Vitamin K and E

VITAMIN K
The principal role of vitamin K is in the posttranslational modilication of various blood clotting factors, in which it serves as a coenzyme in the carboxylation of certain glutamic acid residues present in these proteins. Vitamin K exists in several forms, for example, in plants as phylloquinone (or vitamin K1), and in intestinal bacterial flora as menaquinone (or vitamin K2). A synthetic form of vitamin K, menadione, is available.
A. Function of vitamin K
1. Formation of ?-carboxyglutamate (Gla): Vitamin K is required in the hepatic synthesis of prothrombin and blood clotting factors ll, Vll , lX, and X. These proteins are synthesized as inactive precursor molecules. Formation of the clotting factors requires the vitamin K-dependent carboxylation of glutamic acid residues to Gla residues (Figure 28.26). This forms a mature clotting factor that contains Gla and is capable of subsequent activation. The reaction requires O2, CO2, and the hydroquinone form of vitamin K. The formation of Gla is sensitive to inhibition by dicumarol, an anti-coagulant occurring naturally in spoiled sweet clover, and by warfarin, a synthetic analog of vitamin K.
2. Interaction of prothrombin with platelets: The Gla residues of prothrombin are good chelators of positively charged calcium ions, because of the two adjacent, negatively charged carboxylate groups. The prothrombin-calcium complex is then able to bind to phospholipids essential for blood clotting on the surface of platelets. Attachment to the platelet increases the rate at which the proteolytic conversion of prothrombin to thrombin can occur (Figure 28.27)
3. Role of Gla residues in other proteins: Gla is also present in other proteins (for example, osteocalcin of bone, and in proteins such as protein C involved in limiting the formation of blood clots).


B. Distribution and requirement of vitamin K
Vitamin K is found in cabbage, kale, spinach, egg yolk, and liver. There is also extensive synthesis of the vitamin by the bacteria in the gut. Dietary allowance intake (DAl) for vitamin K is 120 ?g/day for adult males and 90 ?g for adult females.
C. Clinical indications
1. Deficiency of vitamin K:
A true vitamin K deficiency is unusual because adequate amounts are generally produced by intestinal bacteria or obtained from the diet. lf the bacterial population in the gut is decreased, for example, by antibiotics, the amount of endogenously formed vitamin is depressed, and this can lead to hypoprothrombinemia in the marginally malnourished individual, for example, a debilitated geriatric patient. This condition may require supplementation with vitamin K to correct the bleeding tendency. In addition, certain second-generation cephalosporins, for example, cefoperazone, cefamandole, and moxalactam cause hypoprothrombinemia, apparently by a warfarin-like mechanism. Consequently, their use in treatment is usually supplemented with vitamin K.
2. Deficiency of vitamin K in the newborn:
Newborns have sterile intestines and so initially lack the bacteria that synthesize vitamin K. Because human milk provides only about one fifth of the daily requirement for vitamin K, it is recommended that all newborns receive a single intramuscular dose of vitamin K as prophylaxis against hemorrhagic disease.
D. Toxicity of vitamin K
Prolonged administration of large doses of synthetic vitamin K (menadione) can produce hemolytic anemia and jaundice in the infant, due to toxic effects on the membrane of red blood cells; therefore, it is no longer used to treat vitamin K deficiency. No Upper Intake Level (UL) has been set for vitamin K.
13. VITAMIN E
The E vitamins consist of eight naturally occurring tocopherols, of which is the most active (Figure 28.28). The primary function of vitamin E is as an antioxidant in prevention of the nonenzymic oxidation cell components, for example, polyunsaturated fatty acids, by molecular oxygen and free radicals.
Distribution and requirements of vitamin E
Vegetable oils are rich sources of vitamin E, whereas liver and eggs contain moderate amounts. The RDA for ?-tocopherol is 15 mg for adults. The vitamin E requirement increases as the intake of polyunsaturated fatty acid increases.
B. Deficiency of vitamin E
Vitamin E deficiency is almost entirely restricted to premature infants. When observed in adults, it is usually associated with defective lipid absorption or transport. The signs of human vitamin E deficiency include sensitivity of erythrocytes to peroxide, and the appearance of abnormal cellular membranes.
C. Clinical indications
Vitamin E is not recommended for the prevention of chronic disease, such as coronary heart disease or cancer. Clinical trials using vitamin E supplementation have been uniformly disappointing. For example, subjects in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study trial who received high doses of vitamin E not only lacked cardiovascular benefit but also had an increased incidence of stroke.
D. Toxicity of vitamin E
Vitamin E is the least toxic of the fat-soluble vitamins, and no toxicity has been observed at doses of 300 mg/day.
NOTE:
Populations consuming diets high in fruits and vegetables show decreased incidence of some chronic diseases. However, clinical trials have failed to show a definitive benefit from supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease.
The vitamins are summarized in Figure 28.29