Vitamin K

The most studied compounds in the vitamin K group include vitamin K1 (phylloquinone), vitamin K2 (menaquinone) and vitamin K3 (menadione). Vitamin K1 is also called phylloquinone because it is an indirect product of photosynthesis in plant chloroplasts. The naphthoquinone ring has a phytyl side chain.

Vitamin K2 has a poly-isoprenoid unsaturated side chain whose length varies from 4 to 12 units. These compounds are called menaquinones-n or MK-n for short. Animal experiments have shown that MK-7 may play an important role in the prevention of age-related bone loss (1). The results obtained by recent dose-response studies have suggested that the intake of vitamin K should be increased in order to optimize bone mineralization because the diet alone does not provide the adequate amount of vitamin K, particularly in post menopausal women. In addition, menaquinone may be also effective in the prevention of arterial calcification (2).

Vitamin K3 ( 2-methyl 1-4-naphthoquinone) has the same physiological activity in vivo as vitamin K1 after alkylation in position 3 with an isoprenoid chain in the liver.






  • Required for normal process of blood clotting to occur. Thus, vitamin K1 is essential for the synthesis of clotting factors II, VII, IX and X and of the anticoagulant proteins C and S. The reduced form of vitamin K1 (formed through the action of a reductase on phylloquinone) is necessary for the post-translational modification of coagulation factors II, VII, IX and X. The modified protein (contains g-carboxyglutamic acid residues) is able to bind calcium, an essential property of the coagulation factors.
  • Plays an important role in bone and teeth metabolism, i.e. the conversion of osteocalcin (a major noncollagen protein) to its active form, which appears to regulate bone's shape by depositing calcium in a certain way. This way the mineralization of the bone is not impaired (2, 3). Besides osteocalcin there is another protein called matrix Gla protein (MGP), which is involved more directly in mineralization of bones (4). It's interesting to note that onions contain the co-called g-glutamyl peptides, which were shown to increase bone density by inhibiting the activity of osteoclasts. The structure of such a peptide is shown below:


  • Involved in the protection against cardiovascular disease. In healthy arteries the vitamin K2-dependent MGP surrounds the elastic fibers of the tunica media (the anatomy of an arterial wall vessel is shown below) and prevents the formation of calcium salts crystals.

    In early atherosclerosis most MGP occurs in an inert form because there is not enough vitamin K2 around to activate it. As a result MGP associates with calcified structures containing oxidized lipids, macrophages and debris of smooth muscle cells. Patients with severe calcification have high a high percentage of inactive osteocalcin, indicating a deficiency of vitamin K2 (5).
  • Vitamin K2 can induce apoptosis in myeloma and B-cell lymphoma cell lines as recent experimental data have demonstrated (6).
  • Involved in brain metabolism and cognitive function. The brain contains the highest concentration of vitamin K2 after pancreas, salivary glands and the cartilaginous tissue of the sternum. Vitamin K2 supports enzymes that produce the sulfatides (an important group of brain lipids). The decline of sulfatides and vitamin K2 levels are associated with aging and neurodegeneration (7).
  • Synergysm: Vitamin K2 acts synergically with vitamins A and D. Vitamin K2 activates the Ca-binding proteins that were synthesized after vitamin A and D-triggered expression of the genes coding these proteins. Vitamins A and D regulate the expression of matrix Gla protein (this protein has five to six residues of the vitamin K-dependent amino acid, g-carboxyglutamic acid), which is responsible for mineralizing bone and protecting the arteries from calcification; like osteocalcin, however, matrix Gla protein can only fulfill its function once it has been activated by vitamin K2. While vitamins A and D contribute to growth by stimulating growth factors and promoting the absorption of minerals, vitamin K2 makes its own essential contribution to growth by preventing the premature calcification of the cartilaginous growth zones of bones.
  • Interactions: Aspirin, warfarin (a synthetic anticoagulant agent, which inhibits the synthesis of vitamin K-dependent clotting factors), certain antibiotics and higher dosages of vitamin E (over 800 I.U.) may interfere with the biological function of vitamin K..
  • Therapeutic uses: Epidemiological studies in the last 10 years showed that a large portion of the population is vitamin K2 deficient. Although colon bacteria produce this vitamin it is not absorbed by that segment of the GI tract so supplementation may be required for the prevention and treatment of osteoporosis, dental cavities, cardiovascular disease and excessive menstrual bleeding.
  • Best food sources: Dark green leafy vegetables, kale, broccoli, lettuce, spinach, green tea, dairy products especially the fermented ones such as cheese (rich in menaquinone species).

References
1. Tsukamoto, Y. (2004) Biofactors 22 (1-4) 5-19. Studies on action of menaquinone-7 in regulation of bone metabolism and
    its preventive role in osteoporosis.
2. Adams, J. and Pepping, J. (2005) Am.J. Health Syst.Pharm. 62 (15) 1574-1581. Vitamin K in the treatment and prevention
    of osteoporosis and arterial calcification.
3. Boskey, A.L. et al. (1998) Bone 23(3) 187-196. Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-
   deficient mice provides insight into the function of osteocalcin.
4. Koshihara, Y. et al. (1997) J. Bone Miner.Res. 12(3) 431-438. Vitamin K2 enhances osteocalcin accumulation in the
    extracellular matrix of human osteblasts in vitro.
5. Schurgers, L.J. et al. (2005) Arterioscler.Thromb.Vasc.Biol. 25, 1629-1633. Novel conformation-specific antibodies against
    matrix g-carboxyglutamic acid (Gla) protein. Undercarboxylated matrix Gla protein as marker for vascular calcification.
6. Tsujioka, T. et al. (2006) Haematologica 91(5) 613-619. The mechanisms of vitamin K2-induced apoptosis of myeloma
    cells.
7. Han, X. et al. (2002) J.Neurochem. 82(4) 809-818. Substantial sulfatide deficiency and ceramide elevation in very early
    Alzheimer's disease: potential role in disease pathogenesis.