Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized. Here we determined the Cu(I)-binding affinities of five major de-coppering drugs – D-penicillamine, trientine, 2,3-dimercapto-1-propanol, meso-2,3-dimercaptosuccinate and tetrathiomolybdate – by exploring their ability to extract Cu(I) ions from two Cu(I)-binding proteins, the copper chaperone for cytochrome c oxidase, Cox17, and metallothionein. We report that the Cu(I)-binding affinity of these drugs varies by four orders of magnitude and correlates positively with the number of sulfur atoms in the drug molecule and negatively with the number of atoms separating two SH groups. Based on the analysis of structure-activity relationship and determined Cu(I)-binding affinity, we hypothesize that the endogenous biologically active substance, α-lipoic acid, may be suitable for the treatment of Wilson disease. Our hypothesis is supported by cell culture experiments where α-lipoic acid protected hepatic cells from copper toxicity. These results provide a basis for elaboration of new generation drugs that may provide better therapeutic outcomes.
Zinc finger ( ZF ) protein motifs, stabilized by binding of Zn( II ), typically function as interaction modules that bind nucleic acids, proteins and other molecules. The elucidation of the redox states of ZF proteins in cellular conditions, which depend on their midpoint redox potentials, is important for understanding of ZF functioning. In the present study we determined the midpoint redox potentials for representatives of Cys 2 His 2 and Cys 4 types of ZF proteins in apo and Zn( II )‐bound forms using electrospray ionization mass spectrometry. The midpoint redox potentials of the apo forms of Cys 2 His 2 and Cys 4 ZF proteins were −326 and −365 mV ( pH 7.5), respectively. These values are close to the cytosolic redox potential of approx. −350 mV ( pH 7.5) and thus we can conclude that the apo form of Cys 2 His 2 ‐type ZF proteins is predominantly reduced but apo forms of Cys 4 ‐type ZF proteins should be substantially oxidized in the cytoplasm. As expected, Zn( II ) binding stabilized the reduced forms of both ZF proteins: the corresponding redox potential values were −284 and −301 mV , respectively. Consequently, binding of Zn( II ) ions to ZF motifs can act as a sensitive switch that activates the functioning of the ZF motifs within the cell, and also protects them from oxidation and can function as part of a redox‐sensitive regulation mechanism of cellular functions.
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