Abstract
It has been reported that Paulistine in the venom of the wasp Polybia paulista co-exists as two different forms: an oxidized form presenting a compact structure due to the presence of a disulfide bridge, which causes inflammation through an apparent interaction with receptors in the 5-lipoxygenase pathway, and a naturally reduced form (without the disulfide bridge) that exists in a linear conformation and which also causes hyperalgesia and acts in the cyclooxygenase type II pathway. The reduced peptide was acetamidomethylated (Acm-Paulistine) to stabilize this form, and it still maintained its typical inflammatory activity. Oxidized Paulistine docks onto PGHS2 (COX-2) molecules, blocking the access of oxygen to the heme group and inhibiting the inflammatory activity of Acm-Paulistine in the cyclooxygenase type II pathway. Docking simulations revealed that the site of the docking of Paulistine within the PGHS2 molecule is unusual among commercial inhibitors of the enzyme, with an affinity potentially much higher than those observed for traditional anti-inflammatory drugs. Therefore, Paulistine causes inflammatory activity at the level of the 5-lipooxygenase pathway and, in parallel, it competes with its reduced form in relation to the activation of the cyclooxygenase pathway. Thus, while the reduced Paulistine causes inflammation, its oxidized form is a potent inhibitor of this activity.
Highlights
The venoms of the social Hymenoptera insects are part of their chemical arsenal for defensive purposes
A simulation of the docking of both forms of the peptide with prostaglandin-endoperoxide synthase 2 (PGHS2) revealed an unusual interaction between the enzyme and the oxidized form of Paulistine, suggesting the potential use of this peptide as a model for the rational development of a novel drug to be used as an analgesic and/or an anti-inflammatory drug for processes caused by the activation of the cyclooxygenase type II pathway
(purple) docked at their binding site in the substrate channel of catalytic subunit of PGHS2 docked at their binding site in the substrate channel of catalytic subunit of PGHS2 represented by represented ribbon diagrams
Summary
The venoms of the social Hymenoptera insects are part of their chemical arsenal for defensive purposes. The binding of non-substrate fatty acids can potentiate/attenuate the effects of PGHS2 inhibitors, depending on the type of fatty acids and whether the inhibitor binds to the catalytic or allosteric subunit [15] Despite evidence that it is a homodimer, it was reported that PGHS2 functions as a conformational heterodimer, i.e., one of the monomers is considered the catalytic one, while the other (iii) a C‐terminal catalytic domain. A simulation of the docking of both forms of the peptide with PGHS2 revealed an unusual interaction between the enzyme and the oxidized form of Paulistine, suggesting the potential use of this peptide as a model for the rational development of a novel drug to be used as an analgesic and/or an anti-inflammatory drug for processes caused by the activation of the cyclooxygenase type II pathway.
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