Pathway for synthesis of vitamin K-dependent proteins. Vitamin K-dependent proteins are synthesized in the endoplasmic reticulum as precursor proteins containing a signal peptide and a γ-carboxylation recognition site usually found within a propeptide of the proprotein. After cleavage of the signal peptide, the proprotein binds to the endoplasmic reticulum membrane-associated vitamin K-dependent carboxylase via its γ-carboxylation recognition site. Recent data suggest that binding of a glutamic acid-containing substrate to the carboxylase converts it from an inactive to an active state.14 The carboxylase catalyzes the conversion of glutamic acid residues to γ-carboxyglutamic acid residues. As is indicated by an arrow with a question mark connecting two active carboxylase molecules, it is unclear whether carboxylation of proproteins occurs by a processive mechanism. The carboxylated proprotein is trafficked through the cell to the trans Golgi network, where the propeptide is cleaved by an unknown proconvertase. The inactive form of the carboxylase may be carried to the Golgi and then recycled back to the ER. The fully modified, mature protein is then secreted from the cell.