Gamma-glutamyl carboxylase
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Through Enzyme, Gene and Coagulation
Function
Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent proteins. Many of these vitamin K-dependent proteins are involved in coagulation so the function of the encoded enzyme is essential for hemostasis. Most gla domain-containing proteins depend on this carboxylation reaction for posttranslational modification. In humans, the gamma-glutamyl carboxylase enzyme is most highly expressed in the liver.
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Catalytic reaction
Gamma-glutamyl carboxylase oxidizes vitamin K hydroquinone to Vitamin K-2,3-epoxide, while simultaneously adding CO2 to protein-bound glutamic acid (abbreviation = Glu) to form gamma-carboxyglutamic acid (also called gamma-carboxyglutamate, abbreviation = Gla). Presence of two carboxylate groups causes chelation of Ca2+, resulting in change in tertiary structure of protein and its activation. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions.
a [protein]-α-L-glutamate (Glu) + phylloquinol (KH
2) + CO
2 + oxygen → a [protein] 4-carboxy-L-glutamate (Gla) + vitamin K 2,3-epoxide (KO) + H+
+ H
2O
No experimental structure is known for GGCX, limiting understanding of its reaction mechanism. Based on the fact that the two reactions are coupled, a computational study is able to propose how the reactants interact with each other to form the products. Lys228 has been shown to be the residue responsible for starting the reaction. How the enzyme holds the reactants in place to have them interact with each other remains poorly shown. 491-507 and 395-401 are probably responsible for propeptide and glutamate binding respectively.
Clinical significance
Mutations in this gene are associated with vitamin K-dependent coagulation defect and PXE-like disorder with multiple coagulation factor deficiency.