Density Functional Studies on Isomerization of Prostaglandin H₂ to Prostacyclin Catalyzed by Cytochrome P450

Abstract

Reaction mechanisms for the isomerization of prostaglandin H(2) to prostacyclin catalyzed by cytochrome P450 are investigated by the unrestricted Becke's three-parameter plus Lee-Yang-Parr density functional level of theory. The results show that the homolytic O-O bond cleavage of endoperoxide in prostaglandin H(2) is the rate-limiting step and that the isomerization proceeds through proton-coupled electron transfer. We located two reaction pathways through an Fe(IV)-porphyrin intermediate and an Fe(III)-porphyrin pi-cation radical intermediate.

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

“…Yanai and Mori have investigated the isomerization of prostaglandin H 2 to prostacyclin with QM cluster model. It is found that the isomerization catalyzed by a related P450 protein proceeds preferentially (1.3 kcal/mol) via a proton-coupled electron transfer (PCET) mechanism due to its lower activation energy [38]. QM/MM simulations on the P450 BM3 catalytic mechanism have been studied [39].…”

An attempt to evaluate the effect of proton-coupled electron transfer on the H-abstraction step of the reaction between 1,1-dimethylhydrazine and cytochrome P450 compound I

“…Computational studies have also suggested that proton-coupled electron transfer (PCET), which is a process of great importance in chemistry and biochemistry [12,13], operates in several specific steps of P450 reactions, such as the step of Cpd I formation from the precursor Cpd 0 intermediate [4], the C C bond formation in the reaction of P450 StaP [14,15], and the double-bond formation step in the prostacycline biosynthesis catalyzed by CYP8A1 (prostacyclin synthase) [16]. Despite these important contributions of computational chemistry, however, the role of PCET in the H-abstraction process -the most important reaction effected by P450 Cpd I -has yet to be investigated intensively.…”

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…Later, the Yoshizawa group studied the kinetic isotope effect of the C H bond activation of alkane [26,27] and the mechanism of camphor hydroxylation by Cpd I [28]. Since then, P450-catalyzed substrate metabolism has been widely studied using the DFT method, including alkane hydroxylation [28,29], alkene epoxidation [30][31][32][33], aromatic hydroxylation [34][35][36][37][38], S-, N-, O-oxidation and dealkylation [39][40][41][42][43][44], dehalogenation of perhalogenated benzene [45], prostaglandin H 2 isomerization [46], and so on.…”