Mechanism of inhibition of iodothyronine-5'-deiodinase by thioureylenes and sulfite.
Previous studies have demonstrated that thiouracil inhibits the 5'-deiodination of 3,3',5'-triiodothyronine uncompetitively with respect to substrate and competitively with respect to cofactor (thiol compounds). This paper shows that sulfite is also a strong inhibitor of this reaction showing a dose-dependent effect between 1 microM and 1 mM. The mode of inhibition is similar to that described for thiouracil. Dose-dependent inhibition was also observed with thiosulfate (0.01-1 mM), iodide and thiocyanate (both greater than 1 mM). No effect was exerted by up to 10 mM cyanide and up to 100 mM azide. Methimazole and thiourea were weak inhibitors above 0.1 mM but inhibition did not reach completion. These experiments were carried out in the presence of 1 mM dithiothreitol. The effect of thiouracil was found to be competitively obviated by methimazole and thiourea. However, the effect of sulfite and that of methimazole or thiourea were additive. It is proposed that an enzyme-sulfenyl iodide is formed during deiodination (ping-pong mechanism). This sulfenyl iodide may be reduced by cofactor to yield native enzyme. It may also react with thioureylenes, yielding mixed disulfides, or with sulfite, yielding a thiosulfate. The enzyme-methimazole disulfide is apparently less stable than the enzyme-thiouracil complex. It is suggested that sulfite also reacts with the enzyme-thioureylene disulfide.
D000818:Animals; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D008713:Methimazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D051381:Rats; D013447:Sulfites / Q000494:pharmacology*; D013889:Thiouracil / Q000494:pharmacology; D014285:Triiodothyronine, Reverse / Q000378:metabolism
D013447:Sulfites; D008713:Methimazole; D014285:Triiodothyronine, Reverse; D013889:Thiouracil; D010544:Peroxidases; D007453:Iodide Peroxidase