Gamma-carboxyglutamate (Gla) is a modified amino acid found in specific proteins throughout the body. It forms from the amino acid glutamate through a chemical alteration that adds a carboxyl group. This structure gives Gla properties essential for various biological processes.
Its Role in the Body
Gamma-carboxyglutamate’s main function is its ability to bind calcium ions. The additional carboxyl group allows Gla residues to chelate calcium. This calcium binding stabilizes Gla-containing proteins and is essential for their proper function.
Gla-containing proteins are involved in several physiological processes, including blood coagulation and bone metabolism. In the blood clotting cascade, proteins like prothrombin, Factor VII, Factor IX, and Factor X contain Gla residues. These Gla domains enable clotting factors to bind to phospholipid surfaces, a necessary step for blood clot formation. This calcium-mediated membrane association helps localize and accelerate coagulation reactions.
Beyond blood clotting, Gla is also present in proteins involved in bone health. Osteocalcin, a major bone protein, contains Gla residues and plays a role in bone mineralization. Matrix Gla Protein (MGP) is another Gla-containing protein found in bone and cartilage, and it helps prevent abnormal calcification in soft tissues like blood vessels.
The Vitamin K Connection
The formation of gamma-carboxyglutamate is a post-translational modification, occurring after protein synthesis. An enzyme called gamma-glutamyl carboxylase catalyzes this conversion of glutamate to Gla. This enzyme is primarily expressed in the human liver.
The carboxylation reaction depends on vitamin K as a cofactor. Gamma-glutamyl carboxylase uses reduced vitamin K (vitamin K hydroquinone) along with carbon dioxide and oxygen to add the carboxyl group to glutamate. As the reaction proceeds, vitamin K hydroquinone oxidizes to vitamin K epoxide.
To ensure a continuous supply of active vitamin K, a recycling mechanism called the vitamin K cycle exists. Vitamin K epoxide reductase (VKOR) converts vitamin K epoxide back to vitamin K, which is then reduced to vitamin K hydroquinone for further carboxylation. Adequate dietary intake of vitamin K, available as phylloquinone (K1) from plants and menaquinones (K2) from animal products and fermented foods, is necessary for the formation and function of Gla-containing proteins.
Implications for Health
Impaired formation or dysfunction of gamma-carboxyglutamate-containing proteins can have health consequences. A recognized implication is in blood coagulation. Vitamin K deficiency, or drugs interfering with its cycle, lead to under-carboxylated Gla proteins. These proteins have a reduced ability to bind calcium and phospholipid surfaces, impairing the clotting cascade and increasing bleeding risk.
Anticoagulant medications like warfarin (Coumadin) exert their effects by targeting the vitamin K cycle. Warfarin inhibits vitamin K epoxide reductase, preventing the regeneration of reduced vitamin K. This interruption reduces active vitamin K for gamma-glutamyl carboxylase, leading to less functional Gla-containing clotting factors and a reduced clotting response.
Gamma-carboxyglutamate also plays a role in bone health, and its dysfunction can contribute to osteoporosis or abnormal calcification. Low vitamin K levels or under-carboxylated osteocalcin have been associated with a higher risk of fractures and lower bone mineral density. Warfarin therapy may negatively affect bone mineral density and increase fracture risk, likely due to its interference with Gla protein activation in bone. Additionally, Matrix Gla Protein (MGP) dysfunction, potentially due to impaired carboxylation, has been linked to vascular calcification, where calcium deposits accumulate in arteries.