Biochemistry of Vitamin K GIT Block Dec 2015
Overview Types and chemistry of vitamin K Sources and daily requirements Functions Synthesis of -carboxyglutamate in: Vit K-dependent Clotting factors: Prothrombin and blood clotting factors Osteocalcin Protein C and Protein S (anticoagulant proteins) Disorders of vitamin K: Deficiency Toxicity
Types and Chemistry Dietary sources: Occurs in several forms: Vitamin K 1 (Phylloquinone) Vitamin K 2 (Menaquinone) Vitamin K 3 (Menadione) Found in several foods: Cabbage Kale Spinach Egg yolk Liver Cabbage kale spinach
Types and Chemistry Vitamin K 1 (Phylloquinone) Vitamin K 2 (Menaquinone) Vitamin K 3 (Menadione)
Sources of Vitamin K Phylloquinone: Green leafy vegetables Menaquinone: Intestinal bacteria Intestinal bacterial synthesis meets the daily requirement of Vitamin K even without dietary supplement Menadione: synthetic form (will be converted to menaquinone)
RDA for Vitamin K ( g/day) Infant (0-1 year): Children (1-8): Men (19+): 120 Women (19+): 90 Pregnancy / lactation: 90 / 90 UL: Not established
Functions of Vitamin K Coenzyme for the synthesis of prothrombin and blood clotting factors in the liver Prothrombin and clotting factors are protein in nature Synthesis of mature prothrombin and clotting factors VII, IX, X requires carboxylation of their glutamic acid residues (Glu)
Functions of Vitamin K Mature prothrombin and clotting factors contain -carboxyglutamate (Gla) due to carboxylation reaction Vitamin K (Hydroquinone form) is a coenzyme essential for the carboxylase enzyme involved
Active form Warfarin
Analogs of Vitamin K Anticoagulant drugs (warfarin and dicoumarol) are structural analogs of vitamin K They inhibit the activation of vitamin K Hence prothrombin and clotting factors are not carboxylated Blood coagulation time increases upon injury
Functions of Vitamin K – Prothrombin – platelets interaction Each - Carboxy glutamate residue in 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) Converting prothrombin to thrombin and proceeds in blood clot formation
Functions of Vitamin K in other proteins Synthesis of -carboxyglutamate in osteocalcin Osteocalcin is a bone protein It is called Bone Gla Protein (BGP) May have a role in bone formation and mineralization -carboxyglutamate is required for its binding to hydroxyapatite (a mineral) in the bone The function of bone osteocalcin is unclear
Deficiency of Vitamin K Deficiencies are rare: because Vitamin K is synthesized by the intestinal bacteria Causes of vit K deficiency: 1. In the newborn (sterile intestine + insufficient vit K in human milk) 2. Malabsorption of lipids (due to obstructive jaundice) 3. Prolonged diarrhea and intestinal infection 4. Prolonged use of antibiotic
Deficiency of Vitamin K- Causes Deficiency most common in newborn infants, Why? Newborns lack intestinal flora (i.e. sterile intestine) Human milk provides only 1/5 th of the daily requirement for vitamin K
How to protect against the hemorrhagic disease due to Vitamin K Deficiency in the Newborn? Recommendation: prophylactic single IM dose of vitamin K is given to all newborns
Deficiency of Vitamin K- Causes contd…… Prolonged antibiotic therapy especially in the marginally malnourished individuals (e.g. a debilitated geriatric patient) Gastrointestinal infections with diarrhea Both of the above destroy the bacterial flora and can also lead to vitamin K deficiency
Some second-generation cephalosporin antibiotics may have a warfarin-like mechanism i.e. inhibits the vitamin K epoxide reductase hypoprothrombinemia. The use of these antibiotic is supplemented with vitamin K.
Deficiency of Vitamin K- Effects Hypoprothrombinemia: increased blood coagulation time May affect bone growth and mineralization
Clinical manifestations of the Vitamin K deficiency Hemorrhagic disease of the newborn Bleeding tendency Bruising tendency ecchymotic patches mucus membrane hemorrhage post-traumatic bleeding internal bleeding Prolongation of the prothrombin time
Toxicity of vitamin K Rare condition Due to prolonged administration of large doses of synthetic vitamin K in infants It results in toxic effects on the membrane of RBC Manifestations: Hemolytic anemia Jaundice
References Lippincott’s Illustrated Reviews in Biochemistry, 6 th edition, Chapter 28, page Textbook of Biochemistry with clinical correlations by Thomas M Devlin