1. Vitamin K Dr. Amani A. Alrasheedi Associated Professor Nutrition and food Science King Abdul Aziz University

2. History It was named from the Danish word koagulation, which means “coagulation.” In the 1920s, Dam discovered that chicks fed a low-fat and cholesterol-free diet became hemorrhagic (bleed excessively) and that their blood took a long time to clot. In 1943, Dam and Doisy had Nobel prize in medicine for discovering the factor (vitamin K) that corrected the problem and its role in blood clotting.

3. Vitamin K Vitamin K was discovered as a result of investigations into the cause of a bleeding disorder (hemorrhagic disease) of cattle fed on silage made from sweet clover and of chickens fed on a fat-free diet. The missing factor in the diet of the chickens was identified as vitamin K, whereas the problem in the cattle was that the feed contained dicumarol, an antagonist of the vitamin.

4. Chemical forms All vitamin K active compounds have a 2- methyl 1,4- naphthoquinone ring. Phylloquinone (K 1 ): Naturally occurring forms in green plants. Menaquinones (K 2 ): Generally are synthesized by human bacteria. Menadione (K 3 ): Synthetic, water soluble form Complexed to improve stability

5. Vitamin K forms Three compounds have the biological activity of vitamin K: ● Phylloquinone, the normal dietary source, found in green leafy vegetables; ● Menaquinones, a family of related compounds synthesized by intestinal bacteria, with differing lengths of the side-chain; ● Menadiol and menadiol diacetate, synthetic compounds that can be metabolized to phylloquinone.

6. Sources Plants sources: mostly phylloquinone, accounts 90% of intakes. all green leafy vegetables; the richest sources are spring (collard) greens, spinach, and Brussels sprouts. In addition, soybean, rapeseed, cottonseed, and olive oils are relatively rich in vitamin K. Animal sources: a mixture of menaquinones. Found in milk and milk products, meat, liver, fermented foods. GIT bacteria (colon): as source of menaquinones for humans but not sufficient to meet the needs of health children and adults. Exposure to light and heat can result in significant vitamin K destruction.

7. Absorption, Transport and Storage Phylloquinone: Absorbed in small intestine (jejunum). Its absorption occurs as part of micelles and thus is enhanced by presence of dietary fats, bile salts, and pancreatic juice. Menaquinones: (from GIT bacteria) Absorbed in ileum and colon by passive diffusion. The ability to absorb and use the bacterial vitamin varies considerably from person to another.

8. In intestinal cell: phylloquinones are incorporated into the chylomicron, then enters lymphatic and circulatory system for transport to liver and tissues. Chylomicrons transport most phylloquinone. Chylomicron remnants deliver vitamin K to the liver. In liver: Absorbed phylloquinone and menaquinone incorporated into VLDL, and ultimately carried to extrahepatic tissues in LDL and HDL. Absorption, Transport and Storage

9. The dietary vitamin K pathway absorption

10. Storage Vitamin K is stored in several tissues. Phylloquinones are found in higher concentrations in the liver, with lesser amounts in the heart, lungs, kidneys, among other tissues. Hepatic phylloquinone 2 - 20 ng/g liver. Menaquinone-4 (MK-4) found in many tissues [pancreas, salivary glands, brain, and bone]. Circulating plasma phylloquinones 0.15 -1.15 ng/mL. The body pool size of vitamin K [ 50 -100 μg ], is quite low for a fat-soluble vitamin. Turnover of vitamin K is rapid, approximately once every 2.5 hours

11. Metabolic functions of vitamin K Although it has been known since the 1920s that vitamin K was required for blood clotting. It is the cofactor for the carboxylation of glutamate residues in the postsynthetic modification of proteins to form the unusual amino acid γ-carboxyglutamate, abbreviated to Gla.

12. Functions & mechanism of action Necessary for the post-translational carboxylation of glutamyl residues in specific proteins to form γ- carboxyglutamate residues, which enable the protein to bind Ca and interact with other compounds. These interactions are involving in: Blood clotting (hemostasis) Bone mineralization (apoptosis, signal transduction, and growth control).

13. Functions & mechanism of action Necessary for the post-translational carboxylation of glytamyl residues in specific proteins to form ϒ- carboxyglutamate residues, which enable the protein to bind Ca and interact with other compounds. These interactions are involving in: 1- blood clotting (hemostasis) 2- bone mineralization (apoptosis, single transduction, and growth control)

14. Physiological Effects of Vitamin K Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K- dependent proteins. These proteins are involved in: 1) Coagulation 2) Bone Mineralization 3) Cell growth

15. Vitamin K and Blood Clotting Vitamin K–dependent post-translational carboxylation of glutamyl residues forms γ- carboxyglutamate on four major proteins required for coagulation of blood. These 4 proteins [factors II (prothrombin), VII, IX, and X] for coagulation. In addition, proteins C, S, and Z, also require vitamin K for carboxylation, but to inhibit the coagulation process (anticoagulants).

16. Vitamin K Dependent Proteins Factor II (prothrombin) Factor VII (proconvertin) Factor IX (thromboplastin component) Factor X (Stuart factor) Protein C & protein S Protein Z

17. Overview of Blood Clotting For blood to clot, Fibrinogen (soluble protein) ------- fibrin (insoluble fiber Thrombin network) Fibrin molecules ----- fibrin polymer (insoluble clot) fibrin stabilizing factors (XIII)

18. In extrinsic pathway: factor VII -------------- VIIa (carboxylated vit-K dependent) thrombin & Xa and XIIa Factors IX, X ------------ IXa, Xa Factor VIIa + Ca In intrinsic pathway: Prothrombin ---------- thrombin actor Xa-vitamin K fibrinogen -------- fibrin (clot formation)

19. Clotting Cascade

20. Proteins C, S, and Z, also identified as vitamin K–dependent carboxylated proteins. The function of proteins C & S appear to inhibit the blood-clotting process (anticoagulant). p-C + thrombomodulin + Ca ---- protein-Ca Thrombin VIIIa, Va --------- inactive VIII, V (disrupt clotting) Protein-Ca + p-S Protein S found in blood and bone. protein Z function is unknown C, S are important to maintaining the balance between bleeding and clotting Protein C in its activated form has a direct anti-inflammatory function Protein S are widely distributed in tissues and are thought it has roles in protecting the integrity of cellular function (particularly in brain)

21. Vitamin K and bone & nonosseous tissue proteins Bone, cartilage and dentine have 2 vit K–dependent proteins: osteocalcin, bone Gla protein (BGP) and matrix Gla protein (MGP). Synthesis of both proteins stimulated by calcitriol & retinoic acid. Osteocalcin is secreted by osteoblasts during bone formation. Osteocalcin comprises 15-20% of noncollagen protein in bone. With vitamin K–dependent carboxylation, the three Gla residues on osteocalcin facilitate the binding of calcium ions in the hydroxyapatite lattice. Osteocalcin appears to be involved in bone remodeling or calcium mobilization. MGP is found in bone, dentine, and cartilage and is associated with the organic matrix and mobilization of bone calcium. able to prevent the process of calcification of arteries and cartilage in living animals.

22. Vitamin K Cycle Glutamic Acid Gamma Carboxy Glutamic Acid Vitamin K Vitamin K Epoxide Vitamin KH2 Vitamin K Dependent Carboxylase Reductase Epoxide Reductase Warfarin Inhibits

23. Interactions with other nutrients Vitamins A and E are antagonize vitamin K. Excess vitamin A interfere with vitamin K absorption. Vitamin E’s possibly inhibit vitamin K absorption, function, and metabolism by blocking the regeneration of reduced form of vitamin K. Interrelationship among vitamins K, D & A because their relationship to calcium.

24. Metabolism and Excretion Phylloquinone is completely metabolized to a variety of metabolites before being excreted, which degraded much more slowly than menaquinone. Most of phylloquinone metabolites excreted primarily in feces by the bile, and some excreted in urine. little is known about metabolism and excretion of menaquinone, which are excreted in bile and thus in feces) and in urine

25. Physiological effects of vitamin K Post- translational carboxylatio of glutamyl residues. Vitamin K dependent proteins are involved in: 1- coagulation 2- bone mineralization 3- cell growth.

26. Vitamin K and blood clotting Vitamin K- dependent post- translational carboxylation of glutamyl residues forms ϒ- carboxyglutamate on four major proteins required for coagulation of blood. These four proteins (factors 2 (prothrombin) 7, 9 and 10 for coagulation. In addition, proteins C, S and Z also require vitamin K for carboxylation, but to inhibit the coagulation process (anticoagulants).

27. Adequate intake Adequate intake (AI): 30 µg for children (1-3 years) 55 µg for children (4-8 years) 60 µg for children (9-13 years) 75 µg for adolescents (14-18 years) 120 µg for adult men 90 µg for adult women

28. Deficiency A deficiency of vitamin K is unlikely in healthy adults. Risk population groups: Newborn infants (limited vitamin K in milk, low vitamin stores). People treaded with antibiotics. People consuming vitamin K poor diet + prolonged antibiotic drug therapy. People with fat malabsorptive disorders (obstructive jaundice, diarrhea, chronic pancreatitis & liver disease).

29. Toxicity Ingestion of large amounts of vitamin K (both forms) not causing any symptoms of toxicity. Large amounts of synthetic product (menadione) can cause liver damage. in infants menadione supplementation caused hemolytic anemia and severe jaundice.

30. Assessment of nutrient status Plasma phylloquinone conc. reflect recent intake of the vitamin. Routinely measured whole blood clotting times and prothrombin time. normal prothrombin time 11- 14 sec. > 25 sec. (bleeding) Measure undercarboxylated vitamin K– dependent proteins