Fibrin Meshwork Formation : Formation of γ-carboxyglutamate residues

γ-Carboxylation is a posttranslational modification in which 9–12 glutamate residues (at the amino [N]-terminus of the target protein) get carboxylated at the γ carbon, thereby forming Gla residues. The process occurs in the rough endoplasmic reticulum (RER) of the liver.
1. γ-Carboxylation: This carboxylation reaction requires a protein substrate, oxygen (O2), carbon dioxide (CO2), γ-glutamyl carboxylase, and the hydroquinone form of vitamin K as a coenzyme (Fig. 1). In the reaction, the hydroquinone form of vitamin K gets oxidized to its epoxide form as O2 is reduced to water. [Note: Dietary vitamin K, a fat-soluble vitamin , is reduced from the quinone form to the hydroquinone coenzyme form by vitamin K reductase (Fig. 2).]

Figure 1:  γ-Carboxylation of a glutamate (Glu) residue to γ-carboxyglutamate (Gla) by vitamin K–requiring γ-glutamyl carboxylase. The γ carbon is shown in blue. O2 = oxygen; CO2 = carbon dioxide.

Figure 2:  The vitamin K cycle. VKOR = vitamin K epoxide reductase.
2. Inhibition by warfarin: The formation of Gla residues is sensitive to inhibition by warfarin, a synthetic analog of vitamin K that inhibits the enzyme vitamin K epoxide reductase (VKOR). The reductase, an integral protein of the RER membrane, is required to regenerate the functional hydroquinone form of vitamin K from the epoxide form generated in the γ-carboxylation reaction. Thus, warfarin is an anticoagulant that inhibits clotting by functioning as a vitamin K antagonist. Warfarin salts are used therapeutically to limit clot formation.

[Note: Warfarin is used commercially as a pest control agent such as in rat poison. It was developed by the Wisconsin Alumni Research Foundation, hence the name.]
Genetic differences (genotypes) in the gene for catalytic subunit 1 of VKOR (VKORC1) influence patient response to warfarin. For example, a polymorphism  in the promoter region of the gene decreases gene expression, resulting in less VKOR being made, thereby necessitating a lower dose of warfarin to achieve a therapeutic level. Polymorphisms in the cytochrome P450 enzyme (CYP2C9) that metabolizes warfarin are also known. In 2010, the U.S. Food and Drug Administration added a genotypebased dose table to the warfarin label (package insert). The influence of genetics on an individual’s response to drugs is known as pharmacogenetics.

مواضيع ذات صلة

Blood clotting (coagulation)

Platelet Plug Formation: Aggregation

Platelet Plug Formation: Activation

Platelet Plug Formation: Adhesion

Limiting Clotting : Fibrinolysis

Limiting Clotting : Inactivating proteins

Fibrin Meshwork Formation : Pathways

Fibrin Meshwork Formation :Role of phosphatidylserine and calcium

Fibrin Meshwork Formation: Proteolytic cascade

Blood Clotting : Overview

Biotechnology and Human Disease

Transgenic Animals