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Information on EC 1.14.14.25 - cholesterol 24-hydroxylase and Organism(s) Mus musculus and UniProt Accession Q9WVK8

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IUBMB Comments
A P-450 heme-thiolate protein. The enzyme can also produce 25-hydroxycholesterol. In addition, it can further hydroxylate the product to 24,25-dihydroxycholesterol and 24,27-dihydroxycholesterol . This reaction is the first step in the enzymic degradation of cholesterol in the brain as hydroxycholesterol can pass the blood---brain barrier whereas cholesterol cannot . The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase .
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Mus musculus
UNIPROT: Q9WVK8
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Word Map
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
Synonyms
cyp46a1, cyp46, cholesterol 24-hydroxylase, cytochrome p450 46a1, cholesterol 24s-hydroxylase, cholesterol-24s-hydroxylase, ch24h, 24s-hydroxylase, cyp46a, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cholesterol 24S-hydroxylase
-
-
CYP46
-
-
cytochrome P450 cholesterol 24-hydroxylase
-
-
PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
cholesterol,NADPH-hemoprotein reductase:oxygen oxidoreductase (24-hydroxylating)
A P-450 heme-thiolate protein. The enzyme can also produce 25-hydroxycholesterol. In addition, it can further hydroxylate the product to 24,25-dihydroxycholesterol and 24,27-dihydroxycholesterol [2]. This reaction is the first step in the enzymic degradation of cholesterol in the brain as hydroxycholesterol can pass the blood---brain barrier whereas cholesterol cannot [3]. The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase [3].
CAS REGISTRY NUMBER
COMMENTARY hide
213327-78-7
-
50812-30-1
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
-
-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
show the reaction diagram
cholesterol + reduced adrenodoxin + O2
24-hydroxycholesterol + oxidized adrenodoxin + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
24-hydroxylation represents an important pathway by which cholesterol is secreted from the brain. The enzyme contributes little to overall bile acid synthesis but is important in the turnover of cholesterol in the brain
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
-
-
-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
show the reaction diagram
-
the enzyme is important in cholesterol metabolism in the brain, cholesterol dynamics in the fetal and neonatal brain, overview
the product is able to travers the blood-brain barrier, while the substrate is not, transport, and excretion of (24S)-hydroxycholesterol, oxycholesterol transport mechanisms, overview
-
?
cholesterol + reduced adrenodoxin + O2
24-hydroxycholesterol + oxidized adrenodoxin + H2O
show the reaction diagram
-
enzyme deficiency leads to a suppression of the mevalonate pathway and a defect in learning
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-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P-450
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-
NADPH
cytochrome P450
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a cytochrome P450 enzyme
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Fe2+
-
a cytochrome P450 enzyme
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
shRNA
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knockdown
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siRNA
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reduction of the cholesterol 24-hydroxylase, which results in lower levels of Trk phosphorylation
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voriconazole
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voriconazole-induced visual disturbances related to an interaction between the drug and retinal CYP46A1
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
Cyp46A1 mRNA and CYP46A1 protein levels are decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines
Manually annotated by BRENDA team
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cerebellar interneurons and Purkinje cells
Manually annotated by BRENDA team
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pyramidal neurons
Manually annotated by BRENDA team
-
in the cerebellum
Manually annotated by BRENDA team
-
ganglion cells
Manually annotated by BRENDA team
-
small amounts, mRNA does not appear to be translated into protein in the testis
Manually annotated by BRENDA team
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington’s disease phenotype, with spontaneous striatal neuron degeneration and motor deficits. CYP46A1 expression levels are reduced in Huntington's disease. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreases neuronal atrophy, decreases the number, intensity level and size of expansion in huntingtin aggregates and improves motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restores levels of cholesterol and lanosterol and increases levels of desmosterol
physiological function
cholesterol 24-hydroxylase is the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol, regulation of cholesterol homeostasis by CYP46A1. In vitro, CYP46A1 restoration protects SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death
malfunction
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disruption of the cholesterol 24-hydroxylase gene causes an 50% decrease in cholesterol turnover, which is compensated for by an equal decrease in the rate of de novo cholesterol synthesis. Mice lacking cholesterol 24-hydroxylase show that whole-body fatty acid and cholesterol metabolism are normal. Profound learning disabilities in cholesterol 24-hydroxylase-deficient mice are often caused by gross anatomical defects in the subregions of the brain implicated in the behavior. A minimal concentration of 0.2 mM geranylgeraniol is required to restore LTP in hippocampal slices from knockout mice
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
CP46A_MOUSE
500
0
56814
Swiss-Prot
Secretory Pathway (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
56821
x * 56821, calculation from nucleotide sequence
53000
-
immunoblotting
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 56821, calculation from nucleotide sequence
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene CYP46A1, CYP46A1 restoration protects from Exp-HTT-induced striatal dysfunctions in vitro. CYP46A1 restoration in the striatum improves the motor phenotype of R6/2 mice
DNA sequence determination and analysis
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expressed in 293 cells
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full ORF expression clone p46+ including the full cyp46A1 mouse open reading frame. Cyp46A1 overexpressed in 10 days in vitro hippocampal neurons
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gene CYP46A1, expressionin CHO-K1 cells and HEK-293 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
age-associated increase in TrkB activity correlates with a mild yet progressive loss of cholesterol, which, in turn, correlates with increased expression of the cholesterol catabolic enzyme cholesterol 24-hydroxylase. Increased expression of cholesterol-24-hydroxylase in the hippocampus of aged mice
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expression of the gene in the mouse embryo as early as day 11.5 and gradual increase in mRNA and protein in postnatal brain. Over a 14-day culture period, during which the neurons extend processes and form increasing numbers of synapses but do not divide, there is a gradual increase in cholesterol 24-hydroxylase mRNA and protein
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intraperitoneal injection of a high dose of valproate (700 mg/kg) results in a modest induction of the mRNA expression of CYP46A1 in the liver, and CYP46A1 in the brain. Intraperitoneal injection of trichostatin A to male mice results in dose dependent increases in the expression of brain and liver CYP46A1
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Russell, D.W.
Oxysterol biosynthetic enzymes
Biochim. Biophys. Acta
1529
126-135
2000
Mus musculus (Q9WVK8), Homo sapiens (Q9Y6A2)
Manually annotated by BRENDA team
Lund, E.G.; Xie, C.; Kotti, T.; Turley, S.D.; Dietschy, J.M.; Russell, D.W.
Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover
J. Biol. Chem.
278
22980-22988
2003
Mus musculus
Manually annotated by BRENDA team
Lund, E.G.; Guileyardo, J.M.; Russell, D.W.
cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain
Proc. Natl. Acad. Sci. USA
96
7238-7243
1999
Homo sapiens (Q9Y6A2), Homo sapiens, Mus musculus (Q9WVK8), Mus musculus
Manually annotated by BRENDA team
Luetjohann, D.
Cholesterol metabolism in the brain: importance of 24S-hydroxylation
Acta Neurol. Scand.
114 (Suppl. 185)
33-42
2006
Homo sapiens, Mus musculus, Sus scrofa
Manually annotated by BRENDA team
Kotti, T.J.; Ramirez, D.M.; Pfeiffer, B.E.; Huber, K.M.; Russell, D.W.
Brain cholesterol turnover required for geranylgeraniol production and learning in mice
Proc. Natl. Acad. Sci. USA
103
3869-3874
2006
Mus musculus
Manually annotated by BRENDA team
Ramirez, D.M.; Andersson, S.; Russell, D.W.
Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain
J. Comp. Neurol.
507
1676-1693
2008
Mus musculus
Manually annotated by BRENDA team
Russell, D.W.; Halford, R.W.; Ramirez, D.M.; Shah, R.; Kotti, T.
Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain
Annu. Rev. Biochem.
78
1017-1040
2009
Bos taurus, Canis lupus familiaris, Cavia porcellus, Danio rerio (A5WWJ0), Equus caballus, Equus sp., Gallus gallus, Homo sapiens, Macaca mulatta, Mus musculus, Ornithorhynchus anatinus, Oryctolagus cuniculus, Pan troglodytes, Rattus norvegicus, Xenopus laevis (Q7SYY2)
Manually annotated by BRENDA team
Shafaati, M.; O'Driscoll, R.; Bjoerkhem, I.; Meaney, S.
Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors
Biochem. Biophys. Res. Commun.
378
689-694
2009
Homo sapiens, Mus musculus, Mus musculus C57B6-J
Manually annotated by BRENDA team
Shafaati, M.; Mast, N.; Beck, O.; Nayef, R.; Heo, G.Y.; Bjoerkhem-Bergman, L.; Lutjohann, D.; Bjoerkhem, I.; Pikuleva, I.A.
The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase (CYP46A1) in vitro and in vivo
J. Lipid Res.
51
318-323
2010
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Martin, M.G.; Perga, S.; Trovo, L.; Rasola, A.; Holm, P.; Rantamaeki, T.; Harkany, T.; Castren, E.; Chiara, F.; Dotti, C.G.
Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro
Mol. Biol. Cell
19
2101-2112
2008
Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Hudry, E.; Van Dam, D.; Kulik, W.; De Deyn, P.P.; Stet, F.S.; Ahouansou, O.; Benraiss, A.; Delacourte, A.; Bougneres, P.; Aubourg, P.; Cartier, N.
Adeno-associated Virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimers disease
Mol. Ther.
18
44-53
2010
Homo sapiens, Mus musculus, Mus musculus APP23
Manually annotated by BRENDA team
Halford, R.W.; Russell, D.W.
Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimers disease, but does extend lifespan
Proc. Natl. Acad. Sci. USA
106
3502-3506
2009
Mus musculus
Manually annotated by BRENDA team
Boussicault, L.; Alves, S.; Lamaziere, A.; Planques, A.; Heck, N.; Moumne, L.; Despres, G.; Bolte, S.; Hu, A.; Pages, C.; Galvan, L.; Piguet, F.; Aubourg, P.; Cartier, N.; Caboche, J.; Betuing, S.
CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntingtons disease
Brain
139
953-970
2016
Homo sapiens (Q9Y6A2), Homo sapiens, Mus musculus (Q9WVK8), Mus musculus, Mus musculus C57BL/6 (Q9WVK8)
Manually annotated by BRENDA team