Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products.
Nat Chem Biol
; 16(7): 783-790, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32393899
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Triterpenos
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Produtos Biológicos
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Araquidonato 5-Lipoxigenase
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Masoprocol
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Inibidores de Lipoxigenase
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article