The vitamin K cycle

Post-translational modification of glutamate to gamma carboxyl glutamate is required for the activity of vitamin K-dependent proteins. Carboxylation is accomplished by the enzyme gamma glutamyl carboxylase (GGCX) which requires the propeptide-containing substrate and three cosubstrates: reduced vitamin K, CO2, and O-2. Most propeptides bind tightly to GGCX and all of the Glu residues that will be modified are modified during one binding event. Complete carboxylation is thus dependent upon the rate of carboxylation and the dissociation rate constant of the substrate from the GGCX enzyme. If the propeptide is released before carboxylation is complete, partially carboxylated vitamin K-dependent proteins are produced. The rate of carboxylation is mainly controlled by the level of reduced vitamin K available for the reactions while the dissociation rate constant is dependent upon both the propeptide and the Gla domain of the substrate. In addition, there are allosteric effects that increase the rate of dissociation of the fully carboxylated substrates. Carboxylation requires the abstraction of a proton from the 4-carbon of glutamate by reduced vitamin K and results in the conversion of vitamin K to vitamin K epoxide. The vitamin K epoxide must be recycled to vitamin K before it can be reused, a reaction catalyzed by the enzyme vitamin K epoxide reductase (VKOR). The gene for VKOR has recently been identified but the enzyme itself has not been purified to homogeneity. It appears, however, that most of the variability observed in patients response to warfarin may be attributed to variability in the VKOR gene.