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 catal...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-07, Vol.277 (28), p.24976-24982
Main Authors: Lubetsky, Jodi B., Dios, Angeles, Han, Jialian, Aljabari, Bayan, Ruzsicska, Bela, Mitchell, Robert, Lolis, Elias, Al-Abed, Yousef
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Arachidonic Acid - antagonists & inhibitors
Binding Sites
Catalytic Domain
Cell Line
Crystallography, X-Ray
dopachrome-isomerase
Enzyme Inhibitors - pharmacology
Glucocorticoids - antagonists & inhibitors
Humans
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - chemistry
Intramolecular Oxidoreductases - metabolism
Isoxazoles - chemistry
Isoxazoles - pharmacology
macrophage migration inhibitory factor
Macrophage Migration-Inhibitory Factors - antagonists & inhibitors
Macrophage Migration-Inhibitory Factors - metabolism
Molecular Structure
Structure-Activity Relationship
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Summary: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 MIFd-dopachrome tautomerase activity, reveals that ISO-1 binds to the same position of the active site asp-hydroxyphenylpyruvic acid, a substrate of MIF. ISO-1 inhibits several MIF biological activities, further establishing a role for the catalytic active site of MIF.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M203220200