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EC 1.6.5.2 NAD(P)H dehydrogenase (quinone) EC 1.1.4.1 Vitamin-K-epoxide reductase (VKOR) EC 6.4.-.- -y-Glutamyl carboxylase (GGCX)

Figure 28.19 • The vitamin K cycle showing its role in y-carboxylation of glutamate by GGCX. (R, phytyl side chain.)

and cartilage, but is probably widely distributed in the body, and contains five Gla residues.125 Both of these are important in regulating bone mineralization, in conjunction with vitamin D, calcium and other hormones. Specifically, vitamin D increases the synthesis of BGLAP propeptide whereas vitamin K is required for its activation through formation of Gla residues. Deficiency of vitamin K or the use of vitamin K antagonists, such as warfarin, can result in mineral loss and bone malformation. Although maintenance of adequate vitamin K intake is important for bone maintenance, high doses of vitamin K may not lead to remineral-ization. It is important to note that proper maintenance of bone structure is multifaceted with at least two key vitamins, K and D, involved and several other factors. Studies of individual vitamins and their role in bone health may be misleading because increasing intake of a single vitamin may not be sufficient to offset deficiencies in other biomolecules involved in overall bone homeostasis. The promotion of bone formation by vitamin K2 is not solely mediated through its action on Gla proteins; however, it can also directly stimulate messenger ribonucleic acid (mRNA) production of osteoblast mRNA markers and regulate transcription of bone-specific genes.126

Another vitamin K-dependent Gla protein, growth arrest-specific 6 (GAS6), was the most recently discovered which contains 10 to 11 Gla residues.127 GAS6 is a protein initially found to increase approximately 30-fold during the G0 phase of the cell cycle suggesting a role in cell proliferation. Several biological roles related to this function have been elucidated since then, including effects on apoptosis, immune function, inflammation, and cell differentiation, among others.128 Of particular interest is the possible role in diabetic nephropathy.129 Current studies are underway to define the function of this protein, with particular interest in the possible role in cancer. Early evidence indicates a possibility of the menaquinones in decreasing the occurrence of hepatocellular carcinoma.130 The menaquinone analog, menatetrenone, has also been shown to reduce the recurrence rate of hepatocellular carcinoma.131 This work may ultimately lead to an understanding of any value that vitamin K may have in the prevention or treatment of other cancers.

The latest Gla-containing proteins with unknown functions have wide tissue distribution and are rich in proline residues; thus they have been named proline rich Gla 1 (PRRG1) and proline rich Gla 2 (PRRG2)132 and transmembrane Gla proteins 3 and 4 (TGP3 and TGP4).133

Vitamin K deficiency typically results in an increased clotting time and hemorrhagic disorders. This can manifest as easy bruising, continual bleeding from puncture wounds, mucosal hemorrhage such as gastrointestinal or urinary tract bleeding and intracranial hemorrhaging can occur in infants. Dietary deficiency of vitamin K is rare; most cases are caused by decreased absorption (e.g., intestinal polyposis, chronic ulcerative colitis, intestinal fistula, intestinal obstruction, and sprue), liver disease (e.g., atrophy, cirrhosis, or chronic hepatitis), or biliary disease (e.g., obstructive jaundice, biliary fistulas, insufficient or abnormal bile). Vitamin K deficiency can also lead to decreased bone mineralization.

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