Origins of the Selective C−S Bond Formation by the Non-Heme Iron EgtB

The nonheme iron EgtB and OvoA are sulfoxide synthases that catalyze oxidative C−S bond formation in the synthesis of ergothioneine and ovothiol. Despite the extensively experimental and computational studies of the catalytic mecha-nisms of these enzymes, the root causes for the selective C−S bond formation remains elusive. Using combined molecu-lar dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) method, we show here that coordination dynamics of the sulfoxide intermediate is involved in the catalysis of nonheme iron EgtB. Such coordina-tion switch from S to O atom is driven by the S/ electrostatic interactions, which promotes efficiently the observed stereoselective C-S bond formation while bypassing cysteine dioxygenation. As such, the present mechanism high-lights the critical role of coordination dynamics in catalysis, and it is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results.