MECHANISM OF CYANIDE INHIBITION OF THE BLOOD-CLOTTING, VITAMIN-K-DEPENDENT CARBOXYLASE

Abstract

Cyanide is a competitive inhibitor of carbon dioxide in the vitamin K-dependent glutamate carboxylase system, which plays a central role in the function of the blood clotting cascade. The mechanism of cyanide inhibition has been obscure for some time. At pH 7.2, cyanide (pK(a) = 9.21) will exist in solution as hydrogen cyanide to the extent of 99%. Hydrogen cyanide is a linear triatomic molecule able to serve as a surrogate for carbon dioxide at the enzyme active site. Hydrogen cyanide is an acid; it will quench the deprotonated glutamate carbanion precursor to gamma-carboxyglutamate, resulting in inhibition of the carboxylation sequence.