Targeting multiple enzymes in vitamin K metabolism for anticoagulation

Abstract

Vitamin K antagonists (VKAs), such as warfarin, are oral anticoagulants used to treat and prevent pulmonary embolism, deep vein thrombosis, and complications associated with atrial fibrillation and heart valve replacement. VKAs are effective against blood clotting where blood flow is relatively slow, such as in veins, in dysfunctional atria, and behind heart valves. These drugs, however, have a narrow therapeutic window and require frequent anticoagulation monitoring and dose adjustments. To overcome these problems, direct oral anticoagulants (DOACs) targeting factor Xa and thrombin have been developed, with the advantages of less monitoring, fixed dosing, predictable responses, and fewer food interactions.1 The efficacy and safety of DOACs, however, have yet to be demonstrated for a number of specific conditions.2 Moreover, DOACs are more expensive,3 have limited use for patients with renal impairment, and are less effective for those with artificial heart valves4 and acute coronary syndrome.5,6 VKAs remain the primary choice under such conditions. VKAs inhibit the redox cycle of vitamin K to prevent blood coagulation.7 This cycle begins with the epoxidation of vitamin K hydroquinone that is catalyzed by the γ-carboxylase (GGCX). GGCX uses the epoxidation reaction to drive the γ-carboxylation of selected glutamic acid residues in coagulation factors, a posttranslational modification required for their activity. To regenerate the hydroquinone, vitamin K epoxide reductase (VKOR) reduces the epoxide form of vitamin K in two steps, first to the quinone and then back to the hydroquinone.8 VKAs inhibit both these reduction steps to hinder the production of functional coagulation factors in the liver, thereby hindering blood clotting. As the target of VKAs, VKOR’s genotype is a key determinant of the VKA dosage: a single nucleotide polymorphism (SNP)-1639 G > A in the promoter region of VKOR causes ~25% of interpatient variability,9-11 and rare mutations in the protein coding region of VKOR confer various levels of warfarin resistance.12 The vitamin K cycle involves several other human enzymes (Figure 1). A VKOR-like paralog (VKORL), which has similar activities but different tissue distributions, may complement the VKOR function of supporting blood coagulation, particularly during the stages of prenatal and perinatal development.13 Both VKOR and VKORL may support other vitamin-K-dependent processes, such as bone mineralization and inhibition of vascular calcification.14,15 A yet-tobe-identified vitamin K reductase (VKR), which can only reduce the quinone to hydroquinone, may contribute to the antidoting effect of vitamin K,16-18 which is regularly used to reverse VKA overdose and restore coagulation. At the upstream of the vitamin K cycle, the prenyltransferase UBIAD1, together with another unknown enzyme, convert vitamin K1, the major dietary form of vitamin K, to menaquione-4 (MK4)19; both K1 and MK4 can serve as a substrate of VKOR and GGCX. In this issue of the Journal of Thrombosis and Haemostasis, Chen et al present a novel vitamin K–derived compound that inhibits the multiple enzymes involved in the vitamin K cycle, and remarkably, is insensitive to various warfarin-resistant mutations in VKOR. In the search for improved VKAs, the authors synthesized vitamin K derivatives with a naphthoquinone core structure, which is