The formation of the overoxidized cysteine sulfinic acid in proteins has been connected to be associated with various diseases including cancer and age-related diseases. This post-transitional modification of proteins under oxi- dative stress has been known to be irreversible. However, in eukaryotic, the overoxidation of typical 2-Cys perxoiredoxins (Prxs) to sulfinic acid is reversible via a repair enzyme known as sulfiredoxin (Srx) leading to the regulation of both per- oxide signaling and Prxs chaperon activity. In this study, the molecular modeling techniques including molecular dynam- ics simulations (MD) and the hybrid quantum mechanical/molecular mechanical (QM/MM) approach were used to eluci- date the atomistic details of this unique reaction in sulfur chemistry. Our results support the previous experimentally pro- posed mechanism in which the sulfinic acid oxygen perform an in line direct nucleophilic attack on the γ-phosphate of ATP forming sulfinic acid phosphoryl ester intermediate and ADP, via a low barrier of 16.3 kJ mol-1. Subsequently, the formed intermediate is directly reduced via an SN2 mechanism by the Srx-Cys99 forming thiosulfinate. Our results suggest that the rate-limiting step of the reduction mechanism is associated with the reduction step of the thiosulfinate intermedi- ate. This work significantly improves the current knowledge of this unique reaction, which could contribute to the discov- ery of new groups of antioxidants capable of reducing this irreversible overoxidized state in other proteins.
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