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Publication Abstract from PubMed

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 A 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.

Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products.,Gilbert NC, Gerstmeier J, Schexnaydre EE, Borner F, Garscha U, Neau DB, Werz O, Newcomer ME Nat Chem Biol. 2020 May 11. pii: 10.1038/s41589-020-0544-7. doi:, 10.1038/s41589-020-0544-7. PMID:32393899^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.