2Objectives of the Lectures Introduction to the role of vitaminsTypes of vitaminsBiochemistry of water soluble vitaminsImportance of water soluble vitamins in red blood cells formationBiochemistry of the fat soluble vitaminsRole of vitamin K in blood coagulation
3Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans & therefore must be supplied by diet
4Nutritional deficiency of many vitamins may lead to different types of anemia
5Water-soluble vitamins Types of water-soluble vitamins:Non B – Complex :Vitamin CB-Complex:Thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), cobalamin (B12) & folic acidWater-soluble vitamins:Not significantly stored in the bodyMust be supplied regularly in the dietExcess than need is excreted in urine.
6B-Complex vitaminsAvailable in small quantities in different types of foodImportant for growth & good healthHelp in various biochemical processes in cell as many of them are precursors of coenzymes
7Water-soluble vitamins related to the haemopoeitic system Folic acidCobalamin (vitamin B12)Ascorbic Acid (vitamin C)
9So, folic acid is essential for cell division including haemopoetic 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 donorssuch as serine, glycine, and histidine & transfers them to intermediatesThis function is required in synthesis of purines & TMP.Purines & TMP are required for DNA synthesis that is essentialfor cell division.So, folic acid is essential for cell division including haemopoeticcells (as RBCS)
10Folic 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 & TMPPurines & TMP are required for DNA synthesis (required during cell division)
11Folic Acid & AnemiaInadequate serum levels of folic acid is caused by:increased demand (pregnancy & lactation)poor absorption caused by pathology of the small intestinedrugs 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 bydiminished synthesis of purines & TMP (required for DNA molecules synthesis inthe nucleus & hence no division of cells)
12Folic 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.
15Forms of vitamin B12 Cyanocobalamin (commercial preparation) HydroxycobalaminAdenosylcobalamin (major storage form in the liver)Methylcobalamin (mostly found in blood circulation)
16Coenzyme forms of B12 Adenosylcobalamin Methylcobalamin Body can convert other forms of cobalamins into active coenzymes
17Sources & absorption of vitamin B12 Vitamin B12 is Not synthesized 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
19Functions of vitamin B12 Two reactions require B12 Reaction 1: Conversion of methylmalonyl-CoA to succinyl-CoAMethylmalonyl CoA is produced during thedegradation of fatty acids with odd numbers ofcarbon atoms.When vitamin B12 is deficient, abnormal fattyacids accumulate & become incorporated to cellmembranes including those of nervous systemleading to neurological manifestations.
20Functions of vitamin B12 (cont.) Reaction 2:Conversion of homocysteine to methionineMethionine synthase requires B12 in convertinghomocysteine to methionine.When vitamin B12 is deficient, homocysteine accumulatesleading to neurological manifestations.Also, tetrahydrofolate will not be available for formation ofpurine & TMP leading to megaloblastic anemia.
21Vitamin B12 Deficiency Causes of vitamin B12 deficiency: 1- Deficiency of vitamin B12 in diet (rare)2- Deficiency of absorption of vitamin B12 from intestine, called perniciousanemia (more common)due to:- Autoimmune destruction of gastric parietal cells (that synthesizes intr. f).- Partial or total gastrectomyN.B. As liver stores 4-5 mg of vitamin B12 (in contrast to other water solublevitamins), clinical symptoms develop in several years after gastrectomy.
22Clinical 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 to neurological manifestationsBlock of reaction 1:Methyl tetrahydrofolate cannot be converted to tetrahydrofolateHence 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.)
23Neurological manifestations of vitamin B12 deficiency DemyelinationMyelin sheath of neurons is chemically unstable and damagedNeuropathyPeripheral nerve damageCauses of neurological manifestations:Deficiency of vitamin B12 leads to accumulation of methylmalonyl CoAHigh 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
24Treatment 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 dosesor/ IM injection of cyanocobalamin)2- Duration: must be continued life-long
26Vitamin C (Ascorbic acid) Function of ascorbic acid:1- Reducing agent in several different reactions2- Coenzyme in hydroxylation reactions:as hydroxylation of lysine & proline amino acids of collagen.Thus, vitamin C is required for the maintenance of normal connectivetissue & wound healing.3- Helps absorption of dietary iron from the intestine.4- One of the antioxidants available in dietConsumption of diets rich in vitamin C (& other antioxidants as vitamin E &b-carotenes) is associated with a decreased incidence of some chronicdiseases as coronary heart disease & certain cancers.
27Vitamin C (Ascorbic acid) Proline is hydroxylated byprolyl hydroxylase enzymewhich requiresascorbic acid (vitamin C)as a coenzyme
28Vitamin 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 gumsLoose teethFragile blood vesselsSwollen jointsAnemia
31Fat Soluble VitaminsThey are vitamin A, vitamin D, vitamin K & vitamin ECharacteristics of fat-soluble vitamins:Absorbed & transported with fat of diet.Not excreted in the urine (but excreted in bile)Significant quantities are stored in the liver & adipose tissue.Toxicity due to overdose is more common than water-soluble vitamins.
33Types of vitamin K Vitamin K occurs in several forms: Vitamin K1 (Phylloquinone)Vitamin K2 (Menaquinone)Vitamin K3 (Menadione)
34Sources of vitamin K Vitamin K1 (Phylloquinone): Vitamin K1 is available in green leafy vegetablesVitamin K2 (Menaquinone):Vitamin K2 is produced by intestinal bacteria.Intestinal bacterial synthesis meets the daily requirement of vitamin K even without dietary supplementVitamin K3 (Menadione):Synthetic form (for therapy)
35Function 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 liverSynthesis 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).
38Functions of vitamin K (cont.) Prothrombin – platelets interaction:Carboxylated prothrombin contains two carboxylate groups (COO–)These groups bind to Ca2+ forming prothrombin-calcium complexThe 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.
40Anticoagulant drugs (warfarin & dicoumarol) are structural analogs of vitamin K.Hence, prothrombin and clotting factors are not carboxylatedresulting in stopping of the coagulation process (no blood clot formation).Blood coagulation time increases upon injuryAnalogs of vitamin K
41Functions of vitamin K in other proteins Synthesis of g-carboxyglutamate in osteocalcin:Osteocalcin is a bone proteinMay have a role in bone formation & mineralizationg-carboxyglutamate is required for its binding to hydroxyapatite (a mineral) in the boneThe function of bone osteocalcin is unclear
42other causes are in next slide…. Vitamin K DeficiencyCauses of vitamin K deficiency:1- Actual deficiencies are rare as it is synthesized by the intestinal bacteriain addition to being obtained by diet.2- Malabsorption of lipids leads to vitamin K deficiency3- Deficiency most common in newborns (first month of life) as:Newborns lack intestinal floraHuman milk cannot provide enough vitamin K.So, supplements are given by single IM injection of vitamin Kto all newborns to protect them against hemorrhagic diseasesother causes are in next slide….
43Vitamin K Deficiency (cont.) Causes of vitamin K deficiency (cont.):4- Destruction of the normal bacterial flora due to:- Prolonged antibiotic therapy- Gastrointestinal infections with diarrheaBoth of above cause destroy the bacterial flora and can also lead to vitaminK deficiency.5- Second generation cephalosporins cause warafarin-like action
44Vitamin K Deficiency (cont.) Effects of vitamin K deficiency:1- Hypoprothrombinemia: increased blood coagulation time2- Deficiency may affect bone growth and mineralization
45Vitamin K Deficiency (cont.) Clinical manifestations of vitamin K deficiency:Hemorrhagic disease of the newbornBruising tendency, ecchymotic patches, mucus membrane hemorrhagepost-traumatic bleedingInternal bleedingProlongation of the prothrombin time