L8-Biochemistry of vitamin K Team443.pdf

L8: Biochemistry of vitamin K GNT Block Color Index: • • • • • • Main text Female slides Male slides Important Doctor’s notes Extra notes Editing file: Objectives: Identify the types and sources of vitamin K Understand the role of vitamin K in blood Coagulation Recognize the importance of g-c...

L8: Biochemistry of vitamin K GNT Block Color Index: • • • • • • Main text Female slides Male slides Important Doctor’s notes Extra notes Editing file: Objectives: Identify the types and sources of vitamin K Understand the role of vitamin K in blood Coagulation Recognize the importance of g-carboxylation of glutamic acid in coagulation proteins Understand the role of anticoagulant drugs in affecting vitamin K function Discuss the causes and disorders of vitamin K deficiency Lecture presented by : Dr. Sumbul Fatma Dr. Khalid Alsumaily Types & Sources Occurs in several forms: 1 Vitamin K1 (Phylloquinone) 2 Vitamin K2 (Menaquinone) 3 Vitamin K3 (Menadione) Dietary sources: Cabbage, kale, spinach, egg yolk, liver Sources of Vitamin K: 1 Phylloquinone: Green leafy vegetables 2 Menaquinone: Intestinal bacteria Intestinal bacterial synthesis meets the daily requirement of vitamin K even without dietary supplement 3 Menadione: synthetic form A precursor of menaquinone (toxic as a supplement and not used anymore) RDA & Functions RDA stands for recommended daily amount RDA Woman Children 1-8 years: 30-55 (ug/day) 01 02 Infants 0-1 year: 2-2.5 (ug/day) (19+): 90 (ug/day) 03 04 Men (19+): 120 (ug/day) Upper Limit: Not established 05 Pregnancy/Lactation 90/90 (ug/day) Functions of Vitamin K: 1 Coenzyme for the synthesis of prothrombin and blood clotting factors in the liver. 2 Prothrombin and clotting factors are protein in nature. 3 Synthesis of prothrombin, clotting factors II, VII, IX, X require carboxylation of their glutamic acid (Glu) residue. 4 5 6 Mature prothrombin and clotting factors Contain γ-carboxyglutamate (Gla) after carboxylation reaction. Vitamin K is essential for the carboxylase enzyme involved as coenzyme. Dihydroquinone form of vitamin K is essential for this reaction. Functions of Vitamin K Special thanks to 442 -if the epoxide form doesn’t get converted to hydroquinone the coagulation time will increase and this is called “functional deficiency of vitamin K” despite vitamin k is actually abundant clotting clotting factor factor protein In protein In inactive form inactive form Adding Adding γ-carboxyli γ-carboxyli c group to c group Glu to Glu residue residue Active form of Active form of vitamin k vitamin k Anticoagulants Anticoagulants Prolong the Prolong the coagulation by coagulation by inhibiting inhibiting reductase reductase Inactive Inactive competitive competitive inhibitors inhibitors because they because they structurally structurally similar to vit K similar to vit K Analogs of Vitamin K Anticoagulant drugs: warfarin and dicoumarol (Structural analogs of vitamin K) They inhibit the activation of vitamin K to hydroquinone form (inhibiting the reductase enzyme) Prothrombin and clotting factors are not carboxylated Hence blood coagulation time increases upon injury ● Carboxylation of glutamate requires vitamin K ● The process is inhibited by warfarin Function of Vitamin K Functions of Vitamin K: prothrombin - platelet interaction: Carboxylated prothrombin contains 2 carboxylate groups (COO–) These groups bind to Ca2+, forming prothrombin-calcium complex The complex then binds to phospholipids on the surface of platelets (important for blood clotting) Converting prothrombin to thrombin and initiating clot formation 439 Doctor explanation here! Important Synthesis of γ-carboxyglutamate in osteocalcin: Osteocalcin (Also called Bone Gla Protein “BGP”) is a bone turnover protein Involved in bone formation, mineralization and resorption γ-Carboxyglutamate is required for osteocalcin binding to hydroxyapatite (a calcium mineral) in the bone. The binding mechanism is similar to that of prothrombin-platelet binding Deficiency of Vitamin K - Deficiencies are rare because Vitamin k is synthesized by intestinal bacteria. Causes of vit K deficiency: Lipid malabsorption can lead to vitamin K deficiency Some second-generation cephalosporin drugs for long time cause this condition due to 02 warfarin-like effects (antibiotics given with vit. K) Prolonged antibiotic therapy Especially in marginally malnourished individuals (eg debilitated geriatric patients) Gastrointestinal infections with diarrhea Both of the above destroy the bacterial flora leading to vitamin K deficiency Female Dr: Vit K is vital for Ca binding, so when there is a deficiency of it, people may have high Ca levels in their blood, and it may deposit in their arteries, causing heart problems. matrix gla protein (mgp) prevent the calcification by binding to the Ca. y of Vitamin K Clinical Manifestations of the Deficiency: Mucus membrane hemorrhage Hemorrhagic disease of the newborn (called VKBD: vitamin k bleeding deficiency) Post-traumatic bleeding / internal bleeding Bruising tendency, ecchymotic patches (bleeding underneath the skin) Prolonged prothrombin time Deficiency of Vitamin K Deficiency most common in newborn infants: 2 1 Newborns lack intestinal flora 3 Human milk can provide Newborns lack intestinal flora only 1/5th vitamin K lack intestinal flora Supplements are given intramuscularly at birth vit. k cannot pass the placenta Effects of Vit K deficiency: 1 2 Bone growth and mineralization Hypoprothrombinemia: ↑ blood coagulation time Toxicity of Vitamin K: - Prolonged supplementation of large doses of menadione can cause: 1 2 Hemolytic anemia Jaundice - Due to toxic effects on RBC membrane how so? Vit.k is important for synthesis which prevents the accumulation of toxic ROS Take home messages Vitamin K is essential for blood coagulation process It mediates the process by γ-carboxylation of glutamic acid residues of prothrombin and coagulation factors Doctor’s explanation 439 liver synthesizes all the precursors of prothrombin. Once the precursors are formed, they’re not in their active form, they contain only one carboxyl group. An additional carboxyl group is added by the vitamin k reaction by carboxylase. The molecule will have 2 carboxyl groups after the reaction and will go to the circulation and combine with calcium. The calcium complex will interact with the membrane phospholipids of the Platelets Dr question: why add one more carboxyl group? Because the valency of calcium is 2 so it can bind to 2 cooh (to complete the calcium binding) Quiz MCQs Q1: All the following conditions produce a real or functional deficiency of vitamin K except? A- Prolonged oral,broad spectrum antibiotic therapy B- Total lack of red meat in diet C- Total lack of green leafy vegetables in diet D- Being a newborn infant Q2The vitamin that is synthesized by bacteria in the intestine is? A- D B- A C- K D- C Q3:Large doses of vitamin K (toxic dose) can cause? Q4:The form of vitamin K that is required for activation of clotting factors is? A- Prolonged bleeding B- Porphyria C- Bone growth defects D- Jaundice A- Dihydroquinone B- Phylloquinone C- Menaquinone D- Menadione Q5:Vitamin K is required for? Q6:Vitamin K is a cofactor for? A- Change of prothrombin into thrombin B- Synthesis of prothrombin C- Change of fibrinogen to fibrin D- Formation of thromboplastin A- Synthesis of tryptophan B- Formation of γ-amino butyrate C- β-Oxidation of fatty acid D- γ-carboxylation of glutamic acid residue Answers:1-B ,2-C ,3-D 4-A ,5-B ,6-D SAQ Q1:Carboxylation of glutamate requires what?and its inhibited by? A. Vitamin K , Inhibited by Warfarin Q2: Name the sources of Vitamin K? A.Slide 3 Members board Team Leaders Raghad Alhamid Remas Aljeaidi Mohammed Alqutub Team Members Leen Alduaij Zeyad Alotaibi Sultan Almishrafi Wafa Alakeel Mohammed Alarfaj Juwan Al Musma Madawi Alhussain Nazmi A Alqutub Wasan Alanazi Leen K Althunayan Faisal Alshowier Aishah boureggah Dana A Alkheliwi Osama Almashjari Mansour Alotaibi Aldanah Abdullah Nazmi M Alqutub Salma Alsaadoun Layan Al-Ruwaili Fahad Mobeirek Abdulrahman Alosleb Areej Alquraini Sarah Alajaji Waad alqahtani Special Thanks to Aleen Alkulyah for the Design! [email protected]