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Department of Molecular Cardiology/NB50, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
The carboxylase is an integral membrane glycoprotein that uses
vitamin K to modify clusters of glutamyl residues (glu’s) to
-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.
KEY WORDS: • vitamin K • vitamin K–dependent carboxylase
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