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In Vitro Cytochrome P450 46A1 (CYP46A1) Activation by Neuroactive Compounds

Published

Author(s)

Natalia Mast, Kyle Anderson, Kevin Johnson, Thanh Phan, F. Peter Guengerich, Irina A. Pikuleva

Abstract

Cytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) is the central nervous system-specific enzyme responsible for the majority of cholesterol elimination from the brain. Previously we found that CYP46A1 could be activated pharmacologically in mice by the anti-HIV medication efavirenz (EFV). Herein, we investigated whether CYP46A1 could be activated by endogenous compounds, namely by the major neurotransmitters. All studies were conducted in vitro using purified recombinant CYP46A1. CYP46A1 was activated by L-glutamate (Glu), L-aspartate, -aminobutyric acid, and acetylcholine with Glu eliciting the highest, 3-fold increase in enzyme-mediated cholesterol 24-hydroxylation. The characterizations of Glu binding to CYP46A1 revealed that Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which is, however, different from the site of EFV binding. The other principal differences between EFV and Glu in CYP46A1 activation included an apparent lack of Glu binding to the P450 active site and involvement of different secondary structural elements in signal transduction from the allosteric site to the active site. Each, EFV and Glu, similarly increased the CYP46A1 kcat, the rate of the "fast" phase of the enzyme reduction by the redox partner cytochrome P450 oxidoreductase, and the amount of reduced P450; the maximal amplitude of the CYP46A1 spectral response was reduced in the presence of EFV or Glu in titrations with cholesterol. When both were present, EFV and Glu had a synergistic effect on CYP46A1 activation. Collectively, our in vitro data and cell culture/in vivo studies by others suggest that CYP46A1 activation by Glu may be of physiological relevance.
Citation
Journal of Biological Chemistry

Citation

Mast, N. , Anderson, K. , Johnson, K. , Phan, T. , Guengerich, F. and Pikuleva, I. (2017), In Vitro Cytochrome P450 46A1 (CYP46A1) Activation by Neuroactive Compounds, Journal of Biological Chemistry, [online], https://doi.org/10.1074/jbc.M117.794909, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=923493 (Accessed June 12, 2024)

Issues

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Created June 21, 2017, Updated October 12, 2021