Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2016 Apr 9

PMID 27056331

Citations 35

Authors

Kyle W Anderson

Natalia Mast

Jeffrey W Hudgens

Joseph B Lin

Illarion V Turko

Irina A Pikuleva

Affiliations

Soon will be listed here.

Abstract

Cytochrome P450 46A1 (CYP46A1) is a microsomal enzyme and cholesterol 24-hydroxylase that controls cholesterol elimination from the brain. This P450 is also a potential target for Alzheimer disease because it can be activated pharmacologically by some marketed drugs, as exemplified by efavirenz, the anti-HIV medication. Previously, we suggested that pharmaceuticals activate CYP46A1 allosterically through binding to a site on the cytosolic protein surface, which is different from the enzyme active site facing the membrane. Here we identified this allosteric site for efavirenz on CYP46A1 by using a combination of hydrogen-deuterium exchange coupled to MS, computational modeling, site-directed mutagenesis, and analysis of the CYP46A1 crystal structure. We also mapped the binding region for the CYP46A1 redox partner oxidoreductase and found that the allosteric and redox partner binding sites share a common border. On the basis of the data obtained, we propose the mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site.

Citing Articles

Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer's Disease Therapeutics.

Boyarko B, Podvin S, Greenberg B, Arnold S, Juanes A, van der Kant R ACS Pharmacol Transl Sci. 2024; 7(10):2924-2935.

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7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.

Mast N, Li Y, Pikuleva I Int J Mol Sci. 2024; 25(4).

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Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

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The translational potential of cholesterol-based therapies for neurological disease.

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