Either K1 or MK4 may be used as the substrates for the vitamin K cycle enzymesĮmploys a HEK293‐derived cell line that stably expresses a chimeric reporter protein, in which the Gla domain of protein C is exchanged with that of factor IX (FIXgla‐PC) to allow enzyme‐linked immunosorbent assay‐‐based quantification of the reporter's carboxylation level. At the upstream of the vitamin K cycle, an unknown enzyme removes the isoprenyl chain (R1) of vitamin K1 and generates vitamin K3, and UBIAD1 adds a different isoprenyl chain (R2) to K3 and generates MK4. Unlike warfarin, which specially targets VKOR and VKORL, VK‐M‐COT appears to inhibit all enzymes involved in the redox conversion of vitamin K. In addition, an unknown vitamin K reductase (VKR) can reduce vitamin K quinone (K) to KH 2. Regeneration of KH 2 from KO is catalyzed by vitamin K epoxide reductase (VKOR), VKOR‐like paralog (VKORL), with the reducing equivalent provided by reducing partner proteins or reduced glutathione (GSH). The γ‐carboxylation reaction is coupled to the conversion of vitamin K hydroquinone (KH 2) to vitamin K epoxide (KO). ![]() γ‐carboxylase (GGCX) catalyzes the γ‐carboxylation of several coagulation factors and other vitamin‐K‐dependent proteins such as osteocalcin (OCN) and matrix Gla protein (MGP). ![]() FIGURE 1 An expanded view of the vitamin K cycle showing associated enzymes and their inhibition by vitamin K methylene cyclooctatetraene (VK‐M‐COT) and warfarin.
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