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The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators

Abeysinghe, RD; Roberts, PJ; Cooper, CE; MacLean, KH; Hider, RC; Porter, JB; (1996) The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J BIOL CHEM , 271 (14) 7965 - 7972. Gold open access

Abstract

The mechanisms of lipoxygenase inhibition by iron chelators have been investigated in human neutrophils and in isolated soybean lipoxygenase. Their Fe(III)-containing active sites have been targeted by synthesizing novel bidentate chelators from the hydroxypyridinone family sufficiently small to gain access through the hydrophobic channels of lipoxygenase. In stimulated human neutrophils, release of [H-3]arachidonate-labeled eicosanoids is dependent on the lipid solubility of hydroxypyridinones, but larger hexadentate chelators have no effect on this or on total cellular leukotriene B-4 production, Lipophilic hydroxypyridinones inhibit 5-lipoxygenase at equivalent concentrations to the established inhibitor, piriprost, and show additional but minor anti-phospholipase A(2) activity. Soybean 15-lipoxygenase inhibition is also dependent on the lipid solubility and coordination structure of chelators. Inhibition is associated with the formation of chelate-iron complexes, which are removed by dialysis without restoration of enzyme activity. Only after adding back iron is activity restored. Electron paramagnetic resonance studies show the removal of the iron center signal (g = 6) is concomitant with formation of Fe(III)-chelator complexes, identical in spectral shape and g value to 3:1 hydroxypyridinone Fe(III) complexes. Removal of iron is not the only mechanism by which hydroxypyridinones can inhibit lipoxygenase in intact cells, however, as a lipophilic non-iron-binding hydroxypyridinone, which shows no inhibition of the soybean lipoxygenase activity, partially inhibits 5-lipoxygenase in intact neutrophils without inhibiting neutrophil phospholipase A(2).

Type: Article
Title: The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators
Open access status: An open access publication
Publisher version: http://www.jbc.org/content/early/recent/0
Keywords: LEUKOTRIENE SYNTHESIS, HUMAN 5-LIPOXYGENASE, SUPEROXIDE PRODUCTION, ARACHIDONIC-ACID, INHIBITORS, BIOSYNTHESIS, RESIDUES, PROTEIN, MUTAGENESIS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/91643
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