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- Title
Substrate Specificity for Isomerase Activity of Macrophage Migration Inhibitory Factor and Its Inhibition by Indole Derivatives1.
- Authors
Suzuki, Masaki; Sugimoto, Hiroshi; Tanaka, Isao; Nishihira, Jun
- Abstract
Macrophage migration inhibitory factor (MIF) was discovered as a cytokine that inhibits random migration of macrophages and concentrates them at inflammatory loci. We recently reported the tertiary structure of MIF, and revealed its similarity to that of 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, MIF was found to have isomerase activity converting D-dopachrome, a stereoisomer of naturally-occurring L-dopachrome, to 5,6-dihydroxyindole-2-carboxylic acid. In this study, we examined the effects of a series of compounds analogous to D-dopachrome on the enzyme activity to obtain vital information for identification of a natural substrate of MIF. Adrenochrome, lacking a carboxyl group at position 2 of the indolinequinone ring, could not be a substrate. Several indole-ring-containing compounds with a carboxyl group were inhibitory to D-dopachrome isomerase activity, of which indole-3-acrylic acid was the most potent inhibitor, with an inhibitor constant (K1) of 2.8 mM. 2,3-Indol inedione, which lacks a complete indole ring or a carboxyl group but has carbonyl groups at positions 2 and 3, apparently inhibited the enzyme activity in a competitive or mixed manner with a K1 of 0.9 mM. Taken together, these facts suggest that the 2-carboxyl group of the substrate is essential for interaction with the active site of MIF.
- Subjects
EMIGRATION &; immigration; ISOMERASES; MACROPHAGE migration inhibitory factor; CARBOXYLIC acids; DOPACHROME tautomerase
- Publication
Journal of Biochemistry, 1997, Vol 122, Issue 5, p1040
- ISSN
0021-924X
- Publication type
Article
- DOI
10.1093/oxfordjournals.jbchem.a021844