Cholesterol 24-hydroxylase

UniProt Q9Y6A2 Organism Homo sapiens Gene CYP46, CYP46A1 EC 1.14.14.25

Also known as: CYP46, CYP46A1

Function

P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation. By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning (By similarity). Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis. Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain. May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole.

Classification

Family (Pfam): PF00067 p450
InterPro: CYP46A1, Cyt_P450, Cyt_P450_CS, Cyt_P450_E_grp-I, Cyt_P450_sf
Functional cluster: Secreted Growth Factors & Cytokines

Experimental structures · PDB · 21

2Q9F X-ray 1.90A
2Q9G X-ray 2.40A
3MDM X-ray 1.60A
3MDR X-ray 2.00A
3MDT X-ray 2.30A
3MDV X-ray 2.40A
4ENH X-ray 2.50A
4FIA X-ray 2.10A
4J14 X-ray 2.50A
7LRL X-ray 2.00A
7LS3 X-ray 2.15A
7LS4 X-ray 2.05A
… and 9 more

A predicted model is available from AlphaFold.

Gene Ontology · 19

Drugs targeting this protein · 1

SOTICLESTAT inhibitor

Related proteins · sequence + function similarity

Cholesterol 24-hydroxylase 1.00
Cytochrome P450 4A7 0.89
Cytochrome P450 4A5 0.88
Cytochrome P450 4A25 0.88
Taurochenodeoxycholic 6 alpha-hydroxylase 0.88
Cytochrome P450 4A4 0.88
Cytochrome P450 4A6 0.88
Cytochrome P450 4A24 0.86
Cytochrome P450 4A11 0.86
Cytochrome P450 4A22 0.86
Cytochrome P450 4B1 0.85
Cytochrome P450 4B1 0.83

Co-cited proteins · studied together in the literature

Cholesterol 24-hydroxylase 2 shared papers
Sterol 26-hydroxylase, mitochondrial 2 shared papers
Cytochrome P450 7A1 1 shared papers
Sterol 26-hydroxylase, mitochondrial 1 shared papers

Literature · 11 cited papers

Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum. J. Biol. Chem. · 2017
Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450 46A1. J. Lipid Res. · 2014
Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response. J. Biol. Chem. · 2013
Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J. Biol. Chem. · 2010
Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. U.S.A. · 2008
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. · 2004
Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry · 2003
The DNA sequence and analysis of human chromosome 14. Nature · 2003
Metabolism of 4 beta -hydroxycholesterol in humans. J. Biol. Chem. · 2002
cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc. Natl. Acad. Sci. U.S.A. · 1999

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