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Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.

Mast N, White MA, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA
Proc Natl Acad Sci U S A 105 9546-51 (2008)
Cited: 63 times
EuropePMC logo PMID: 18621681

Abstract

By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-A structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-A resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B'-C loop insertion (residues 116-120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics.

Reviews - 2q9g mentioned but not cited (1)

  1. Conformational plasticity and structure/function relationships in cytochromes P450. Pochapsky TC, Kazanis S, Dang M. Antioxid Redox Signal 13 1273-1296 (2010)

Articles - 2q9g mentioned but not cited (7)

  1. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Mast N, White MA, Bjorkhem I, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA. Proc Natl Acad Sci U S A 105 9546-9551 (2008)
  2. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. Mast N, Charvet C, Pikuleva IA, Stout CD. J Biol Chem 285 31783-31795 (2010)
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  6. In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds. Mast N, Verwilst P, Wilkey CJ, Guengerich FP, Pikuleva IA. J Med Chem 63 6477-6488 (2020)
  7. Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants. Kaur K, Devi B, Agrawal V, Kumar R, Sandhir R. J Proteins Proteom 13 227-245 (2022)


Reviews citing this publication (14)

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  15. Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1. Mast N, Zheng W, Stout CD, Pikuleva IA. Mol Pharmacol 84 86-94 (2013)
  16. Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. Anderson KW, Mast N, Hudgens JW, Lin JB, Turko IV, Pikuleva IA. J Biol Chem 291 11876-11886 (2016)
  17. Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy. Mast N, Lin JB, Pikuleva IA. Mol Pharmacol 88 428-436 (2015)
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  35. N,N-Dimethyl-3β-hydroxycholenamide Reduces Retinal Cholesterol via Partial Inhibition of Retinal Cholesterol Biosynthesis Rather Than its Liver X Receptor Transcriptional Activity. El-Darzi N, Astafev A, Mast N, Saadane A, Lam M, Pikuleva IA. Front Pharmacol 9 827 (2018)
  36. Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols. van Lier JE, Mast N, Pikuleva IA. Angew Chem Int Ed Engl 54 11138-11142 (2015)
  37. Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [11C]CO2 fixation method. Chen Z, Chen J, Mast N, Rong J, Deng X, Shao T, Fu H, Yu Q, Sun J, Shao Y, Josephson L, Collier TL, Pikuleva I, Liang SH. Bioorg Med Chem Lett 30 127068 (2020)
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Related citations provided by authors (1)

  1. Use of complementary cation and anion heavy-atom salt derivatives to solve the structure of cytochrome P450 46A1.. White MA, Mast N, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA Acta Crystallogr D Biol Crystallogr 64 487-95 (2008)

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