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Published on: November 28, 2015
Ketone bodies affect the enzymatic activity of macrophage migration inhibitory factor
János Garai1, Tamás Lóránd, Valéria Molnár
1Department of Pathophysiology, University of Pécs, Medical School, Pécs, H-7624 Pécs, Szigeti u. 12, Hungary.
Abstract:
Macrophage migration inhibitory factor (MIF), a long known proinflammatory cytokine exhibits perplexing enzymatic activities: tautomeric conversion of D-dopachrome and phenylpyruvate. Whether these catalytic activities bear functional relevance regarding MIF's multifaceted roles is under current scrutiny. Nevertheless, intense search has already started for pharmacological agents that target MIF's tautomerase activity. We have probed several antiinflammatory compounds against keto--enol (enolase) and enol--keto (ketonase) conversion of phenylpyruvate by MIF with spectrophotometry. We have identified acidic CH groups as markers of inhibitor potency toward MIF phenylpyruvate tautomerase. Among simple model molecules with strong acidic CH groups we found acetylacetone the best inhibitor particularly against the ketonase activity. Ketones of physiological importance - ketone bodies - also feature acidic CH groups and have been reported to exert certain anti-inflammatory effects. In this paper we report that ketone bodies inhibit preferentially the ketonase activity of MIF in vitro. Future studies should address whether such an interaction might operate in vivo and delineate its possible relevance concerning cytokine and non-cytokine roles of MIF.
Insights
Macrophage migration inhibitory factor (MIF) has enzymatic activity. Ketone bodies, containing acidic CH groups, were found to preferentially inhibit MIF
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine.
- MIF possesses enzymatic activities, including tautomerase activity, which is a target for drug development.
- The functional relevance of MIF's catalytic activities is under investigation.
Purpose of the Study:
- To investigate the inhibitory effects of anti-inflammatory compounds on MIF's phenylpyruvate tautomerase activity.
- To identify structural features of inhibitors that correlate with potency against MIF tautomerase.
- To explore the potential of ketone bodies as inhibitors of MIF's enzymatic activity.
Main Methods:
- Spectrophotometry was used to assay MIF's keto-enol and enol-keto conversion of phenylpyruvate.
- Various anti-inflammatory compounds and model molecules were tested for inhibitory effects.
- The role of acidic CH groups in inhibitor potency was analyzed.
Main Results:
- Acidic CH groups were identified as markers of inhibitor potency against MIF phenylpyruvate tautomerase.
- Acetylacetone demonstrated significant inhibition, particularly of the ketonase activity.
- Ketone bodies were found to preferentially inhibit the ketonase activity of MIF in vitro.
Conclusions:
- The study identifies acidic CH groups as key features for inhibiting MIF's tautomerase activity.
- Ketone bodies show potential as preferential inhibitors of MIF's ketonase activity.
- Further in vivo studies are needed to confirm the relevance of these findings for MIF's biological roles.
