As predicated, Tyr103 and Glu115 facilitated the transfer of oxygen atom to DMS via the formation of hydrogen bond (Fig. S2A). The Phe73 and Trp74 increased the binding of DMS to the pocket via the hydrophobic force. To validate this model, three single site mutants (Cys72Ser, Tyr103Ala, and Glu115Ala) were built. The peroxidase activity was measured by the ability to scavenge hydroxyl radicals in EPR tests (Fig. 1E). Notably, mutagenesis of Cys72 strongly diminished the peroxidase activity (Cys72Ser: 2 ± 2% of wild‐type), while the catalytic activity of Tyr103Ala and Glu115Ala decreased remarkably to 74 ± 6% and 67 ± 6% of wild‐type (P < 0.01), respectively, indicating that Cys72 is the most critical one among these three residues. Furthermore, it was found that the predicted key residues (Cys72, Tyr103, and Glu115) were conservative in various organisms (Fig. S1), indicating that this catalytic mechanism may exist extensively.