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STRUCTURAL BIOLOGY

5-LOX inhibition by natural products

Nature Chemical Biology volume 16, pages 714–715 (2020)Cite this article

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The enzyme 5-lipoxygenase (5-LOX) initiates the biosynthesis of leukotrienes (LT), potent mediators of the inflammatory response. The first crystal structures of two complexes of inhibitor bound to 5-LOX reveal the functional consequences of the binding, including a change in the regiospecificity toward a 12/15-lipoxygenating enzyme.

In particular, the authors were interested in the redox-type inhibitor nordihydroguaiaretic acid (NDGA), thought to bind in the active site, and the allosteric inhibitor 3-acetyl-11- keto-β-boswellic acid (AKBA). Consistent with their two different inhibitory mechanisms, NDGA and AKBA bound to different 5-LOX sites. Whereas NDGA was lodged in the active site, AKBA was found at a unique location outside of the active site, causing disruption of a highly conserved cation–π interaction in the catalytic domain. Strikingly, when the authors monitored the effects of NDGA and AKBA on classical enzymatic products formed from AA, they detected an alteration in the regiospecificity of the enzyme toward a 12/15-lipoxygenating enzyme. This change in regiospecificity of 5-LOX promotes direct SPM formation.

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Fig. 1: 5-LOX catalyzes the conversion of AA to LT through the formation of 5-HETE as an intermediate.

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  1. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República and Centro de Investigaciones Biomédicas (CEINBIO), Montevideo, Uruguay

    Homero Rubbo & Irene Wood

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  1. Homero Rubbo
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  2. Irene Wood
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Correspondence to Homero Rubbo.

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The authors declare no competing interests.

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Rubbo, H., Wood, I. 5-LOX inhibition by natural products. Nat Chem Biol 16, 714–715 (2020). https://doi.org/10.1038/s41589-020-0568-z

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  • DOI: https://doi.org/10.1038/s41589-020-0568-z

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