REVIEW ARTICLE Vitamin K-Dependent Biosynthesis of g-Carboxyglutamic Acid

VITAMIN K, AN ESSENTIAL vitamin, is a cofactor fora single known enzymatic reaction: the conversion of glutamic acid to g-carboxyglutamic acid in vitamin K-dependent proteins during their biosynthesis. Since the discovery of vitamin K and its association with blood coagula-tion,1 many milestones have been passed on the road to understanding the biological role of vitamin K. Important early landmarks include the discovery of vitamin K antagonists and their introduction as pharmacologic agents for anticoagulation2; the discovery of g-carboxyglutamic acid in blood clotting proteins3,4; the identification of g-carboxyglutamic acid as a metal binding amino acid that confers metal binding properties on proteins, a requirement for protein-membrane interaction5,6; the detection of an enzymatic activity (ie, the vitamin K-dependent g-glutamyl-carboxylase) that catalyzes the incor-poration of CO2 into glutamic acid5; the identification of a