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Published on: July 21, 2021
Cofactor-specific modulation of 11beta-hydroxysteroid dehydrogenase 1 inhibitor potency
Bhavana Sahni-Arya1, Michael J Flynn, Laurie Bergeron
1Department of Chemical Enzymology, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, USA.
Biochimica Et Biophysica Acta
|August 21, 2007
Summary
Researchers investigated the reaction mechanism and inhibition of 11beta-hydroxysteroid dehydrogenase 1 (11β-HSD1). Inhibitor interactions with the cofactor NADP(H) determined selectivity for reductase versus dehydrogenase activity, impacting potential in vivo effects.
Area of Science:
- Biochemistry
- Enzymology
- Pharmacology
Background:
- 11beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is crucial for regulating tissue cortisol levels.
- This enzyme interconverts cortisone and cortisol, acting as both a reductase and dehydrogenase.
- Understanding 11β-HSD1's mechanism and inhibition is key for developing targeted therapies.
Purpose of the Study:
- To elucidate the reaction mechanism of soluble human 11β-HSD1.
- To investigate the inhibition patterns of three distinct classes of 11β-HSD1 inhibitors.
- To determine how inhibitor binding to the cofactor NADP(H) influences enzyme activity and selectivity.
Main Methods:
- Studied the reaction mechanism of soluble human 11β-HSD1.
- Utilized three different classes of selective inhibitors (Compound A, B, and C).
- Analyzed inhibitor binding kinetics in relation to NADP(H) and steroid binding.
Main Results:
- Catalysis proceeds via an ordered mechanism with NADP(H) binding before the steroid.
- All inhibitors bound to the steroid pocket but exhibited differential interactions with NADP(H).
- Compound A favored the NADPH-bound enzyme, Compound B was unaffected by NADP(H), and Compound C preferred the NADP+ -bound form.
Conclusions:
- Inhibitor interactions with NADP(H) dictate selectivity for inhibiting 11β-HSD1's reductase or dehydrogenase activity.
- This cofactor-dependent selectivity offers potential for differential therapeutic outcomes in vivo.
- The findings provide insights into rational drug design for modulating 11β-HSD1 activity.
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