Abstract
Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Allosteric Site
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Arachidonate 5-Lipoxygenase / chemistry*
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Arachidonate 5-Lipoxygenase / genetics
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Arachidonate 5-Lipoxygenase / metabolism
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Biological Products / chemistry*
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Biological Products / metabolism
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Catalytic Domain
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Cloning, Molecular
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Crystallography, X-Ray
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Humans
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Hydroxyeicosatetraenoic Acids / chemistry
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Hydroxyeicosatetraenoic Acids / metabolism
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Leukotriene B4 / chemistry
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Leukotriene B4 / metabolism
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Lipoxygenase Inhibitors / chemistry*
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Lipoxygenase Inhibitors / metabolism
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Masoprocol / chemistry*
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Masoprocol / metabolism
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Models, Molecular
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Substrate Specificity
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Triterpenes / chemistry*
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Triterpenes / metabolism
Substances
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Biological Products
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Hydroxyeicosatetraenoic Acids
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Lipoxygenase Inhibitors
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Recombinant Proteins
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Triterpenes
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acetyl-11-ketoboswellic acid
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Leukotriene B4
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5-hydroxy-6,8,11,14-eicosatetraenoic acid
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Masoprocol
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Arachidonate 5-Lipoxygenase
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ALOX5 protein, human