Gammacarboxylated

Gamma-carboxylation is a vitamin K–dependent post-translational modification in which specific glutamate residues in certain secreted and membrane proteins are converted to gamma-carboxyglutamate (Gla). The modification is catalyzed by gamma-glutamyl carboxylase in the endoplasmic reticulum and requires reduced vitamin K as a cofactor. The vitamin K cycle, involving reduction of vitamin K and regeneration by vitamin K epoxide reductase (VKOR), sustains continual carboxylation.

The gamma-carboxylation reaction adds a second carboxyl group to the gamma position of glutamate, creating negatively charged Gla residues that coordinate calcium ions. This calcium binding is essential for the function of many vitamin K–dependent proteins (VKDPs), enabling interaction with phospholipid surfaces and participation in biological processes such as coagulation and mineral metabolism.

Key VKDPs include coagulation factors II (prothrombin), VII, IX, and X, and the anticoagulant proteins C and S. Other important VKDPs are bone Gla-protein (osteocalcin) and matrix Gla protein (MGP), which are involved in bone formation and inhibition of vascular and soft tissue calcification, respectively. The gamma-carboxylation status of these proteins is crucial for their activity, particularly in calcium binding and proper function at sites of injury or mineralization.

Clinical relevance includes exposure to warfarin and other VKOR inhibitors, which reduce gamma-carboxylation and produce undercarboxylated, functionally impaired proteins. Nutritional vitamin K deficiency or defects in the carboxylation pathway can lead to bleeding disorders and, in some contexts, abnormal bone mineralization. Detection of gamma-carboxylation status can be performed by antibodies against Gla residues or by mass spectrometry-based proteomics.