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Haemopoietic Functions- Related Vitamins

Haemopoietic Functions- Related Vitamins. HMIM224. Objectives of the Lectures. Introduction to the role of vitamins Types of vitamins Biochemistry of water soluble vitamins Importance of water soluble vitamins in red blood cells formation Biochemistry of the fat soluble vitamins

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Haemopoietic Functions- Related Vitamins

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  1. Haemopoietic Functions- Related Vitamins HMIM224

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

  3. 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. Water-soluble vitamins Types of water-soluble vitamins: • Non B – Complex : Vitamin C • B-Complex: Thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), cobalamin (B12) & folic acid Water-soluble vitamins: • Notsignificantly stored in the body • Mustbe supplied regularly in the diet • Excess than need is excreted in urine .

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

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

  8. Biochemistry of Folic Acid

  9. Folic acid • Synthesized by: microorganisms (not synthesized by humans) • Active form : Tetrahydrofolate (activation occurs in human cells) • Function: Active form of folic acid receives one-carbon fragments from donors such as serine, glycine, and histidine & transfers them to intermediates This function is required in synthesis of purines & TMP. 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)

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

  11. Folic Acid & Anemia Inadequate serum levels of folic acid is caused by: • increased demand (pregnancy & lactation) • poor absorption caused by pathology of the small intestine • drugs for example, methotrexate (inhibit activation of folic acid) • A folate-free diet (rare) can cause a deficiency within a few weeks. Effect of folic acid deficiency: 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)

  12. Folic Acid & Anemia (cont.) • 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. • Deficiency of folic acid leads to neural tube defects in fetus.

  13. Biochemistry of Vitamin B12 (Cobalamin)

  14. Vitamin B12 (Cobalamin)

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

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

  17. Sources & absorption of vitamin B12 Vitamin B12 is Notsynthesized in the body (synthesized only by microorganism) Humans obtain vitamin B12: - performed by natural bacterial flora - 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

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

  19. Functions of vitamin B12 Two reactions require B12 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 leading to neurological manifestations.

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

  21. Vitamin B12 Deficiency Causes of vitamin B12 deficiency: 1- Deficiency of vitamin B12 in diet(rare) 2- Deficiency of absorptionof 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. As liver stores 4-5 mg of vitamin B12 (in contrast to other water soluble vitamins), clinical symptoms develop in several years after gastrectomy.

  22. Clinical manifestations of vitamin B12 deficiency • Block of reaction 1 & 2: B12 deficiency causes accumulation of homocysteine and methylmalonic acid which are harmful for nervous tissue leading toneurological manifestations • Block of reaction 1: Methyl tetrahydrofolate cannot be converted to tetrahydrofolate Hence folate is trapped as N5-methyltetrahydrofolate (folate trap) 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.)

  23. Neurological manifestations of vitamin B12 deficiency Demyelination Myelin sheath of neurons is chemically unstable and damaged Neuropathy 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. Myelin sheath is synthesized with these abnormal fatty acids is unstable and degraded causing neuropathy

  24. Treatment of vitamin B12 deficiency Caution: 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 : 1- Route: Oral: High doses or/ IM injection of cyanocobalamin) 2- Duration: must be continued life-long

  25. Biochemistry of Vitamin C (Ascorbic Acid)

  26. Vitamin C (Ascorbic acid) Function of ascorbic acid: 1- Reducing agent in several different 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. 3- Helps absorption of dietary iron from the intestine. 4- One of the antioxidantsavailable in diet Consumption of diets rich in vitamin C (& other antioxidants as vitamin E & b-carotenes) is associated with a decreased incidence of some chronic diseases as coronary heart disease & certain cancers.

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

  28. Vitamin C (Ascorbic acid) • Deficiency of ascorbic acid (Scurvy) • Hydroxylation of collagen is deficient resulting in weakness of collagen present in connective tissue & blood vessels. • 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

  29. Bruises in lower limb in a case of scurvy

  30. Fat Soluble Vitamins

  31. Fat Soluble Vitamins They are vitamin A, vitamin D, vitamin K & vitamin E Characteristics of fat-soluble vitamins: Absorbed & transported with fat of diet. Notexcreted in the urine (but excreted in bile) Significant quantities are storedin the liver & adipose tissue. Toxicitydue to overdose is more common than water-soluble vitamins.

  32. Biochemistry of Vitamin K

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

  34. Sources of vitamin K Vitamin K1 (Phylloquinone): Vitamin K1 is available in green leafy vegetables Vitamin K2 (Menaquinone): 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 form (for therapy)

  35. Function of vitamin K (cont.) • 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).

  36. Functions of vitamin K (cont.) • Prothrombin – platelets interaction: • Carboxylatedprothrombin contains two carboxylate groups (COO–) • These groups bind to Ca2+ forming prothrombin-calcium complex • The complex then binds to phosholipidson 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.

  37. Analogs of vitamin K Anticoagulant drugs (warfarin & dicoumarol) are structural analogs of vitamin K. Hence, prothrombin and clotting factors are notcarboxylated resulting in stopping of the coagulation process (no blood clot formation). Blood coagulation time increases upon injury

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

  39. Vitamin K Deficiency • Causes of vitamin K deficiency: • 1- Actual deficiencies are rare as it is synthesized by the intestinal bacteria • in addition to being obtained by diet. • 2- Malabsorption of lipids leads to vitamin K deficiency • 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….

  40. Vitamin K Deficiency (cont.) Causes of vitamin K deficiency (cont.): 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. 5- Second generation cephalosporinscause warafarin-like action

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

  42. Vitamin K Deficiency (cont.) • 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

  43. References • Lippincott’s Illustrated Biochemistry • Harper’s Biochemistry

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