1.14.14.25: cholesterol 24-hydroxylase
This is an abbreviated version!
For detailed information about cholesterol 24-hydroxylase, go to the full flat file.
Word Map on EC 1.14.14.25
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1.14.14.25
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alzheimer
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24s-hydroxycholesterol
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oxysterols
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cyp27a1
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efavirenz
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24-hydroxylation
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medicine
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27-hydroxylase
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24s-ohc
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epsilon4
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lathosterol
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desmosterol
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cholesterol-metabolizing
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drug development
- 1.14.14.25
- alzheimer
- 24s-hydroxycholesterol
- oxysterols
- cyp27a1
- efavirenz
-
24-hydroxylation
- medicine
-
27-hydroxylase
-
24s-ohc
-
epsilon4
- lathosterol
- desmosterol
-
cholesterol-metabolizing
- drug development
Reaction
Synonyms
24S-hydroxylase, CH24H, cholesterol 24-hydroxylase, cholesterol 24-monooxygenase, cholesterol 24S hydroxylase, cholesterol 24S-hydroxylase, cholesterol hydroxylase, cholesterol-24S-hydroxylase, CYP46, CYP46A, CYP46A1, cytochrome P-450 46A1, cytochrome P450 46A1, cytochrome P450 cholesterol 24-hydroxylase, EC 1.14.13.98
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General Information
General Information on EC 1.14.14.25 - cholesterol 24-hydroxylase
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malfunction
metabolism
physiological function
additional information
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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
malfunction
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a single nucleotide polymorphism the in CYP46A1 gene, designated as rs754203, is a risk factor for glaucoma. The enzyme participates to retinal ganglion cell loss under pathophysiological conditions
malfunction
CYP46A1 expression levels are reduced in Huntington's disease. CYP46A1 protein levels are decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis is implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors
malfunction
knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntingtons 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
malfunction
polymorphisms in the CYP46 gene and CYP46A1 enzyme dysfunction are involved in neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The 24(S)-hydroxycholesterol levels in cerebrospinal fluid are higher in patients with Alzheimer's disease compared to healthy control. CYP46A1 inhibition by voriconazole decreases 24S-hydroxycholesterol levels in the retina and affects cholesterol homeostasis and function in the retina
malfunction
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knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntingtons 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
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CYP46A1 gene variations (rs7157609 and rs4900442) influence the risk factor for Alzheimer's disease via an influence on brain cholesterol metabolism, especially the interaction term of both SNPs and the resulting haplotype reveal a strong association with the risk of Alzheimers disease
metabolism
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cholesterol 24S-hydroxylase is a cholesterol metabolic enzyme with regulatory function in traumatic brain injury, overview
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amyloid precursor protein expression and amyloid plaque deposition in the cortex and hippocampus of male and female Alzheimer's disease mice between the ages of 3 to 15 months are similar in the presence and absence of cholesterol 24-hydroxylase. Loss of one or both cholesterol 24-hydroxylase alleles increases longevity in Alzheimers disease mice. Cholesterol synthetic rates are reduced in animals lacking 24-hydroxylase, and this reduction is specific to cholesterol
physiological function
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cholesterol 24-hydroxylase regulates TrkB activity in mature hippocampal neurons
physiological function
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cholesterol 24-hydroxylase regulates TrkB activity in mature hippocampal neurons
physiological function
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CYP46A1 gene may act to modulate the course of cognitive deterioration in late life. IVS2-150 polymorphism is associated with a higher risk of cognitive deterioration in Chinese older persons. IVS3-128 CC genotype is higher in improved or stable group, suggesting a protective role. Ppolymorphisms IVS1-192 and IVS4-122 do not show any significant association with cognitive function
physiological function
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overexpression of human CYP46A1 gene does not modify the expression of endogenous murine Cyp46A1 gene
physiological function
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polymorphisms in the human gene are linked to neurodegenerative disorders, such as Alzheimer's disease
physiological function
recombinant CYP46A1 is catalytically active when associated with Escherichia coli membranes
physiological function
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selective overexpression of CYP46A1 in neurons can reduce Abeta peptides and amyloid deposits in mouse models of Alzheimer's disease when the overexpression of CYP46A1 is induced before or after the formation of amyloid plaques. Injection of adeno-associated vector encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces Abeta peptides, amyloid deposits and trimeric oligomers at 12 months of age. Neuronal overexpression of CYP46A1 decreases microgliosis and astrocytosis and improves cognitive deficits in APP23 mice. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 mice after the onset of amyloid deposits also reduces markedly the number of amyloid plaques in the hippocampus, and to a less extent in the cortex, 3 months after the injection
physiological function
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the capacity to turn over cholesterol via the cholesterol 24-hydroxylase pathway may be acquired early during development of the central nervous system. The enzyme reduces the excretion of sterols from the brain but does not abolish this removal process
physiological function
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the rs754203 SNP in CYP46A1 is associated with a risk for primary open angle glaucoma. Frequency of the TT-genotype and T-allele in the CYP46A1 intron 2 rs754203 polymorphism is significantly higher in the population of primary open angle glaucom patients compared to control group
physiological function
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24S-hydroxycholesterol and LXR agonist TO-901317 both increase SREBP-1 mRNA levels while 24S-hydroxycholesterol decreases SREBP-2 mRNA levels, real-time PCR quantification, overview
physiological function
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CYP46A1 overexpression enhances spatial memory retention in aged female mice
physiological function
cholesterol 24-hydroxylase controls cholesterol elimination from the brain
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
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
physiological function
cholesterol 24S-hydroxylase converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina
physiological function
mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site, overview
physiological function
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overexpression of human CYP46A1 gene does not modify the expression of endogenous murine Cyp46A1 gene
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physiological function
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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
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physiological function
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cholesterol 24S-hydroxylase converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina
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Cyp46 is upregulated in traumatic brain injury. Membrane damage during traumatic brain injury alters the brain homeostasis of cholesterol and other lipids. Reaction product 24S-hydroxycholesterol decreases mRNA levels of the cholesterol synthesis genes HMG CoA reductase, squalene synthase, and FPP synthase but does not alter levels of the mRNA of fatty acid synthesis genes acetyl CoA carboxylase or fatty acid synthase
additional information
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increased expression of cholesterol 24S-hydroxylase in brain results in disruption of glial glutamate transporter EAAT2 association with lipid rafts with a potential role in Alzheimers disease, overview
additional information
mapping of the binding region for CYP46A1 redox partner oxidoreductase and identification of allosteric and redox partner binding sites which share a common border, by using a combination of hydrogen-deuterium exchange coupled to mass spectrometry, computational modeling, site-directed mutagenesis, and analysis of the CYP46A1 crystal structure, overview. Residues K422 and R424 are important for enzyme activity