A catalytic intermediate of PRX3 is a molecular target of thiostrepton.

(A) Superposition of human Prx2 and bovine Prx3. The monomers of the Prx2 and Prx3 dimer are shown in blue/light blue and green/light green, respectively. The sulfur atoms of the Cys residues are shown as spheres. (B) Proximity of Cys residues. All Cys residues are conserved. The residue numbers indicated are for human Prx2/Prx3. Distances shown are in Angstroms. PDB codes 1QMV and 1ZYE. Note that the C-terminus of Prx3 is disordered and not shown. (C) Model for TS adduction of Prx3. During the PRX3 reaction cycle the formation of a disulfide bond at one catalytic dyad promotes local unfolding. We propose that this conformation change favors adduction of Cys108 and Cys229 in the neighboring catalytic center by TS, leading to an irreducible, crosslinked PRX3 dimer and loss of peroxidase activity. Pro-oxidant compounds such as gentian violet, Mito-CP or arsenic trioxide and oxidative stress increase the level of PRX3 disulfide-bonded dimers and promote adduction by TS. Dimedone attacks sulfenic acid moieties and blocks disulfide formation, thereby blocking modification of PRX3. Similarly, mutant forms of PRX3 lacking the peroxidatic or resolving cysteines are not targets of TS.