Destroy and Exploit: Catalyzed Removal of Hydroperoxides from the Endoplasmic Reticulum
Figure 4
Suggested reaction mechanisms of GPx7. (a) Following peroxide-mediated oxidation of the active site Cys (C57), sulfenylated C57 is either directly subjected to nucleophilic attack by a (deprotonated) Cys in the reducing substrate (PDIs/GRP78) or attacked by (deprotonated) Cys86, which results in formation of an intramolecular disulfide bond. In a second step, this intramolecular disulfide is attacked by a Cys in the reducing substrate. Both pathways converge in the formation of an intermolecular disulfide-bonded intermediate between GPx7 and the reducing substrate prior to the completion of the reaction cycle, which gives rise to regenerated, reduced GPx7 and oxidized PDIs/GRP78. (b) Hypothesized conformational change prior to formation of a Cys57–Cys86 disulfide bond in GPx7 is depicted on the structure of reduced GPx7 (PDB ID 2KIJ). Active site rearrangement upon oxidation of Cys57 might involve a stacking interaction between the conserved aromatic side chains of Phe89 and Trp142 (green), which would move away Trp142 from Cys57 (dashed white arrow).
