The vitamin K-dependent carboxylase.
The carboxylase is an integral membrane glycoprotein that uses vitamin K to modify clusters of glutamyl residues (glu's) to gamma-carboxylated glutamyl residues (gla's) post-translationally in vitamin K-dependent (VKD) proteins as they pass through the endoplasmic reticulum. Carboxylation is required for VKD protein functions in hemostasis, bone metabolism, growth control and signal transduction. Carboxylation of multiple glu residues is accomplished via a processive mechanism, which occurs with at least some order and involves carboxylation of the carboxylase. The carboxylase has a high affinity binding site for VKD proteins, which in most cases is a VKD propeptide sequence; it also appears to have a low affinity site for those glu's undergoing catalysis. The propeptide activates binding of the glu's; together, the two contact points between the carboxylase and VKD protein increase the affinity of the carboxylase for vitamin K. Biochemical mapping to identify where these events occur in the carboxylase remains a challenge, despite the availability of recombinant protein. The affinity of the carboxylase for the propeptide of several VKD proteins that are coexpressed in liver varies over a 100-fold range. Treatment with anticoagulants such as warfarin that indirectly block carboxylation likely decreases the rate of VKD protein catalysis and increases the accumulation of VKD precursors, leading to a competitive state among these proteins, which results in the premature dissociation of undercarboxylated, inactive protein.
Department of Molecular Cardiology/NB50, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
K L
KL
Berkner
D000818:Animals; D001665:Binding Sites; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D011498:Protein Precursors / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification; D014812:Vitamin K / Q000502:physiology*
D011498:Protein Precursors; D011994:Recombinant Proteins; D014812:Vitamin K; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase