Interactions of inhibitors of the lipoxygenase and cyclooxygenase pathways with a supplementary binding site on soybean lipoxygenase.
The oxygenation of [1-14C]-arachidonic acid by a soluble soybean lipoxygenase (E.C.1.13.11.12) preparation was determined in the presence of various cyclo-oxygenase and lipoxygenase inhibitors. The results showed that several non-inhibitory compounds drastically blunted the inhibitory potency of potent lipoxygenase inhibitors. Studies on the combined effects of a variety of structurally unrelated inhibitors of lipoxygenase, cyclo-oxygenase or both oxygenation pathways provided strong evidence for the existence of a supplementary binding site on soybean lipoxygenase which reduces the effective interactions of inhibitors with the catalytic site. Thus several cyclo-oxygenase inhibitors (which do not inhibit at the lipoxygenase catalytic site), as well as low concentrations of lipoxygenase inhibitors, interact with this putative supplementary site and blunt the inhibitory efficacy of potent lipoxygenase inhibitors. Although the degree of interaction with the catalytic site determines the absolute potency of inhibitors, the additional interaction at the putative supplementary binding site is also obligatory for inhibitory potency. In this new multiple-site model the potent lipoxygenase inhibitors (e.g. acetone phenylhydrazone, phenidone) possess high affinities for both sites, whereas weak inhibitors and certain cyclo-oxygenase inhibitors (e.g. benoxaprofen, phenylbutazone, indomethacin) interact predominantly with the supplementary site on the lipoxygenase but lack affinity for the catalytic site.
D001665:Binding Sites; D002396:Catechols / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013025:Glycine max / Q000201:enzymology
D002396:Catechols; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011720:Pyrazoles; C011677:benoxaprofen; D009637:Masoprocol; C015429:phenidone