Mechanism of Action of Vitamin K

Abstract

Vitamin K is the blood clotting vitamin; it is important as an obligatory cofactor for the enzyme which carboxylates selected glutamate residues in the proteins of the blood coagulation cascade, including prothrombin (factor II), factors VII, IX, and X and proteins C, S, Z, and M. Molecular oxygen is required for the carboxylation. A new model, based on 2,4-dimethyl-1-naphthol demonstrates that spontaneous oxidation of the corresponding 2,4-dimethyl-1-naphthoxide anion 1 leads to the tertiary alkoxide 9. The latter is a sufficiently strong base to effect the Dieckmann condensation of diethyl adipate (2) to ethyl cyclopentanonecarboxylate (4), a model for the carboxylation. In thermochemical terms this base strength amplification is driven by the oxidation to the extent of approximately -50 kcal/mol. It is proposed that the model oxidation proceeds through a dioxetane intermediate 8, which demands that the epoxide be cis to the alcohol in the product 3. This has been demonstrated by X-ray crystallography. Likewise, treatment of 2,3,4-trimethyl-1-naphthol (16) with oxygen in chloroform yielded the crystalline hydroperoxide 15. The latter rearranged to the epoxy alcohol 18 upon treatment with potassium hydride. The structure of 17 was established by X-ray crystallography. Thermochemical analysis shows that the oxidation of vitamin K hydroquinone to vitamin K oxide is exothermic to the extent of -62 kcal/mol. The new mechanism suggests that a second atom of oxygen-18 might be incorporated in an O-18(2) labeling experiment. Analysis of mass spectral data in the literature indicates that this probably is the case, lending support to the new mechanistic proposal.