Quinone oxidoreductases and vitamin K metabolism.

Vitamin K1, K2, and K3 are essential nutrients associated with blood clotting and bone metabolism. Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2)] are among the selected enzymes that catalyze reduction of vitamin K to vitamin K hydroquinone. NQO1 catalyzes high affinity reduction of vitamin K3 but has only weak affinity for reduction of vitamin K1 and K2. Vitamin K hydroquinone serves as a cofactor for vitamin K gamma-carboxylase that catalyzes gamma-carboxylation of specific glutamic acid residues in Gla-factors/proteins leading to their activation and participation in blood clotting and bone metabolism. Concomitant with Gla modification, a reduced vitamin K molecule is converted to vitamin K epoxide, which is converted back to vitamin K by the enzyme vitamin K epoxide reductase to complete vitamin K cycle. Vitamin K is also redox cycled. One-electron reduction of vitamin K3 leads to the formation of semiquinone that in the presence of oxygen is oxidized back to vitamin K3. Oxygen is reduced to generate reactive oxygen species (ROS) that causes oxidative stress and cytotoxicity. Vitamin K is used as radiation sensitizer or in mixtures with other chemotherapeutic drugs to treat several types of cancer. ROS generated in redox cycling contributes to anticancer activity of vitamin K. NQO1 competes with enzymes that redox cycle vitamin K and catalyzes two-electron reduction of vitamin K3 to hydroquinone. This skips formation of semiquinone and ROS. Therefore, NQO1 metabolically detoxifies vitamin K3 and protects cells against oxidative stress and other adverse effects. On the contrary, NQO2 catalyzes metabolic activation of vitamin K3 leading to cytotoxicity. The role of NQO1 and NQO2 in metabolic detoxification and/or activation of vitamin K1 and K2 remains to be determined. Future studies are also required to identify the enzymes that catalyze high affinity reduction of vitamin K1 and K2 to hydroquinone for use in gamma-carboxylation reactions.