THE RESPONSE OF COPPER TRANSPORT PROTEINS DURING OXYGEN AND COPPER STRESS

The biosynthesis of copper transport proteins, including both Cu(I)-th ionein and Cu,Zn-superoxide dismutase has been shown to be distinctive ly affected in the presence of rising copper concentrations. A dose an d time-dependent increase, up to 3-fold, of the steady-state level of Cu,Zn-superoxide dismutase mRNA was observed in human K562 cells. A co mparable increase was also observed for actin and ribosomal protein L3 2 mRNAs,but not for metallothionein mRNA which was augmented more than 50-fold and showed a different induction pattern. At the same time el evated copper concentrations in the intestinal tract stimulated the fo rmation of Cu(I)-thionein. Both copper proteins are known to react cat alytically with superoxide k(Cat)/Cu = 10(9) L mol(-1) s(-1) for Cu,Zn -superoxide dismutase and 0.8 x 10(7) L mol(-1) s(-1) in the presence of Cu(I)-thionein. In the latter protein Cu(I)-stabilised thiyl radica ls are the active components. Depending on the chemical environment of either copper-protein, and in the light of this reactivity, the conce ntration of oxygen free radicals is controlled. Uncontrolled transport of hydrated or chelated Cu(II)-ions in the form of freely migrating l ow M-r-complexes must be discarded. As a consequence there would be ma ny undesired reactions of hydroxyl radicals created by Fenton chemistr y that would lead to irreversible destruction of cellular components. By way of contrast, either copper protein proved to be most appropriat e for the controlled transport of copper. Little is known on the relea se of copper from these proteins. Some promising results have been obt ained using Cu(I)-thionein. One of the latest observations includes th e phenomenon that hypothiocyanate, OSCN-, a transiently formed derivat ive of thiocyanate, SCN-, is capable of releasing copper from the Cu(I )thiolate clusters ex vivo. The demetallised protein could be reconsti tuted under reductive conditions. In conclusion both Cu(I)thionein and Cu,Zn-superoxide dismutase are perfectly designed proteins to control both oxygen and copper stress situations.