Abstract
It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. In the present study, we use phenol as a model compound to investigate the mechanism by which the peroxidase activity of human COXs is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interaction of phenol with the peroxidase site of COXs and the reactivation mechanism. It is found that the oxygen atom associated with the Fe ion in the heme group (i.e., the complex of Fe ion and porphyrin) of COXs can be removed by addition of two protons. Following its removal, phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme. This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site.
Highlights
It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood
We find that either the binding energies between phenol molecule and PPIX+FeIV=O are positive, or the distances between phenol’s oxygen and the FeIV ion are longer than 5 Å, which indicate that the presence of the Fe=O group in P PIX+FeIV=O would prevent the binding of phenol or phenol ion inside the peroxidase active site close to the heme group (Fig. 1, Table 1)
We further test the possibility of whether phenol in its non-ionized or ionized state can be docked inside the peroxidase active sites of COX-1 and COX-2 when the O atom is absent in the Fe=O group
Summary
It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. Phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site. The COX-1 and COX-2 enzymes have two functionally-coupled active sites: the cyclooxygenase site that converts arachidonic acid (AA) to prostaglandin G2 (PGG2), and the peroxidase site that catalyzes the reaction which reduces PGG2 to prostaglandin H 2 (PGH2) These two catalytic activities are linked in a proposed branched model[6], in which hydroperoxide is required to initiate the catalytic cycle by oxidizing the resting heme group. Detailed molecular orbital analysis of reaction 1 is shown in Scheme 2
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