ArticleThe Journal of biological chemistry2016
Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 54 citations in OpenAlex.
- CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Mass spectrometry footprinting reveals microsomal CYP2A6 structural changes induced by interaction with its reductase flavin mononucleotide domain.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Efavirenz treatment improves retinal vaso-obliteration and pathological neovascularization in a mouse model of retinopathy of prematurity.Frontiers in medicine · 2026Article
- Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.Nature metabolism · 2025Article
- Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.JCI insight · 2025Article
- Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation.Journal of xenobiotics · 2025Review
- Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer's Disease Therapeutics.ACS pharmacology & translational science · 2024Review
- Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.Brain : a journal of neurology · 2024Review
- 7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.International journal of molecular sciences · 2024Article
- The translational potential of cholesterol-based therapies for neurological disease.Nature reviews. Neurology · 2023Review
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Cholesterol and its reciprocal association with prion infection.Cell and tissue research · 2023Review
- Efavirenz restored NMDA receptor dysfunction and inhibited epileptic seizures inFrontiers in neuroscience · 2023Article
- Assessment of cholesterol homeostasis in the living human brain.Science translational medicine · 2022Article
- Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs.ACS omega · 2022Article
- Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz.International journal of molecular sciences · 2022Article
- The Hydroxylation Position Rather than Chirality Determines How Efavirenz Metabolites Activate Cytochrome P450 46A1 In Vitro.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Lipids, hyperreflective crystalline deposits and diabetic retinopathy: potential systemic and retinal-specific effect of lipid-lowering therapies.Diabetologia · 2022Review
- Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants.Journal of proteins and proteomics · 2022Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.