Regular Article

Theoretical Chemistry Accounts

, Volume 128, Issue 2, pp 191-206

First online:

Theoretical studies on model reaction pathways of prostaglandin H2 isomerization to prostaglandin D2/E2

  • Naoto YamaguchiAffiliated withGraduate School of Science and Engineering, Ibaraki UniversityVALWAY Technology Center, NEC Soft, LtdNational Security Solutions Division, NEC Corporation
  • , Tatsuya NaikiAffiliated withGraduate School of Science and Engineering, Ibaraki UniversityFaculty of Science, Ibaraki University
  • , Takamitsu KohzumaAffiliated withGraduate School of Science and Engineering, Ibaraki UniversityFrontier Research Center for Applied Atomic Sciences, Ibaraki University
  • , Toshikazu TakadaAffiliated withNEC CorporationResearch and Development Program for Next-Generation Computational Research, RIKEN
  • , Fumihiko SakataAffiliated withGraduate School of Science and Engineering, Ibaraki University
  • , Seiji MoriAffiliated withGraduate School of Science and Engineering, Ibaraki UniversityFaculty of Science, Ibaraki UniversityFrontier Research Center for Applied Atomic Sciences, Ibaraki University Email author 

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Abstract

Model reaction mechanisms in the biosynthesis of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) from prostaglandin H2 with PGD2/E2 synthase were examined using the ab initio second-order Møller–Plesset perturbation method and density functional theory. The reaction was modeled similar to the isomerization of 2,3-dioxabicyclo[2.2.1]heptane to 3-hydroxycyclopentanone in the presence of MeS. An explicit solvation of two H2O molecules was also considered, and two probable types of reaction mechanisms were demonstrated. One mechanism starts with proton abstraction from an oxygen-bound carbon at the endoperoxide by a thiolate ion and the other is stepwise and involves attack of a thiolate anion on an oxygen of the endoperoxide group in the first step with protonation of the other oxygen, followed by deprotonation from a carbon-attached oxygen to break an O–S bond to yield PGD2 or PGE2. We also found that the mPW1LYP hybrid method was superior to the B3LYP functional for systems with respect to the state-of-the-art CCSD(T) energetics.

Keywords

Prostaglandin H2 Prostaglandin D2 Prostaglandin E2 Prostaglandin D2 synthase Prostaglandin E2 synthase Model reaction mechanisms mPW1LYP hybrid functional