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