Recently, Associate Professor Jianqiang Xu's team unveiled the molecular mechanism of selenoenzyme catalysis, contributing to the understanding of the structural and functional aspects of intracellular anticancer targets. The related findings were published in the top journal Redox Biology in the field of biology.
In the realm of redox biology, cytoplasmic thioredoxin reductase stands out as a crucial selenoenzyme for maintaining the redox balance within higher organisms' cells, with its redox-active site playing a pivotal role. Previous studies have shown that the orientation loop proximal to the selenoenzyme's carboxy terminus spatially approaches the redox motif, influencing carboxy terminus activity, substrate binding, inhibitor binding, and electron transfer.
This study, through site-directed mutagenesis of the orientation loop structure, revealed that alterations in the orientation loop sequence affect selenoenzyme electron flux and enzyme stability, resulting in changes in inhibitor binding and catalytic properties. The research delved into the interaction between membrane pit proteins and selenoenzymes, identifying the orientation loop sequence as a binding motif for membrane pit proteins, capable of binding to their scaffold domain. Additionally, the study validated the binding and inhibitory activity of scaffold domain peptides with selenoenzymes, confirming that the inhibitory effect depends on the integrity of the peptide structure.
Furthermore, the study confirmed that a reversible selenoenzyme inhibitor, LCS3, co-incubated with orientation loop mutants, did not alter enzyme activity, rectifying the inaccurate predictions made by other international laboratories.
Related Paper Information: https://doi.org/10.1016/j.redox.2024.103050
