Vitamin K-dependent gamma-glutamylcarboxylation: an ancient posttranslational modification

Abstract

The vitamin K-dependent carboxylase carries out the posttranslational modification of specific glutamate residues in proteins to gamma-carboxy glutamic acid (Gla) in the presence of reduced vitamin K, molecular oxygen, and carbon dioxide. In the process, reduced vitamin K is converted to vitamin K epoxide, which is subsequently reduced to vitamin K, by vitamin K epoxide reductase (VKOR) for use in the carboxylation reaction. The modification has a wide range of physiological implications, including hemostasis, bone calcification, and signal transduction. The enzyme interacts with a high affinity gamma-carboxylation recognition sequence (gamma-CRS) of the substrate and carries out multiple modifications of the substrate before the product is released. This mechanism ensures complete carboxylation of the Gla domain of the coagulation factors, which is essential for their biological activity. gamma-Carboxylation, originally discovered in mammals, is widely distributed in the animal kingdom. It has been characterized in sea squirt (Ciona intestinalis), in flies (Drosophila melanogaster), and in marine snails (Conus textile), none of which have a blood coagulation system similar to mammals. The cone snails express a large array of gamma-carboxylated peptides that modulate the activity of ion channels. These findings have led to the suggestion that gamma-carboxylation is an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates. I will first summarize recent understanding of gamma-carboxylase and gamma-carboxylation gleaned from experiments using the mammalian enzyme, and then I will briefly describe the available information on gamma-carboxylation in D. melanogaster and C. textile.