Open AccessDynamics of Radical Intermediates in Prostaglandin H Synthase-1 Cyclooxygenase Reactions is Modulated by Multiple Factors
Author(s) -
Gang Wu,
Alan C. Tsai
Publication year - 2016
Publication title -
protein and peptide letters/protein and peptide letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 58
eISSN - 1875-5305
pISSN - 0929-8665
DOI - 10.2174/0929866523666161007151812
Subject(s) - chemistry , arachidonic acid , hydroxyl radical , prostaglandin h2 , radical , photochemistry , substrate (aquarium) , heme , stereochemistry , cyclooxygenase , prostaglandin , atp synthase , radical ion , oxygen , hydrogen atom abstraction , peroxidase , enzyme , biochemistry , organic chemistry , ion , oceanography , geology
Prostaglandin H synthase (PGHS) catalyzes the biosynthesis of PGG2 and PGH2, the precursor of all prostanoids, from arachidonic acid (AA). PGHS exhibits two enzymatic activities following a branched-chain radical mechanism: 1) a peroxidase activity (POX) that utilizes hydroperoxide through heme redox cycles to generate the critical Tyr385 tyrosyl radical for coupling both enzyme activities; 2) the cyclooxygenase (COX) activity inserting two oxygen molecules into AA to generate endoperoxide/hydroperoxide PGG2 through a series of radical intermediates. Upon the generation of Tyr385 radical, COX catalysis is initiated, with C13 pro-S hydrogen abstraction from AA by Tyr385 radical to generate arachidonyl substrate radical. Oxygen provides a large driving force for the subsequent fast steps leading to the formation of PGG2, including radical redistributions, ring formations, and rearrangements. On the other hand, if the supply of oxygen is severed, equilibrium between arachidonyl radical and tyrosyl radical(s) biases largely towards the latter. In this study, we demonstrate that such equilibrium is shifted by many factors, including temperature, chemical structures of fatty acid substrates and limited supply of oxygen. We also, for the first time, reveal that this equilibrium is significantly affected by co-substrates of POX. The presence of efficient POX co-substrates, which reduces heme to its ferric state, apparently biases the equilibrium towards arachidonyl radical. Therefore a dynamic interplay exists between the two activities of PGHS.