gammacarboxylation

Gamma-carboxylation is a post-translational modification in which gamma-carboxyl groups are added to specific glutamate residues in vitamin K–dependent proteins, forming gamma-carboxyglutamate (Gla). The reaction is catalyzed by gamma-glutamyl carboxylase in the endoplasmic reticulum and requires reduced vitamin K (vitamin K hydroquinone) as a cofactor. The carboxylation uses CO2 as a substrate and results in the oxidation of vitamin K to vitamin K epoxide, which is recycled back to the active hydroquinone form by vitamin K epoxide reductase (VKOR). The process is calcium- and phospholipid-dependent and occurs on membrane surfaces.

Many vitamin K–dependent proteins contain Gla-rich domains, most notably the coagulation factors II (prothrombin), VII, IX, and X, and the anticoagulant proteins C, S, and Z. Other Gla-containing proteins include osteocalcin and matrix Gla protein (MGP), which are involved in bone mineralization and vascular biology. The presence of gamma-carboxyl groups confers high affinity for calcium ions, enabling proper calcium binding and function.

Physiological significance: Gamma-carboxylation is essential for the calcium-dependent function of these proteins, particularly in the coagulation cascade, where insufficient carboxylation impairs clotting. Pharmacologically, inhibition of VKOR by warfarin-like anticoagulants reduces gamma-carboxylation, producing anticoagulation, and vitamin K deficiency can lead to bleeding tendencies and defective bone and vascular Gla proteins. Genetic defects in GGCX or VKOR can produce similar phenotypes.