Vitamin K epoxide reductase

Vitamin K epoxide reductase

Vitamin K epoxide reductase (VKOR) is a key enzyme in the vitamin K cycle, which is crucial for the post-translational modification of certain proteins, mainly involved in the blood coagulation process and bone metabolism. This enzyme catalyzes the reduction of vitamin K 2,3-epoxide to its active form, vitamin K hydroquinone, thereby enabling the carboxylation of glutamate residues on the prothrombin precursors of clotting factors II, VII, IX, and X, as well as proteins C, S, and Z. This carboxylation step is essential for their biological activity.

Function

VKOR plays a pivotal role in the vitamin K cycle, a critical pathway in the body's ability to form blood clots. The active form of vitamin K, produced by VKOR, is a cofactor for the enzyme gamma-glutamyl carboxylase, which modifies glutamate residues in certain proteins to gamma-carboxyglutamate (Gla). These modifications allow the proteins to bind calcium ions, which is necessary for their activity in the coagulation cascade.

Clinical Significance

Mutations in the VKORC1 gene, which encodes the VKOR enzyme, can lead to deficiencies in vitamin K-dependent clotting factors, resulting in bleeding disorders. Additionally, VKOR is the target of anticoagulant drugs, such as warfarin. These drugs inhibit the enzyme, preventing the activation of vitamin K and thus the clotting factors, which is useful in the treatment of thromboembolic diseases.

Pharmacology

Warfarin and other vitamin K antagonists (VKAs) are widely used as anticoagulants. The action of these drugs is monitored by measuring the prothrombin time (PT) and adjusting the dose to maintain the international normalized ratio (INR) within a therapeutic range. Resistance to warfarin, due to mutations in the VKORC1 gene, requires higher doses to achieve the desired anticoagulant effect.

Genetics

The VKORC1 gene is located on chromosome 16 and consists of three exons. Variants in this gene can affect the enzyme's activity and the individual's response to vitamin K antagonists. Genetic testing can identify these variants to guide the dosing of warfarin and reduce the risk of bleeding or thrombosis.

See Also

• Vitamin K
• Blood coagulation
• Warfarin
• Prothrombin time
• International normalized ratio