Density Functional Studies on Thromboxane Biosynthesis: Mechanism and Role of the Heme‐Thiolate System

Reaction mechanisms for the isomerization of prostaglandin H₂ to thromboxane A₂, and degradation to 12‐L‐hydroxy‐5,8,10‐heptadecatrienoic acid (HHT) and malondialdehyde (MDA), catalyzed by thromboxane synthase, were investigated using the unrestricted Becke‐three‐parameter plus Lee–Yang–Parr (UB3LYP) density functional level theory. In addition to the reaction pathway through Fe^IV‐porphyrin intermediates, a new reaction pathway through Fe^III‐porphyrin π‐cation radical intermediates was found. Both reactions proceed with the homolytic cleavage of endoperoxide O? O to give an alkoxy radical. This intermediate converts into an allyl radical intermediate by a C? C homolytic cleavage, followed by the formation of thromboxane A₂ having a 6‐membered ring through a one electron transfer, or the degradation into HHT and MDA. The proposed mechanism shows that an iron(III)‐containing system having electron acceptor ability is essential for the 6‐membered ring formation leading to thromboxane A₂. Our results suggest that the step of the endoperoxide O? O homolytic bond cleavage has the highest activation energy following the binding of prostaglandin H₂ to thromboxane synthase.