Re-Interpretation Of Structure-Function Correlations And Inhibitions Of Mammalian Cyclooxygenase Isozymes With Murburn Concept

As per the acclaimed classical mechanism, cyclooxygenase (COX) supposedly has two functional sites: an aqueous phase exposed peroxidase (perox) site and a lipid-phase buried cyclooxygenase (cyclox) site. Peroxidative reaction of heme-Fe at perox site forms a high-potential Compound I species, which supposedly generates a tyrosine radical within the cyclox site via an electron-tunneling mechanism. Thereafter, two molecules of triplet oxygen are purportedly inserted into the bound lipid substrate at cyclox site to yield PGG2. Subsequently, PGG2 is moved to perox site where it is converted to PGH2. Herein, we surveyed diverse COX proteins and tested out in silico binding interactions with various substrates and inhibitors. We found that our ligand-docking results and significant experimental reports in literature support a DRS (diffusible reactive species)-based murburn mechanism, wherein the actual “oxygen-insertion reaction step” may occur beyond the physical constraints of the deep-seated active-site (wherein Fe-O or TyrO species directly interact with the substrates’ C-atom). Further, our interpretations are also supported by the earlier reports that question the wisdom of using “induced fit” type mechanism for fitting the protein’s crystal-structure, by invoking extensive “conformation-change” based explanations. Biomed Rev 2024; 35: 71-113