Vitamin K-dependent proteins

Abstract

Vitamin K is required for the synthesis of gamma-carboxyglutamate (Gla) during postribosomal protein modification. Substrates include blood clotting proteins, bone proteins, cell signaling, and receptor proteins. In addition, Gla is a component of short toxin peptides from the marine snail Conus. Studies of structure-function relationships are the most advanced for the blood coagulation proteins. Reviews of vitamin K action and blood coagulation are presented. Special focus is on the structure-function role of Gla in blood coagulation and the impact of this amino acid on enzyme reaction kinetics. This amino acid forms calcium and membrane binding sites for these proteins. Two proposed mechanisms of protein-membrane attachment are reviewed. One involves membrane attachment by protein insertion into the hydrocarbon region of the membrane, while another considers attachment by specific interactions with phospholipid head groups. Membrane attachment generates the potential for several forms of nonclassical enzyme kinetic behaviors, all of which have been observed in vitro. For example, the reaction may be limited by properties of the enzyme active site, a condition that allows use of classic steady-state enzyme kinetic parameters. However, the reaction may be limited by substrate binding to the membrane, by substrate flux through solution, and/or by solvent flow rates across the membrane surface. These states provide special mechanisms that are not anticipated by classical steady-state kinetic derivations. They may be used to regulate coagulation in vivo. Overall, vitamin K research spans the spectrum of biological research and experience. Exciting new ideas and findings continue to emanate from vitamin K-related research.