Single Amino Acid Change in Metallothionein Metal-Binding Cluster Influences Interaction with Cisplatin

Abstrakt

The issue of tumour cell resistance to anticancer drugs is a major problem in the treatment of this grave disease and it is still not satisfactorily explained. Its base lies in the interaction of a cytostatic with biomolecules synthesized by tumour cells.

One of the generally accepted mechanisms of resistance to some metal based cytostatics is the overexpression of metallothionein in tumour cells. In this study, electrochemical profile of interaction between 23 sulphur-rich fragments of the metal-binding protein metallothionein and cisplatin was studied.

To evaluate the results, interaction constants were suggested. Here, we found that the maximum increased interaction (more than 100 %) occurred, when conservative aminoacids were substituted for more than one position outside the cysteine cluster.

On the contrary, amino acid substitution within the cysteine cluster led to a reduction in interaction constants (up to 10-25% of average). This result clearly indicates that aminoacids outside cysteine binding motif are of high importance for interactions of metallothionein with cisplatin.

Based on the results it can be assumed that the substitution of individual aminoacids in the peptide chain of protein markedly influences the interaction with cisplatin, which could be used for designing new types of cytostatics.