysteine to methionine Methionine synthase requires B 12 in converting homocysteine to methionine. When vitamin B12 is deficient, homocysteine accumulates neurological manifestations. leading to neurological manifestations. Also, tetrahydrofolate will not be available for formation of megaloblastic anemia purine & TMP leading to megaloblastic anemia. Functions of vitamin B12 Functions of vitamin B12 (cont.)

21 Causes of vitamin B12 deficiency: diet 1- Deficiency of vitamin B12 in diet (rare) absorption 2- Deficiency of absorption of vitamin B12 from intestine, called pernicious anemia (more common) due to: - Autoimmune destruction of gastric parietal cells (that synthesizes intr. f). - Partial or total gastrectomy N.B N.B. As liver stores 4-5 mg of vitamin B12 (in contrast to other water soluble vitamins), clinical symptoms develop in several years after gastrectomy. Vitamin B12 Deficiency

22 Block of reaction 1 & 2 : neurological manifestations B 12 deficiency causes accumulation of homocysteine and methylmalonic acid which are harmful for nervous tissue leading to neurological manifestations Block of reaction 1 : Methyl tetrahydrofolate cannot be converted to tetrahydrofolate Hence folate is trapped as N 5 -methyltetrahydrofolate (folate trap) not This leads to folate deficiency (not available for purine synthesis). So, vitamin B12 deficiency (indirectly) causes megaloblastic anemia. TREATMENT OF THIS CASE BY FOLIC ACID ONLY CURES ANAEMIA ONLY BUT NERVOUS MANIFESTATIONS ARE NOT CURED (masking of B12 def.) Clinical manifestations of vitamin B12 deficiency

23 Demyelination Myelin sheath of neurons is chemically unstable and damagedNeuropathy Peripheral nerve damage Causes of neurological manifestations: Deficiency of vitamin B12 leads to accumulation of methylmalonyl CoA High levels of methylomalonyl CoA is used instead of acetyl CoA for fatty acid synthesis resulting in synthesis of abnormal fatty acids. neuropathy Myelin sheath is synthesized with these abnormal fatty acids is unstable and degraded causing neuropathy Neurological manifestations of vitamin B12 deficiency

24 Treatment of vitamin B12 deficiency Caution Caution : folic acid and vitamin B12 Administration of high levels of folic acid can mask vitamin B12 deficiency. So, therapy is initiated with folic acid and vitamin B12 until the cause of the anemia can be determined (either due to folic acid def. or vit.B12 def.). Therapy with vitamin B12 : Route 1- Route: Oral: High doses or/ IM injection of cyanocobalamin) Duration 2- Duration: must be continued life-long

25 Biochemistry of Vitamin C (Ascorbic Acid)

26 Function of ascorbic acid: Reducing agent 1- Reducing agent in several different reactions Coenzyme in hydroxylation reactions 2- Coenzyme in hydroxylation reactions: as hydroxylation of lysine & proline amino acids of collagen. Thus, vitamin C is required for the maintenance of normal connective tissue & wound healing. absorption of dietary iron 3- Helps absorption of dietary iron from the intestine. antioxidants 4- One of the antioxidants available in diet Consumption of diets rich in vitamin C (& other antioxidants as vitamin E & -carotenes) is associated with a decreased incidence of some chronic diseases as coronary heart disease & certain cancers. Vitamin C (Ascorbic acid)

27 Proline is hydroxylated by prolyl hydroxylase enzyme which requires ascorbic acid (vitamin C) ascorbic acid (vitamin C) as a coenzyme Vitamin C (Ascorbic acid)

28 Deficiency of ascorbic acid (Scurvy) weakness of collagen Hydroxylation of collagen is deficient resulting in weakness of collagen present in connective tissue & blood vessels. anemia This results in fragile blood vessels that causes hemorrhage which if severe & prolonged may lead to anemia. Also, absorption of iron is low which may end in iron deficiency anemia. Clinical manifestations: Sore, spongy gums Loose teeth Fragile blood vessels Swollen joints Anemia Vitamin C (Ascorbic acid)

29 Bruises in lower limb in a case of scurvy

30 Fat Soluble Vitamins

31 They are vitamin A, vitamin D, vitamin K & vitamin E Characteristics of fat-soluble vitamins: with fat Absorbed & transported with fat of diet. Not Not excreted in the urine (but excreted in bile) stored Significant quantities are stored in the liver & adipose tissue. Toxicity Toxicity due to overdose is more common than water-soluble vitamins. Fat Soluble Vitamins

32 Biochemistry of Vitamin K

33 Types of vitamin K Vitamin K occurs in several forms: Vitamin K1 (Phylloquinone) Vitamin K1 (Phylloquinone) Vitamin K2 (Menaquinone) Vitamin K2 (Menaquinone) Vitamin K3 (Menadione) Vitamin K3 (Menadione)

34 Sources of vitamin K Vitamin K1 (Phylloquinone): green leafy vegetables Vitamin K1 is available in green leafy vegetables Vitamin K2 (Menaquinone): intestinal bacteria Vitamin K2 is produced by intestinal bacteria. Intestinal bacterial synthesis meets the daily requirement of vitamin K even without dietary supplement Vitamin K3 (Menadione): Synthetic Synthetic form (for therapy)

35 Function of vitamin K Function of vitamin K (cont.) Coenzyme Vitamin K is a Coenzyme essential for the carboxylase enzyme involved for the synthesis of prothrombin & blood clotting factors in the liver Synthesis of prothrombin & clotting factors II, VII, IX, X require carboxylation of their glutamic acid (Glu) at Ɣ-carbon by carboxylase enzyme. Prothrombin & clotting factors that get Ɣ-carboxyglutamate are capable of subsequent activation ending in coagulation (formation of blood clot).



38 Prothrombin – platelets interaction: Prothrombin – platelets interaction: – Carboxylated prothrombin contains two carboxylate groups (COO – ) – These groups bind to Ca 2+ forming prothrombin-calcium complex – The complex then binds to phosholipids on the surface of platelets (important for blood clotting) – This will convert prothrombin to thrombin and thus blood coagulation process is proceeded ending in blood clot formation. Functions of vitamin K Functions of vitamin K (cont.)


40 Anticoagulant drugs Anticoagulant drugs (warfarin & dicoumarol) are structural analogs of vitamin K. not Hence, prothrombin and clotting factors are not carboxylated resulting in stopping of the coagulation process (no blood clot formation). Blood coagulation time increases upon injury Analogs of vitamin K

41 Functions of vitamin K in other proteins Synthesis of -carboxyglutamate in osteocalcin: – Osteocalcin is a bone protein – May have a role in bone formation & mineralization – -carboxyglutamate is required for its binding to hydroxyapatite (a mineral) in the bone – The function of bone osteocalcin is unclear

42 Causes of vitamin K deficiency: Actual deficiencies rare 1- Actual deficiencies are rare as it is synthesized by the intestinal bacteria in addition to being obtained by diet. Malabsorption of lipids 2- Malabsorption of lipids leads to vitamin K deficiency most common in newborns 3- Deficiency most common in newborns (first month of life) as: Newborns lack intestinal flora Human milk cannot provide enough vitamin K. So, supplements are given by single IM injection of vitamin K to all newborns to protect them against hemorrhagic diseases other causes are in next slide…. Vitamin K Deficiency

43 Causes of vitamin K deficiency Causes of vitamin K deficiency (cont.): Destruction of the normal bacterial flora due to 4- Destruction of the normal bacterial flora due to: - Prolonged antibiotic therapy - Gastrointestinal infections with diarrhea Both of above cause destroy the bacterial flora and can also lead to vitamin K deficiency. Second generation cephalosporins 5- Second generation cephalosporins cause warafarin-like action Vitamin K Deficiency Vitamin K Deficiency (cont.)

44 Effects of vitamin K deficiency : Hypoprothrombinemia 1- Hypoprothrombinemia: increased blood coagulation time 2- Deficiency may affect bone growth and mineralization Vitamin K Deficiency Vitamin K Deficiency (cont.)

45 Clinical manifestations of vitamin K deficiency: Hemorrhagic disease of the newborn Bruising tendency, ecchymotic patches, mucus membrane hemorrhage post-traumatic bleeding Internal bleeding Prolongation of the prothrombin time Vitamin K Deficiency Vitamin K Deficiency (cont.)

46 References Lippincotts Illustrated Biochemistry Lippincotts Illustrated Biochemistry Harpers Biochemistry Harpers Biochemistry

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