Role of Vitamin K in the Synthesis of Gamma Carboxyglutamic Acid

Vitamin K is a cofactor for a single known enzymatic reaction: the conversion of glutamic acid to -carboxyglutamic acid on vitamin K-dependent proteins during their biosynthesis. Since the discovery of vitamin K and its association with blood coagulation, many milestones have contributed to the understanding of the biological role of vitamin K. Some highlights include the discovery of -carboxyglutamic acid in blood clotting proteins, the identification of -carboxyglutamic acid as a metal binding amino acid that confers metal binding properties on proteins and is required for protein-membrane interaction, the detection of enzymatic activity (i.e. the -carboxylase) that catalyzes the incorporation of CO2 into glutamic acid, the requirement for and the sufficiency of the -carboxylation recognition site within the propeptide in directing synthesis of -carboxyglutamic acid on the adjacent Gla domain on the precursor protein, the purification and cloning of the vitamin K-dependent carboxylase, proposal of a mechanism of vitamin K-mediated base enhancement of carboxylase action, and the regulation of vitamin K epoxidase activity of the vitamin K-dependent carboxylase from an inactive to an active state upon substrate binding. Since carboxylase activity is found in essentially all mammalian tissues and since -carboxyglutamic acid has been observed in both vertebrates and invertebrates, this amino acid must play an important biological role in protein function. The biosynthesis and function of -carboxyglutamic acid has been a major topic in this laboratory.

In order to study the mechanism of synthesis and the function of gamma-carboxyglutamic acid in invertebrates, the Furie laboratory maintains a satellite laboratory at the Marine Biological Laboratory (MBL) in Woods Hole MA. The focus is on the conotoxins elaborated by the venomous cone snail since many of these conotoxins contain gamma-carboxyglutamic acid. The MBL lab operates year-round and its personnel are closely interdigitated with the Boston laboratory.