Inhibition of vitamin K-dependent carboxylase by metal ions and metal complexes: a reassessment.
The vitamin K-dependent enzymatic carboxylation of glutamyl residues in blood protein precursors and in synthetic peptides is inhibited in vitro by transition metal complexes. Some authors suggested it is a result of metal ions interaction with intermediary oxygenated species. Using an oxygraph we have observed increases in the rate of oxygen utilization in the carboxylating system containing reduced vitamin K after addition of some transition metal ions and complexes. Kinetic studies indicate that, although oxygen utilization is increased by the addition of Cu2+, Fe3+, and hematin, the initial rate of carboxylation is not affected. The rate of carboxylation rapidly decreases at oxygen concentrations below 50 microM and reaches zero when oxygen is depleted. UV spectroscopy revealed simultaneous acceleration of the conversion of vitamin K hydroquinone into the parent quinone. The magnitude of these effects, as well as carboxylation inhibition, depends on the oxidation potential of the complexed ion and its lipophilicity. Addition of stable Mn parallel ion, which has no inhibitory effect on carboxylation, does not increase the rate of oxygen utilization nor the hydroquinone oxidation. The results suggest that inhibition of carboxylation by transition metals is mainly due to depletion of the necessary components (oxygen, vitamin K hydroquinone) of the carboxylating system rather than quenching of activated, oxygen-containing intermediates.
D000818:Animals; D019735:Carbon-Carbon Ligases; D066298:In Vitro Techniques; D008025:Ligases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D008297:Male; D008670:Metals / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000378:metabolism
D008670:Metals; C028843:vitamin K1 hydroquinone; D010837:Vitamin K 1; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase