Mechanism of action of t-butyl hydroperoxide in the inhibition of vitamin K-dependent carboxylation☆
1982
Abstract t-Butyl hydroperoxide has been studied as a possible competitive inhibitor of the vitamin K-dependent
carboxylationof the pentapeptide PheLeuGluGluIle. Under standard
carboxylatingconditions the concentrations of reduced phylloquinone and phylloquinone were followed by high-pressure liquid chromatography during 30-min incubations of Triton-solubilized microsomes from rat liver. Under these conditions supporting linear rates of carbon dioxide fixation for 20–30 min, the vitamin KH 2 concentration decreased exponentially to less than 5% of its initial value in 30 min principally due to autooxidation. In the presence of 10 m m t-butyl-OOH, however, the oxidation of vitamin KH 2 was greatly accelerated with none being detected after 7 min. In general, the rate of
carboxylationof peptide paralleled the KH 2 concentration. After cessation of
carboxylationin the presence of t-butyl-OOH the readdition of KH 2 stimulated additional 14 CO 2 fixation. A known competitive inhibitor of vitamin K, 2-chlorophylloquinone, did not accelerate the oxidation of KH 2 but nonetheless inhibited the vitamin K-dependent
carboxylationin a competitive manner. These data have led us to conclude that t-butyl-OOH is not a competitive inhibitor of the
vitamin K-dependent carboxylaseat the active site of the enzyme but merely acts to promote the oxidation of KH 2 .
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