Vitamin K

Chemical
Functions
Sources
Metabolism
Requirements
Deficiency
Toxicity

I.  Chemical

1. Phylloquinone (Ki)
2. Menaquinone (K₂)
3. Menadiomcs(synthetic)
4. Vitamin K antagonists

II.  Functions

Vitamin K appears to be required for the y-carboxylation of glutamate residues, allowing firm binding Ca⁺²

1. Several of the blood clotting factors* of the coagulation cascade depend on vitamin K.  (* prothrombin, II_a thrombin, V, VII_a, IX, Xa_a, XI, XI_a, XII, XII_a)
   1. Fibrinogen (soluble) must be converted to fibrin (insoluble) by thrombin
   2. Thrombin (factor IIa) circulates in the blood as prothrombin (factor II)
   3. Thrombin for blood clotting is generated from prothrombin by two pathways:
      1. Intrinsic pathway
         1. Factor XII is activated to XII_a, by absorption onto collagen
         2. Factor XII_a cleaves XI to generate the active XI_a
         3. XI_a cleaves factor IX to IX_a which is vitamin K dependent
         4. Once carboxylated (by vitamin K) Factor IX_a binds Ca⁺² and with phospholipids from aggregaled platelets, it converts X to X_a which is also vitamin K dependent
         5. Xa in turn can hydrolyze prothrombin (factor II) into thrombin (II_a) which completes conversion of fibrinogen to fibrin for clot formation
      2. Extrinsic pathway (functions with tissue injury)
         1. Tissue thromboplastin activates VII which is vitamin K dependent to VII_a
         2. Once VII_a is carboxylated, it binds Ca²⁺ and with phospholipids from aggregated platelets, and converts X to X_a
         3. As in the intrinsic pathway this results in conversion of prothrombin to thrombin
2. Vitamin K dependent protein in skeletal tissue
   1. Bone glutamate a protein (Gla) (BGP) (osteocalcin)
      1. Secreted by osteoblasts in bone and dentine
      2. When carboxylated (involving vitamin K), Gla facilitates binding of Ca²
      3. Long-term vitamin K deficiency interrupts longitudinal growth and bone crystallization
   2. Matrix Gla protein (MGP)
      1. Found in bone dentine and cartilage associated with the organic matrix
   3. Both osteocalcin and MGP are thought to promote mobilization of bone Ca
   4. Their synthesis appears to be stimulated by 1,25(OH)₂D₃
3. Carboxylation of proteins by vitamin K is a cyclic process (vitamin K cycle)
   1. Vitamin K is present in the body in its oxidized quinone form (O₂ in blood)
   2. Vitamin K quinose is reduced to the active form (Kp) quinone reductase requiring dithiol (RSH-HSR) or NAD(P)H
   3. KH₂ + 0₂ + CO₂ ^carboxylase ®Gla + vitamin K_2.3-epoxide
   4. Vitamin K_2.3 ^{epoxide reductase}®.vitamin K quinone
   5. Vitamin K quinone®KH₂ (see "b" above)

III.  Sources

1. Normally, rumen or intestinal synthesis should meet the needs in most species except poultry
2. Food sources include green leafy materials, liver and egg

IV.  Metabolism

1. Absorption and transport
   1. Phylloquinone is absorbed from the small intestine by a saturable, energy dependent process
   2. Menaquinones (either dietary or synthesized by bacteria) and menadione appear to be absorbed from the distal small intestine and colon by passive diffusion
   3. In the intestinal cell, vitamin K is incorporated into the chylomicron that enters the lymphatic and then the circulatory system
   4. In the liver, menaquinone is alkylated and with phylloquinone and menaquinone is incorporated into VLDL and carried to other tissues in LDL
   5. An estimated 50 to 100 ug of vitamin K (low for a fat soluble vitamin) is stored in tissues
2. Excretion
   1. Phylloquinone is converted to 2,3 epoxide (vitamin K cycle), then 3-hydroxyquinone and other metabolites are excreted as glucaronides in urine and via bile in feces
   2. Menadione is metabolized to malmitol which reacts with phosphate, sulfate, or glucuronide
      1. The phosphate and sulfate are excreted in urine and via bile in feces
      2. The glucoronides are excreted mostly via bile in feces

V.  Requirements

1. Diet is unlikely to give rise to a deficiency (except in chickens)
2. Synthesis by microorganisms is another source
3. Factors likely to increase requirement:
   1. Hemorrhagic sweet clover disease in cattle
      1. Coumerol is a normal constituent of sweet clover
      2. If mold develops when hay is made, coumerol is converted to dicoumerol (section B-4)
      3. Dicoumerol is an antagonist to vitamin K
   2. Poor fat absorption
      1. Obstructive jaundice which interrupts delivery of bile
      2. Steatorrheas (malabsorption syndrome)
   3. Antibiotics
      1. Bowel microorganisms which provide a source of vitamin K killed
   4. Anticoagulants, used therapeutically
   5. Newborn
      1. Insufficient synthesis of factors II, VII, IX and X has occurred by time of birth
      2. Especially likely when birth is premature
      3. In the Bible, the Hebrews were instructed to not circumcise an infant before 7 days
4. Recommended allowances
   1. Human.....65-80 ug/day
   2. Chick........0.5 mg/kg of diet

VI.  Deficiency

1. Spontaneous subcutaneous hemorrhages
2. Lowered prothrombin levels
3. Increased blood clotting times

VII.  Toxicity

1. Toxicity in humans is very rare
   1. 150 mg/day caused nausea
2. The unsubstituted carbon 3 of menadione can combine with sulfhydryl groups
   1. Glutathione oxidation and excretion
   2. Oxidation of membrane phospholipids
3. Toxic effects reported in infants
   1. Hemolytic anemia
   2. Hyperbilirubinemia
   3. Severe jaundice

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