Structural requirements for the binding of fatty acids to 5-lipoxygenase-activating protein

• Published in: European journal of pharmacology Vol. 267; no. 3; pp. 275 - 280
• Main Authors: Charleson, Stella, Evans, Jilly F., Léger, Serge, Perrier, Hélène, Prasit, Petpiboon, Wang, Zhaoyin, Vickers, Philip J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17.05.1994; Elsevier
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5-Lipoxygenase; 5-Lipoxygenase-activating protein; 5-Lipoxygenase-Activating Proteins; Arachidonic acid; Arachidonic Acid - metabolism; Binding Sites - drug effects; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Fatty acid; Fundamental and applied biological sciences. Psychology; Humans; Hydroxyeicosatetraenoic Acids - pharmacology; Indoles - metabolism; Leukocytes - metabolism; Leukotriene; Leukotrienes - biosynthesis; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Prostaglandins. Arachidonic acid metabolites; Quinolines - metabolism; Radioligand Assay; Vertebrates: endocrinology; 5-Lipoxygenase-activating protein; Leukotriene; Arachidonic acid; Fatty acid; 5-Lipoxygenase; Enzyme; Arachidonic acid derivatives; Lipids; Activation; Fatty acids; Proteins; Biological fixation; Synthesis; Structure activity relation; Oxidoreductases; Lipoxygenase; Mechanism of action
• ISSN: 0922-4106; 0014-2999
• DOI: 10.1016/0922-4106(94)90151-1

5-Lipoxygenase-activating protein is required for cellular leukotriene synthesis and is the target of the leukotriene biosynthesis inhibitors MK-886 (3-[1-( p-chlorophenyl)-5-isopropyl-3- tert-butylthio-1 H0indol2-yl]-2,2-dimethylpropanoic acid) and MK-591 (3-[1-(4-chlorobenzyl)-3-( t-butylthio)-5-(quinolin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid). Recent studies demonstrate that 5-lipoxygenase-activating protein binds arachidonic acid and stimulates the utilization of this substrate by 5-lipoxygenase. The present study utilizes a radioligand binding assay to assess the affinity of 5-lipoxygenase-activating protein for arachidonic acid and the specificity of the fatty acid binding site on 5-lipoxygenase-activating protein. Our findings demonstrate that the presence of a free carboxyl group of fatty acids or leukotriene biosynthesis inhibitors which interact with 5-lipoxygenase-activating protein is not required for specific binding to the protein. However, the degree of saturation significantly affects the affinity of fatty acids for 5-lipoxygenase-activating protein.