Title
Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products
Document Type
Article
Publication Date
7-1-2020
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 Source (Journal or Book title)
Nature chemical biology
First Page
783
Last Page
790
Recommended Citation
Gilbert, N. C., Gerstmeier, J., Schexnaydre, E. E., Börner, F., Garscha, U., Neau, D. B., Werz, O., & Newcomer, M. E. (2020). Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products. Nature chemical biology, 16 (7), 783-790. https://doi.org/10.1038/s41589-020-0544-7