Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

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, whereas the larger inhibitor 23d blocks the enzyme active site.

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

“…Surprisingly, tail-modified AA derivatives result in both different target specificity as well as activating or inhibiting effects. Compounds bearing alkoxy substituents as in PK147 constituting a branched tail direct the inhibitory activity towards 5-lipoxygenase (residual activity: 50% at 50 µM PK147), whereas PK131 with an unbranched fully saturated but shortened tail inverts the biological effect and acts as 5-lipoxygenase activator (150% at 50 µM)[156].…”

Exploring allosteric activation of LigAB from Sphingobium sp. strain SYK-6 through kinetics, mutagenesis and computational studies

“…This suggests that a heteroallosteric feed-forward activation (FFA) mechanism may be at work in this pathway. Enzymes that are subject to allosteric activation described in the literature can have rate enhancements from 11% [57] ranging to systems that absolutely require the activator to have any activity [58]. The phenomena of allosteric activation by a metabolic precursor has not been previously reported for a non-heme iron intradiol or extradiol dioxygenase of any type (Type I, II or III), and rate enhancement by small molecule effectors of any kind has been reported in only two instances for dioxygenases in general.…”

Microsporols A-C from the Plant Endophytic Fungus Pestalotiopsis microspora

“…The fermented rice substrate was extracted with EtOAc (5 × 500 mL), and the organic solvent was evaporated to dryness under reduced pressure to afford a crude extract (5.0 g), which was fractionated by silica gel VLC using petroleum ether (PE)-CH [15]: Compounds 1, 3, and 4 were tested for their inhibitory effects against human 5-LOX. The human 5-LOX enzyme was diluted 1꞉4000 with 50 mM Tris buffer (pH 7.5) containing 2 mM each of EDTA and CaCl 2 .…”