Semiempirical simulation of a theta‐class glutathione S‐transferase‐catalyzed glutathione attack to the allelochemical DIMBOA

We evaluated by the semiempirical method PM3 possible mechanisms of a putative interaction between a cereal allelochemical, the cyclic hydroxamic acid 2,4‐dihydroxy‐7‐metoxy‐2 H ‐1,4‐benzoxazin‐3(4 H )‐one (DIMBOA), and the tripeptide glutathione (GSH) inside the active site of a theta‐class glutathione S‐transferase. Based on a preliminary study of transition states from DIMBOA reactions with methanethiolate as a simple model of GSH, we investigated the roles of catalytic residues of the enzyme during nucleophilic additions of GSH to the carbonyl groups of DIMBOA and of its phenol/aldehyde isomer inside the active site model. Our results suggest that a tyrosine residue, Tyr113, makes the most important contributions for the catalytic mechanism. In the modeled reaction steps, Tyr113 behaves as a double hydrogen bond donor catalyst for nucleophilic additions of GSH to substrates: It initially helps stabilize the strongly nucleophilic reduced GSH with a hydrogen bond intermediated by a water molecule; during substrate approach, small conformational changes enable the residue to make a direct hydrogen bond to the substrate group that develop negative charge after addition of reduced GSH. © 2002 Wiley Periodicals, Inc.; Int J Quantum Chem, 2002