Gla Proteins (γ-carboxyglutamate)
The proteins vitamin K activates to steer calcium where it belongs
Definition
Gla proteins are a family of vitamin K-dependent proteins that carry γ-carboxyglutamic acid (Gla) residues. These residues arise from a post-translational modification —carboxylation— performed by the enzyme γ-glutamyl carboxylase using vitamin K as a cofactor. The Gla groups give these proteins an exceptionally high affinity for calcium, letting them direct where the mineral goes: driving blood coagulation, mineralizing bone (osteocalcin), and preventing calcification of the arteries (matrix Gla protein). Without adequate vitamin K they remain "undercarboxylated" and inactive.
Detailed explanation
Carboxylation converts glutamate (Glu) residues into γ-carboxyglutamate (Gla) by adding a second carboxyl group. The reaction occurs in the endoplasmic reticulum and is catalyzed by γ-glutamyl carboxylase (GGCX), which oxidizes vitamin K hydroquinone to obtain the energy required; the oxidized vitamin K is then recycled by VKOR (the target of coumarin anticoagulants such as warfarin).
The two carboxyl groups of each Gla residue form a "claw" that chelates calcium ions with high affinity. This explains the family's key functions: clotting factors (II, VII, IX, X) anchor to calcium-rich phospholipid membranes; osteocalcin binds calcium to bone hydroxyapatite; and matrix Gla protein (MGP) sequesters calcium in the arterial wall to block its calcification —MGP-null mice die from massive aortic calcification.
In longevity, the status of these proteins is measured with biomarkers such as undercarboxylated osteocalcin (ucOC) and undercarboxylated MGP (dp-ucMGP), which reflect a functional vitamin K deficit linked to greater vascular calcification and bone fragility. Vitamin K2 (menaquinone) supplementation improves the carboxylation of both MGP and osteocalcin.
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