The effect of changes in iron redox state on the activity of enzymes sensitive to modification of SH groups.
Iron ions in micromolar concentrations induced a rapid and selective inhibition of the activity of skeletal muscle creatine kinase (CK), sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and pyruvate kinase (PK). This effect of iron was dependent on the presence of adenine nucleotides and on the redox state of iron. Changing the redox state of the media created different Fe2+/Fe3+ ratios which selectively depressed different enzymes: depression of PK activity occurred when iron was predominantly in its reduced form and, consequently, when there was a high Fe2+/Fe3+ ratio; depression of SR Ca2+ uptake and SR Ca(2+)-ATPase activity occurred when the Fe2+/Fe3+ ratio was close to 1; depression of CK activity occurred when iron was predominantly in its oxidized form and the Fe2+/Fe3+ ratio was low. All iron-sensitive enzymes possessed sulfhydryl groups, accessible to N-ethylmaleimide (NEM), which were essential for their activity. The rate of inhibition of enzyme activity with NEM increased in the order PK < Ca(2+)-ATPase < CK. Iron-induced depression of CK and PK activities was reversible by dithiotreithol. Results suggest that changes in the redox state of cellular microenvironments, which inevitably occur during reperfusion of ischemic tissue or rapid increase in tissue oxygen consumption, may selectively depress the activity of several enzymes bearing SH groups that are sensitive to modifications and that are essential for their activity. Iron-induced depression of enzyme activity depends on the availability of iron bound to adenine nucleotides and possibly to other low molecular weight chelators and on the Fe2+/Fe3+ ratio generated by the induced redox change.
Korge
P
P
Department of VCAPP, Washington State University, Pullman 99164.
Campbell
K B
KB
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004789:Enzyme Activation; D004798:Enzymes / Q000187:drug effects / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D005954:Glucosephosphate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D006593:Hexokinase / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D004798:Enzymes; D005290:Ferric Compounds; D005296:Ferrous Compounds; D013438:Sulfhydryl Compounds; D007501:Iron; D007770:L-Lactate Dehydrogenase; D008291:Malate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D006593:Hexokinase; D003402:Creatine Kinase; D000252:Calcium-Transporting ATPases; D003676:Deferoxamine; D005033:Ethylmaleimide; D002118:Calcium