Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection |
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Authors: | Rosalina Wisastra Petra AM Kok Nikolaos Eleftheriadis Matthew P Baumgartner Carlos J Camacho Hidde J Haisma Frank J Dekker |
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Institution: | 1. Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;2. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, United States |
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Abstract: | Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a KA of 8.65 μM, αKA of 0.38 μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid binding, whereas the larger inhibitor 23d blocks the enzyme active site. |
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Keywords: | Human 5-lipoxygenase Anacardic acid Cyclooxygenase-2 Enzyme kinetics Allosteric binding |
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