A quantum chemical study of the synthesis of prostaglandin G₂ by the cyclooxygenase active site in prostaglandin endoperoxide H synthase 1

The mechanism for prostaglandin G₂ synthesis in the cyclooxygenase active site of prostaglandin H synthase has been investigated using hybrid density functional theory (B3LYP). The calculations show that the six-step radical mechanism for the transformation of arachidonic acid to prostaglandin G₂ suggested by Hamberg and Samuelsson is energetically feasible. The overall driving force for the reaction starting with the arachidonic acid and the active-site tyrosyl radical is estimated to be about 37 kcal/mol, and two barriers are found to be about 15 kcal/mol, in good agreement with the experimental rate corresponding to a barrier of 14.8 kcal/mol. Competing reactions are also investigated.