Unraveling the molecular details of the complete mechanism that governs the synthesis of prostaglandin G2 catalyzed by cyclooxygenase-2
Cebrián Prats, Anna (Universitat Autònoma de Barcelona. Departament de Química)
González-Lafont, Àngels (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Departament de Química)

Data:	2019
Resum:	Cyclooxygenase-2 (COX-2) is the key enzyme involved in the synthesis pathway of prostaglandin G₂ (PGG₂) by transformation of arachidonic acid (AA). Although COX-₂ is one of the principal pharmacological targets by the implication of PGG₂2 in several human diseases, the classical all-radical mechanism proposed for COX-₂ catalysis has never been validated at the molecular level. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations were combined to analyze the six steps of the all-radical mechanism. The results show that O₂ addition on C₁₁ of AA can follow an antarafacial or suprafacial approach with respect to tyrosine 385, but only the antarafacial addition leads to the product with the correct 11R stereochemistry as established in the mechanistic proposal. Moreover, only the reaction pathway coming from the antarafacial intermediate describes a viable 8,12-cyclization to form the prostaglandin-like bicyclo endoperoxide that finally leads, by kinetic control, to PGG₂ with the 15S stereochemistry found experimentally. The formation of the more stable trans ring isomer of natural PGG₂ in an enzymatic environment is also explained. Our molecular analysis shows how COX-2 uses its relatively narrow channel in the active site to restrain certain conformational changes of AA and of the reaction intermediates, so that the PGG2 enzymatic synthesis turns out to be highly regiospecific and stereospecific. A more recent 10-step carbocation-based mechanistic proposal has been discarded.
Ajuts:	Agencia Estatal de Investigación CTQ2017-83745-P
Nota:	This is an open access article published under an ACS AuthorChoice License. See Standard ACS AuthorChoice/Editors' Choice Usage Agreement
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Hydrogen ; Carbon ; Oxygen ; Molecular structure ; Potential energy
Publicat a:	ACS omega, Vol. 4, issue 1 (Jan. 2019) , p. 2063-2074, ISSN 2470-1343

DOI: 10.1021/acsomega.8b03575

12 p, 4.0 MB

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