The paradoxical effect of increasing of the final yield of reaction product during inhibition of self-inactivating bifunctional enzyme prostaglandin H synthase by nonsteroidal antiinflammatory drugs

Barkhatov, V.; Krivoshey, A.; Efremov, A.; Matveishina, E.; Panova, V.; Vrzheshch, P.

Авторы: Barkhatov V., Krivoshey A., Efremov A., Matveishina E., Panova V., Vrzheshch P.
Журнал: FEBS open bio
Том: 11
Номер: S1
Год издания: 2021
Издательство: John Wiley & Sons Inc.
Местоположение издательства: United States
Первая страница: 452
Последняя страница: 453
DOI: 10.1002/2211-5463.13205
Аннотация: Dimeric enzyme prostaglandin H synthase (PGHS) catalyzes two sequential reactions – cyclooxygenase (COX) reaction and peroxidase (POX) reaction – in prostaglandin biosynthesis. PGHS undergo irreversibly inactivation during both catalyzed reactions. COX reaction is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). There is some evidence of interactions between active sites of PGHS and subunits in PGHS dimer. In this study, we used the PGHS-1 isoform isolated from sheep vesicular glands. The cyclooxygenase reaction was detected amperometrically by consumption of dissolved molecular oxygen. The peroxidase reaction was detected spectrophotometrically by accumulation of oxidized electron donor. We observed a paradoxical effect of increasing of final yield of COX reaction in presence of some COX inhibitors (naproxen, tolmetin, ibuprofen, and fenoprofen but not for indomethacin, diclofenac) while the initial rate predictably decreased. It is consistent with the discovery of the negative cooperativity for naproxen (previously published in: Filimonov IS et al. (2018) Biochemistry (Mosc) 83, 119–128) and tolmetin. This paradoxical effect can be explained by slower inactivation of the second enzyme subunit during the reaction in case of association of an inhibitor molecule with the first subunit. It was also shown that addition of COX inhibitor naproxen increases final yield of POX reaction product while initial rate does not change. It can be explained by allosteric interactions between the active sites of COX and POX reactions within the same subunit. The obtained results should be taken into account when investigating the pharmacological action of NSAIDs in vivo.
Добавил в систему: Кривошей Александр Владимирович

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The paradoxical effect of increasing of the final yield of reaction product during inhibition of self-inactivating bifunctional enzyme prostaglandin H synthase by nonsteroidal antiinflammatory drugsстатья Тезисы

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