The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents.
Macrophage migration inhibitory factor (MIF) is an immunoregulatory protein that is a potential therapeutic target for a number of inflammatory diseases. Evidence exists that an unexpected catalytic active site of MIF may have a biological function. To gain further insight into the role of the catalytic active site, a series of mutational, structural, and biological activity studies were performed. The insertion of an alanine between Pro-1 and Met-2 (PAM) abolishes a non-physiological catalytic activity, and this mutant is defective in the in vitro glucocorticoid counter-regulatory activity of MIF. The crystal structure of MIF complexed to (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of MIF d-dopachrome tautomerase activity, reveals that ISO-1 binds to the same position of the active site as p-hydroxyphenylpyruvic acid, a substrate of MIF. ISO-1 inhibits several MIF biological activities, further establishing a role for the catalytic active site of MIF.
Lubetsky
Jodi B
JB
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Dios
Angeles
A
Han
Jialian
J
Aljabari
Bayan
B
Ruzsicska
Bela
B
Mitchell
Robert
R
Lolis
Elias
E
Al-Abed
Yousef
Y
D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D016718:Arachidonic Acid; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase