Information on EC 1.14.13.98 -

Information on EC 1.14.13.98 - cholesterol 24-hydroxylase:

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EC NUMBER	COMMENTARY
1.14.13.98	-

RECOMMENDED NAME	GeneOntology No.
cholesterol 24-hydroxylase	GO:0033781

REACTION	REACTION DIAGRAM	COMMENTARY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
cholesterol + NADPH + H+ + O2 = (24S)-24-hydroxycholesterol + NADP+ + H2O		-	-	-	-
cholesterol + NADPH + H+ + O2 = (24S)-24-hydroxycholesterol + NADP+ + H2O		-	Homo sapiens	-	657671
cholesterol + NADPH + H+ + O2 = (24S)-24-hydroxycholesterol + NADP+ + H2O		structure-function relationship	Homo sapiens	-	673298

REACTION TYPE	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
oxidation	Homo sapiens	-	-	657671
redox reaction	Homo sapiens	-	-	657671
reduction	Homo sapiens	-	-	657671

PATHWAY	KEGG Link	MetaCyc Link
No entries in this field

SYSTEMATIC NAME	IUBMB Comments
cholesterol,NADPH:oxygen oxidoreductase (24-hydroxylating)	A heme-thiolate protein (P-450). 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 enzymatic degradation of cholesterol in the brain as hydroxycholesterol can pass the blood---brain barrier whereas cholesterol cannot [3].

SYNONYMS	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
CH24H	Homo sapiens	-	-	660012
cholesterol 24-hydroxylase	Homo sapiens	-	-	698342
cholesterol 24-hydroxylase	Rattus norvegicus	-	-	712120
cholesterol 24-monooxygenase	Homo sapiens	-	-	657671
cholesterol 24S hydroxylase	Rattus norvegicus	-	-	688555
cholesterol 24S-hydroxylase	Homo sapiens	-	-	657671, 704109, 705008, 711641, 712816
cholesterol 24S-hydroxylase	Mus musculus	-	-	705008
CYP46	Homo sapiens	-	-	657671, 658159, 660011, 705920, 711641, 712816
CYP46	Rattus norvegicus	-	-	688555, 712120
CYP46	Mus musculus	-	-	706536
CYP46A1	Homo sapiens	-	-	657671, 659374, 659516, 671173, 673298, 689814, 695874, 698342, 701715, 702028, 703580, 704109, 705008, 705825, 712869
CYP46A1	Mus musculus	-	-	671173, 687987, 701715, 702028, 705008, 705612, 705825
CYP46A1	Sus scrofa	-	-	671173
CYP46A1	Rattus norvegicus	-	-	701715, 705612
CYP46A1	Bos taurus, Canis lupus familiaris, Cavia porcellus	-	-	701715
CYP46A1	Danio rerio	A5WWJ0	-	701715
CYP46A1	Equus caballus, Equus sp., Gallus gallus, Macaca mulatta, Ornithorhynchus anatinus, Oryctolagus cuniculus, Pan troglodytes	-	-	701715
CYP46A1	Xenopus laevis	Q7SYY2	-	701715
cytochrome P-450 46A1	Homo sapiens	-	-	657671
cytochrome P450 46A1	Homo sapiens	-	-	657971, 689814, 695874
cytochrome P450 cholesterol 24-hydroxylase	Homo sapiens	-	-	702028, 703580
cytochrome P450 cholesterol 24-hydroxylase	Mus musculus	-	-	702028

CAS REGISTRY NUMBER	COMMENTARY
213327-78-7	-
50812-30-1	-

ORGANISM	COMMENTARY	LITERATURE	SEQUENCE CODE	SEQUENCE DB	SOURCE
Bos taurus	-	701715	-	-
Bos taurus	calf	686258	-	-
Canis lupus familiaris	-	701715	-	-
Cavia porcellus	-	701715	-	-
Danio rerio	-	701715	A5WWJ0	UniProt
Equus caballus	-	701715	-	-
Equus sp.	zebra	701715	-	-
Gallus gallus	-	701715	-	-
Homo sapiens	-	657671, 657971, 659374, 659516, 660011, 660012, 671173, 673298, 698342, 701715, 702028, 703580, 704109, 705008, 705825, 705920, 711641, 712816	-	-
Homo sapiens	-	658159, 660401, 689814, 695874, 712869	Q9Y6A2	SwissProt
Homo sapiens	gene CYP46A1	684856	-	-
Macaca mulatta	-	701715	-	-
Mus musculus	-	658159, 660401	Q9WVK8	SwissProt
Mus musculus	-	659216, 671173, 676852, 687987, 705008, 705612, 706536	-	-
Mus musculus	APP23 mouse	705825	-	-
Mus musculus	C57/B6-J mice	702028	-	-
Mus musculus	C57BL/6J and 129S6/SvEv mice	701715	-	-
Mus musculus APP23	APP23 mouse	705825	-	-
Mus musculus C57/B6-J	C57/B6-J mice	702028	-	-
Ornithorhynchus anatinus	-	701715	-	-
Oryctolagus cuniculus	-	701715	-	-
Pan troglodytes	-	701715	-	-
Rattus norvegicus	-	701715, 705612, 712120	-	-
Rattus norvegicus	Sprague-Dawley rats	688555	-	-
Rattus norvegicus	Wistar rats	675535, 686258	-	-
Sus scrofa	-	671173	-	-
Xenopus laevis	-	701715	Q7SYY2	UniProt

GENERAL INFORMATION	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
malfunction	Mus musculus	-	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	701715
metabolism	Homo sapiens	-	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 Alzheimer�s disease	703580
physiological function	Homo sapiens	-	recombinant CYP46A1 is catalytically active when associated with Escherichia coli membranes	695874
physiological function	Homo sapiens	-	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	698342
physiological function	Homo sapiens	-	polymorphisms in the human gene are linked to neurodegenerative disorders, such as Alzheimer's disease	701715
physiological function	Mus musculus	-	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	701715
physiological function	Homo sapiens	-	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	704109
physiological function	Mus musculus	-	visual disturbances in CYP46A1 gene knockout mice	705008
physiological function	Mus musculus, Rattus norvegicus	-	cholesterol 24-hydroxylase regulates TrkB activity in mature hippocampal neurons	705612
physiological function	Homo sapiens	-	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	705825
physiological function	Mus musculus	-	overexpression of human CYP46A1 gene does not modify the expression of endogenous murine Cyp46A1 gene	705825
physiological function	Mus musculus	-	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 Alzheimer�s disease mice. Cholesterol synthetic rates are reduced in animals lacking 24-hydroxylase, and this reduction is specific to cholesterol	706536
physiological function	Homo sapiens	-	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	711641
metabolism	Homo sapiens	-	cholesterol 24S-hydroxylase is a cholesterol metabolic enzyme with regulatory function in traumatic brain injury, overview	711641
additional information	Homo sapiens	-	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	711641
additional information	Homo sapiens	-	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	712816

SUBSTRATE	PRODUCT	REACTION DIAGRAM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY/ Substrate	LITERATURE/ Substrate	COMMENTARY/ Product	LITERATURE/ Product	Reversibility r=reversible ir=irreversible ?=not specified
(24S)-24-hydroxycholesterol + NADPH + O2	24,25-dihydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	657671, 657971	-	-	?
(24S)-24-hydroxycholesterol + NADPH + O2	24,27-dihydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	657671, 657971	-	-	?
(24S)-hydroxycholesterol + NADPH + O2	24,25-dihydroxycholesterol + 24,27-dihydroxycholesterol + NADP+ + H2O		Homo sapiens	-	preferred substrate in vitro	673298	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Cavia porcellus	-	-	701715	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	-	659216, 687987, 701715, 705008, 705825, 706536	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	657671, 657971, 684856, 701715, 705008, 705825, 705920, 711641	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	689814	-	-	r
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus	-	-	686258, 688555, 701715	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Bos taurus	-	-	686258, 701715	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Oryctolagus cuniculus, Equus caballus	-	-	701715	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	Q9Y6A2	-	658159	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	712869	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	Q9WVK8	-	658159	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	Q9Y6A2	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	658159	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	Q9WVK8	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	658159	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	cholesterol 24-hydroxylase constitutes a major tissue-specific pathway for cholesterol turnover in the brain	659216	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	initiates cholesterol degradation in the brain. In addition to the involvement in cholesterol homeostasis in the brain, this enzyme may participate in metabolism of neurosteroids and drugs that can cross the blood-brain barrier and are targeted to the central nervous system	657971	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus	-	24-hydroxycholesterol induces, through the liver X receptor, activation of genes involved in cholesterol efflux, including the ATP-binding cassette transporter A1 and apolipoprotein E, overview	688555	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	a major pathway for excretion of excess cholesterol from the brain, polymorphisms within the CYP46A1 gene are associated with Alzheimer�s disease incidence. The ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain, overview	684856	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus, Bos taurus	-	the enzyme is important in cholesterol homeostasis in cerebral structures, CYP46A1 might be involved in retinal pathologies like age-related macular degeneration or glaucomas, overview	686258	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	the enzyme is required for learning and memory formation, mice deficient in CYP46A1 exhibit impaired learning and defective hippocampal long-term potentiation, overview	687987	-	-	?
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	cholesterol enters the enzyme through the membrane. In CYP46A1, the three putative membrane-interacting peptides in the soluble domain, 59V-K69, 77V-K94, and 217L-K231, form the entrance to the substrate access channel and represent the secondary structural elements (the A helix and beta1 sheet and F-G loop regions)	695874	-	-	?
cholesterol + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Mus musculus, Homo sapiens	-	-	671173	-	-	?
cholesterol + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	673298	-	-	?
cholesterol + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Sus scrofa	-	-	671173	-	-	?
cholesterol + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	the enzyme is important in cholesterol metabolism in the brain, cholesterol dynamics in the fetal and neonatal brain, overview	671173	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 + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Homo sapiens, Sus scrofa	-	the enzyme is important in cholesterol metabolism in the brain, overview	671173	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 + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	the enzyme is responsible for cholesterol elimination from brain, (24S)-hydroxycholesterol can cross the blood-brain barrier, enter the circulation, and then be delivered to the liver for further degradation, cholesterol metabolism, overview, CYP46A1 may participate in metabolism of neurosteroids and drugs that are targeted to the central nervous system	673298	-	-	?
cholesterol + NADPH + O2	24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	-	676852	-	-	?
cholesterol + NADPH + O2	24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus	-	-	675535	-	-	?
cholesterol + NADPH + O2	24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	enzyme deficiency leads to a suppression of the mevalonate pathway and a defect in learning	676852	-	-	?
cholesterol 3-sulfate + NADPH + H+ + O2	(24S)-24-hydroxycholesterol 3-sulfate + NADP+ + H2O		Homo sapiens	-	-	689814	-	-	?
dextromethorphan + NADPH + O2	?		Homo sapiens	-	O- and N-demethylation	673298	-	-	?
phenacetin + NADPH + O2	?		Homo sapiens	-	O-deethylation	673298	-	-	?
diclofenac + NADPH + O2	?		Homo sapiens	-	4'-hydroxylation	673298	-	-	?
additional information	?	-	Homo sapiens	-	CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease	659374	-	-	-
additional information	?	-	Homo sapiens	-	regulation of cholesterol synthesis is more important for maintenance of cholesterol homeostasis in brain than is the corresponding regulation of cholesterol removal	659516	-	-	-
additional information	?	-	Homo sapiens, Mus musculus	-	the enzyme is a mediator of cholesterol homeostasis in the brain	660401	-	-	-
additional information	?	-	Homo sapiens	-	the enzyme is able to carry out side chain hydroxylations of two endogenous C27-steroids with and without a double bond between C5-C6 (7R-hydroxycholesterol and cholestanol, respectively) and introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone). P450 46A1 metabolizes xenobiotics carrying out dextromethorphan O-demethylation and N-demethylations, diclofenac 4'-hydroxylation, and phenacetin O-deethylation	657971	-	-	-
additional information	?	-	Homo sapiens	-	(24S)-hydroxycholesterol is a potent activator of the LXR receptor, CYP46A1-deficiency plays a role in the pathogenesis of this neurological disorder, such as Alzheimer's disease	673298	-	-	-
additional information	?	-	Homo sapiens	-	cholesterol metabolism is important in Alzheimer's disease pathogenesis, the enzyme is a risk factor for Alzheimer's disease, along with cholesterol 25-hydroxylase and ATP-binding cassette transporter A1, overview	660012	-	-	-
additional information	?	-	Homo sapiens	-	CYP46A1 shows broad substrate specificity	673298	-	-	-
additional information	?	-	Homo sapiens	-	(24S)-24-hydroxycholesterol activates alpha- and beta-secretases, while (27S)-27-hydroxycholesterol inhbits them, overview	684856	-	-	-
additional information	?	-	Homo sapiens	-	active site structure and substrate binding, overview	689814	-	-	-

NATURAL SUBSTRATES	NATURAL PRODUCTS	REACTION DIAGRAM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY SUBSTRATE	LITERATURE (Substrate)	COMMENTARY PRODUCT	LITERATURE (Product)
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	-	711641, 689814, 712869	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	Q9Y6A2	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	658159	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	Q9WVK8	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	658159	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	cholesterol 24-hydroxylase constitutes a major tissue-specific pathway for cholesterol turnover in the brain	659216	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	initiates cholesterol degradation in the brain. In addition to the involvement in cholesterol homeostasis in the brain, this enzyme may participate in metabolism of neurosteroids and drugs that can cross the blood-brain barrier and are targeted to the central nervous system	657971	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus	-	24-hydroxycholesterol induces, through the liver X receptor, activation of genes involved in cholesterol efflux, including the ATP-binding cassette transporter A1 and apolipoprotein E, overview	688555	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	a major pathway for excretion of excess cholesterol from the brain, polymorphisms within the CYP46A1 gene are associated with Alzheimer�s disease incidence. The ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain, overview	684856	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus, Bos taurus	-	the enzyme is important in cholesterol homeostasis in cerebral structures, CYP46A1 might be involved in retinal pathologies like age-related macular degeneration or glaucomas, overview	686258	-	-
cholesterol + NADPH + H+ + O2	(24S)-24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	the enzyme is required for learning and memory formation, mice deficient in CYP46A1 exhibit impaired learning and defective hippocampal long-term potentiation, overview	687987	-	-
cholesterol + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	the enzyme is important in cholesterol metabolism in the brain, cholesterol dynamics in the fetal and neonatal brain, overview	671173	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 + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Homo sapiens, Sus scrofa	-	the enzyme is important in cholesterol metabolism in the brain, overview	671173	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 + NADPH + O2	(24S)-hydroxycholesterol + NADP+ + H2O		Homo sapiens	-	the enzyme is responsible for cholesterol elimination from brain, (24S)-hydroxycholesterol can cross the blood-brain barrier, enter the circulation, and then be delivered to the liver for further degradation, cholesterol metabolism, overview, CYP46A1 may participate in metabolism of neurosteroids and drugs that are targeted to the central nervous system	673298	-	-
cholesterol + NADPH + O2	24-hydroxycholesterol + NADP+ + H2O		Rattus norvegicus	-	-	675535	-	-
cholesterol + NADPH + O2	24-hydroxycholesterol + NADP+ + H2O		Mus musculus	-	enzyme deficiency leads to a suppression of the mevalonate pathway and a defect in learning	676852	-	-
additional information	?	-	Homo sapiens	-	CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease	659374	-	-
additional information	?	-	Homo sapiens	-	regulation of cholesterol synthesis is more important for maintenance of cholesterol homeostasis in brain than is the corresponding regulation of cholesterol removal	659516	-	-
additional information	?	-	Homo sapiens, Mus musculus	-	the enzyme is a mediator of cholesterol homeostasis in the brain	660401	-	-
additional information	?	-	Homo sapiens	-	(24S)-hydroxycholesterol is a potent activator of the LXR receptor, CYP46A1-deficiency plays a role in the pathogenesis of this neurological disorder, such as Alzheimer's disease	673298	-	-
additional information	?	-	Homo sapiens	-	cholesterol metabolism is important in Alzheimer's disease pathogenesis, the enzyme is a risk factor for Alzheimer's disease, along with cholesterol 25-hydroxylase and ATP-binding cassette transporter A1, overview	660012	-	-

COFACTOR	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
cytochrome P-450	Homo sapiens	-	-	657671, 658159, 660401	-
cytochrome P-450	Mus musculus	-	-	660401	-
cytochrome P450	Mus musculus	-	a cytochrome P450 enzyme	687987	-
cytochrome P450	Homo sapiens	-	-	689814	-
heme	Homo sapiens	-	-	689814	2D-image
NADPH	Homo sapiens	-	-	657671, 657971, 658159, 671173, 673298, 684856, 689814, 695874, 701715, 705008, 705825, 705920, 711641	2D-image
NADPH	Mus musculus	-	-	658159, 659216, 671173, 676852, 687987, 701715, 705008, 705825, 706536	2D-image
NADPH	Sus scrofa	-	-	671173	2D-image
NADPH	Rattus norvegicus	-	-	675535, 686258, 688555, 701715	2D-image
NADPH	Bos taurus	-	-	686258, 701715	2D-image
NADPH	Cavia porcellus, Equus caballus, Oryctolagus cuniculus	-	-	701715	2D-image

METALS and IONS	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
Fe2+	Mus musculus	-	a cytochrome P450 enzyme	687987
Fe2+	Homo sapiens	-	a heme-containing cytochrome P450 enzyme	689814

INHIBITORS	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
clobenpropit	Homo sapiens	-	complete inhibition	689814	2D-image
shRNA	Mus musculus	-	knockdown	705612	-
siRNA	Mus musculus	-	reduction of the cholesterol 24-hydroxylase, which results in lower levels of Trk phosphorylation	705612	-
thioperamide	Homo sapiens	-	66% inhibition	689814	2D-image
Tranylcypromine	Homo sapiens	-	complete inhibition	689814	2D-image
voriconazole	Homo sapiens	-	binds with high affinity to CYP46A1 in vitro and efficiently inhibits CYP46A1-catalyzed cholesterol hydroxylations in the reconstituted system	705008	2D-image
voriconazole	Mus musculus	-	voriconazole-induced visual disturbances related to an interaction between the drug and retinal CYP46A1	705008	2D-image

ACTIVATING COMPOUND	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
cholesterol 3-sulfate	Homo sapiens	-	i.e. CH-35	689814	2D-image
lovastatin	Rattus norvegicus	-	induces and activates the enzyme, acts neuroprotectively in hippocampus after kainate injury, overview	675535	2D-image
additional information	Rattus norvegicus	-	cortical injury increases cholesterol 24S hydroxylase levels in the rat brain, overview	688555	-

KM VALUE [mM]	KM VALUE [mM] Maximum	SUBSTRATE	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
0.0015	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
0.0022	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	full length enzyme	657671	2D-image
0.0039	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
0.0053	-	cholesterol	Homo sapiens	-	-	673298	2D-image
0.0054	-	cholesterol	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
0.0077	-	cholesterol	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
0.0033	-	cholesterol 3-sulfate	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
0.0049	-	cholesterol 3-sulfate	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
additional information	-	additional information	Homo sapiens	-	Km-value of truncated enzyme forms	657671	-

TURNOVER NUMBER [1/s]	TURNOVER NUMBER MAXIMUM[1/s]	SUBSTRATE	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
0.00117	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	full length enzyme	657671	2D-image
0.0142	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
0.0153	-	(24S)-24-hydroxycholesterol	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
0.0018	-	cholesterol	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
0.0072	-	cholesterol	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
0.11	-	cholesterol	Homo sapiens	-	-	673298	2D-image
0.0076	-	cholesterol 3-sulfate	Homo sapiens	-	recombinant wild-type enzyme	689814	2D-image
0.042	-	cholesterol 3-sulfate	Homo sapiens	-	recombinant truncation mutant enzyme	689814	2D-image
additional information	-	additional information	Homo sapiens	-	turnover-numbers of truncated enzyme forms	657671	-

kcat/KM VALUE [1/mMs^-1]	kcat/KM VALUE [1/mMs^-1] Maximum	SUBSTRATE	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
No entries in this field

Ki VALUE [mM]	Ki VALUE [mM] Maximum	INHIBITOR	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
1.1e-05	-	voriconazole	Homo sapiens	-	-	705008	2D-image

IC50 VALUE [mM]	IC50 VALUE [mM] Maximum	INHIBITOR	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	IMAGE
No entries in this field

SPECIFIC ACTIVITY [µmol/min/mg]	SPECIFIC ACTIVITY MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

pH OPTIMUM	pH MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
7.2	-	Homo sapiens	-	assay at	689814

pH RANGE	pH RANGE MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

TEMPERATURE OPTIMUM	TEMPERATURE OPTIMUM MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
37	-	Homo sapiens	-	assay at	689814

TEMPERATURE RANGE	TEMPERATURE MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

pI VALUE	pI VALUE MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

SOURCE TISSUE	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE	SOURCE
astrocyte	Homo sapiens	-	in normal brain	659374
astrocyte	Homo sapiens	-	-	705920
astrocyte	Rattus norvegicus	-	-	712120
astrocyte	Homo sapiens	-	primary	712816
brain	Homo sapiens	-	-	657971, 658159, 689814, 705008, 705920
brain	Mus musculus	-	-	658159, 659216, 671173, 676852, 687987, 702028, 706536
brain	Homo sapiens	-	in neurons and some astrocytes in the normal brain, in Alzheimer's disease the enzyme shows prominent expression in astrocytes and around amyloid plaques	659374
brain	Homo sapiens	-	abnormal induction of the enzyme in patients with Alzheimer�s disease	660011
brain	Homo sapiens	-	predominantly expressed in. The 24-hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate with age	660401
brain	Mus musculus	-	predominantly expressed in	660401
brain	Homo sapiens	-	cholesterol 24-hydroxylase is expressed predominantly in the brain	671173
brain	Sus scrofa	-	low activity	671173
brain	Homo sapiens	-	specific	673298
brain	Rattus norvegicus	-	enzyme levels in healthy and injured brain, primary rat microglia, overview	688555
brain	Bos taurus, Equus caballus	-	-	701715
brain	Homo sapiens	-	fetus, is largely confined to the brain	701715
brain	Mus musculus	-	is largely confined to the brain, neuron-specific expression	701715
brain	Rattus norvegicus	-	-	701715
brain	Homo sapiens	-	greater CYP46A1 levels in the brain than in the liver	702028
brain	Homo sapiens	-	expression of Cyp46 in the brain is altered during normal development but is relatively stable in normal adult brain	711641
brain	Rattus norvegicus	-	expression profile of Cyp46 in the brains of intact, sham-operated, and lesioned animals, overview. Ablation of the sensorimotor cortex induces increase of Cyp46 immunoreactivity in the ipsilateral cortex	712120
brain	Homo sapiens	-	quantitative RT-PCR and real-time PCR CYP46 expression analysis, overview	712816
brain	Homo sapiens	-	quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview	712869
central nervous system	Homo sapiens	-	almost exclusive expression of gene CYP46A1	684856
cerebellum	Mus musculus	-	cerebellar interneurons and Purkinje cells	687987
cerebral cortex	Mus musculus	-	pyramidal neurons	687987
dendritic cell	Mus musculus	-	-	687987
embryo	Mus musculus, Rattus norvegicus	-	-	705612
glial cell	Homo sapiens	-	abnormal induction of the enzyme in patients with Alzheimer�s disease	660011
glial cell	Homo sapiens	-	-	705920, 712816
glial cell	Rattus norvegicus	-	-	712120
hippocampus	Rattus norvegicus	-	after kainate lesions	675535
hippocampus	Mus musculus	-	-	676852, 705612, 706536
hippocampus	Mus musculus	-	pyramidal neurons	687987
hippocampus	Rattus norvegicus	-	-	688555, 705612
hippocampus	Mus musculus	-	high levels	701715
leukocyte	Homo sapiens	-	-	703580
liver	Homo sapiens	-	-	658159, 671173
liver	Mus musculus	-	-	671173, 702028
liver	Sus scrofa	-	-	671173
liver	Mus musculus	-	small amounts, level is 100fold lower in the liver than in the brain	701715
liver	Homo sapiens	-	greater CYP46A1 levels in the brain than in the liver	702028
neural retina	Mus musculus	-	-	705008
neuroblastoma cell	Homo sapiens	-	-	684856, 711641
neuron	Homo sapiens	-	in normal brain	659374
neuron	Mus musculus	-	-	671173, 687987, 705612
neuron	Homo sapiens	-	-	671173, 712869
neuron	Sus scrofa	-	-	671173
neuron	Rattus norvegicus	-	hippocampal	675535
neuron	Bos taurus, Rattus norvegicus	-	of the neural retina, specific expression of CYP46A1	686258
neuron	Rattus norvegicus	-	primary hippocampal neurons	688555
neuron	Mus musculus	-	large pyramidal cells and their dendrites in cortical layers II, III, V, and VI. Is absent from nonpyramidal cells that compose layer IV	701715
neuron	Rattus norvegicus	-	-	705612
neuron	Rattus norvegicus	-	expression in cell bodies, dendrites, and axons	712120
Purkinje cell	Mus musculus	-	in the cerebellum	687987
retina	Bos taurus, Rattus norvegicus	-	specific high expression of CYP46A1 in the neural retina, low expression in the retinal pigment epithelium, no expression in the ciliary body	686258
retina	Mus musculus	-	ganglion cells	687987
retina	Homo sapiens	-	neuronal part	704109
retina	Homo sapiens	-	quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview	712869
SH-SY5Y cell	Homo sapiens	-	-	684856, 702028, 711641
SH-SY5Y cell	Homo sapiens	-	contains cholesterol 24-hydroxylase mRNA but does not synthesize 24S-hydroxycholesterol	701715
testis	Mus musculus	-	small amounts, mRNA does not appear to be translated into protein in the testis	701715
microglia	Homo sapiens	-	-	711641
additional information	Bos taurus, Rattus norvegicus	-	immunohistochemic analysis of enzyme distribution	686258
additional information	Mus musculus	-	immunohistochemic analysis of enzyme distribution, overview	687987
additional information	Mus musculus	-	the enzyme is absent from a cortical section from a cholesterol 24-hydroxylase knockout mouse	701715
additional information	Mus musculus	-	N2a cell line	705825
additional information	Homo sapiens	-	quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview	712869

LOCALIZATION	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	GeneOntology No.	LITERATURE	SOURCE
cytosol	Homo sapiens	-	truncated enzymes are distributed at about a 1:1 ratio between the membrane fraction and the cytosol in low ionic strength buffer, when expressed in Escherichia coli	5829	657671
endoplasmic reticulum	Homo sapiens	-	-	5783	658159, 660401, 671173, 673298
endoplasmic reticulum	Mus musculus	-	-	5783	658159, 660401, 671173, 701715
endoplasmic reticulum	Mus musculus	-	dendritic	5783	687987
membrane	Homo sapiens	-	truncated enzymes are distributed at about a 1:1 ratio between the membrane fraction and the cytosol in low ionic strength buffer, when expressed in Escherichia coli	16020	657671
membrane	Homo sapiens	-	-	16020	695874
membrane	Homo sapiens	-	associated	16020	712869
microsome	Sus scrofa	-	of brain	-	671173
microsome	Mus musculus	-	-	-	687987
microsome	Bos taurus, Rattus norvegicus	-	-	-	701715
mitochondrion	Sus scrofa	-	of liver	5739	671173

PDB	SCOP	CATH	ORGANISM
2q9f, download	SCOP (2q9f)	CATH (2q9f)	Homo sapiens
2q9g, download	SCOP (2q9g)	CATH (2q9g)	Homo sapiens
3mdm, download	SCOP (3mdm)	CATH (3mdm)	Homo sapiens
3mdr, download	SCOP (3mdr)	CATH (3mdr)	Homo sapiens
3mdt, download	SCOP (3mdt)	CATH (3mdt)	Homo sapiens
3mdv, download	SCOP (3mdv)	CATH (3mdv)	Homo sapiens
4enh, download	SCOP (4enh)	CATH (4enh)	Homo sapiens

MOLECULAR WEIGHT	MOLECULAR WEIGHT MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
53000	-	Mus musculus	-	immunoblotting	701715

SUBUNITS	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
?	Homo sapiens	-	x * 56821, calculation from nucleotide sequence; x * 56842	658159
?	Mus musculus	-	x * 56821, calculation from nucleotide sequence	658159
monomer	Homo sapiens	-	1 * 49000, truncated enzyme form, SDS-PAGE	657671
additional information	Homo sapiens	-	structure-function relationship	673298

POSTTRANSLATIONAL MODIFICATION	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

Crystallization/COMMENTARY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
a recombinant C-terminally His4-tagged CYP46A1 lacking the first 50 N-terminal amino acid residues, substrate-free enzyme or enzyme in complex with cholesterol 3-sulfate, X-ray diffraction structure determination and analysis at 2.4 A and 1.9 A resolution, respectively, structure modeling	Homo sapiens	-	689814

pH STABILITY	pH STABILITY MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

TEMPERATURE STABILITY	TEMPERATURE STABILITY MAXIMUM	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

GENERAL STABILITY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
No entries in this field

ORGANIC SOLVENT	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
No entries in this field

OXIDATION STABILITY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
No entries in this field

STORAGE STABILITY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
No entries in this field

Purification/COMMENTARY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
-	Homo sapiens	-	695874, 705008
partial	Homo sapiens	-	657971
recombinant His-tagged enzyme by nickel affinity chromatography	Homo sapiens	-	689814
truncated enzyme forms	Homo sapiens	-	657671

Cloned/COMMENTARY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
-	Homo sapiens	-	658159, 660401, 705008
5'-upstream region of human CYP46 gene	Homo sapiens	-	659516
adeno-associated vectors expressing wild-type (AAV5-wtCYP46A1) or mutated (AAV5-mtCYP46A1) CYP46A1 cDNA tagged with the hemaglutinin epitope injected in hippocampus, frontal, and parietal cortices of both hemispheres of 3-month-old APP23 mice. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 mice. Overexpression in N2a-APP17 cells	Homo sapiens	-	705825
co-expression of human CYP46 with glial glutamate transporter EAAT2 in primary Rattus norvegicus astrocytes. Quantitative RT-PCR and real-time PCR CYP46 expression analysis	Homo sapiens	-	712816
DNA and amino acid sequence determnination and analysis, determination of single nucleotide polymorphisms in North American Caucasians and Caribbean Hispanic Alzheimer patients, overview	Homo sapiens	-	660012
DNA sequence determination and analysis, located on chromosome14q32.1	Homo sapiens	-	671173
expressed in Escherichia coli	Homo sapiens	-	701715
expression Escherichia coli, HEK293 cells transfected with CYP46A1	Homo sapiens	-	657971
expression in Escherichia coli	Homo sapiens	-	673298
expression in Escherichia coli, wild-type and trucation mutatants. All four mutants lack the N-terminal transmembrane region (residues 3�27), and, in addition, DELTA46A1 has a 4 His-tag fused to the C-terminus, HDELTA46A1 has the N-terminal 4 His-tag, HDELTA46A1DELTA has a 4 His-tag at the N-terminus and does not contain a proline-rich region at the C-terminus (residues 494�499), and DELTA46A1DELTA lacks the C-terminal proline-rich region	Homo sapiens	-	657671
full-length and truncated (DELTA2-50) CYP46A1 expressed in Escherichia coli membranes	Homo sapiens	-	695874
His-tagged enzyme	Homo sapiens	-	689814
-	Mus musculus	-	660401
DNA sequence determination and analysis	Mus musculus	-	671173
expressed in 293 cells	Mus musculus	-	701715
full ORF expression clone p46+ including the full cyp46A1 mouse open reading frame. Cyp46A1 overexpressed in 10 days in vitro hippocampal neurons	Mus musculus	-	705612
gene CYP46A1, expressionin CHO-K1 cells and HEK-293 cells	Mus musculus	-	687987

EXPRESSION	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
gradual increase in mRNA and protein in postnatal brain	Homo sapiens	-	701715
marked time-dependent derepression of the expression of CYP46A1, in response to treatment with the potent histone deacetylase inhibitor trichostatin A. Treatment with 0.0005 mM trichostatin A for 48 h shows highly significant 150fold increase in CYP46A1 expression	Homo sapiens	-	702028
Cyp46 is upregulated in traumatic brain injury, specifically in microglia	Homo sapiens	-	711641
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	Mus musculus	-	701715
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	Mus musculus	-	702028
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	Mus musculus	-	705612
ablation of the sensorimotor cortex induces an increase of Cyp46 immunoreactivity in the ipsilateral cortex in the brain	Rattus norvegicus	-	712120

ENGINEERING	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
A1309C	Homo sapiens	-	destroys its heme structure, resulting in the complete lack of cholesterol 24-hydroxylase activity	705825
additional information	Homo sapiens	-	four truncation mutants: all lack the N-terminal transmembrane region (residues 3 �27), and, in addition, DELTA46A1 has a 4 His-tag fused to the C-terminus, HDELTA46A1 has the N-terminal 4 His-tag, HDELTA46A1DELTA has a 4 His-tag at the N-terminus and does not contain a proline-rich region at the C-terminus (residues 494 �499), and DELTA46A1DELTA lacks the C-terminal proline-rich region. Truncated enzymes have moderately decreased catalytic efficiencies for either cholesterol or 24S-hydroxycholesterol or both, whereas their substrate-binding constants are either unchanged or decreased 2fold.The two forms, DELTA64A1DELTA and HDELTA46A1DELTA both lacking the C-terminal proline-rich region are good candidates for future crystallographic studies because they contain only 0.3 �0.8% of high molecular weight aggregates and their catalytic efficiencies are decreased no more than 2.3fold	657671
additional information	Homo sapiens	-	determination of single nucleotide polymorphisms in North American Caucasians and Caribbean Hispanic Alzheimer patients, overview	660012
additional information	Homo sapiens	-	polymorphisms within the CYP46A1 gene are associated with Alzheimer�s disease incidence	684856
additional information	Homo sapiens	-	construction of an mutant CYP46A1, in which the first 50 N-terminal amino acid residues are deleted, and a His4 tag is added at the C-terminus. The truncation removed a 23-residue transmembrane-anchoring domain and renders this membrane P450 more soluble compared to the wild-type, overview	689814
additional information	Mus musculus	-	construction of knockout mice, concentration and the pool of cholesterol in the CNS is unchanged compared with control animals, but synthesis is suppressed by about 25% in the CYP46a1-deficient mice, but not in those lacking 7a- or 27-hydroxylase activity, the concentrations of 24S-hydroxycholesterol in the brain and plasma decline to very low levels, the CNS in the mouse apparently responds appropriately to loss of this excretory pathway by suppressing endogenous synthesis by an amount exactly equal to the mass of cholesterol that would normally be excreted as 24S-hydroxycholesterol	671173
additional information	Mus musculus	-	brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway, this suppression causes a defect in learning, 24-hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation, the effects of genetic elimination of 24-hydroxylase on long-term potentiation are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol, phenotype, overview	676852

Renatured/COMMENTARY	ORGANISM	UNIPROT ACCESSION NO.	LITERATURE
No entries in this field

APPLICATION	ORGANISM	UNIPROT ACCESSION NO.	COMMENTARY	LITERATURE
medicine	Homo sapiens	-	CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease	659374
medicine	Homo sapiens	-	genotyping of CYP46A1 gene polymorphisms (associated with the risk of Alzheimer's disease in Chinese)	698342
medicine	Homo sapiens	-	abnormal expression of cholesterol 24S-hydroxylase in astrocytes in Alzheimer's disease, which may limit the usefulness of the plasma marker 24S-hydroxycholesterol in this specific disease	705920

DISEASE	TITLE OF PUBLICATION	LINK TO PUBMED
Alzheimer Disease	$CYP46A1$ Functional Promoter Haplotypes Decipher Genetic Susceptibility to Alzheimer's Disease.	PubMed
Alzheimer Disease	A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease.	PubMed
Alzheimer Disease	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 Alzheimer's Disease.	PubMed
Alzheimer Disease	An intronic CYP46A1 polymorphism is associated with Alzheimer disease in a Chinese Han population.	PubMed
Alzheimer Disease	APOE promoter, ACE1 and CYP46 polymorphisms and beta-amyloid in Alzheimer's disease.	PubMed
Alzheimer Disease	Association between a T/C polymorphism in intron 2 of cholesterol 24S-hydroxylase gene and Alzheimer's disease in Chinese.	PubMed
Alzheimer Disease	Association of CYP46 intron 2 polymorphism in Finnish Alzheimer's disease samples and a global scale summary.	PubMed
Alzheimer Disease	Cholesterol 24-hydroxylase (CYP46A1) polymorphisms are associated with faster cognitive deterioration in Chinese older persons: a two-year follow up study.	PubMed
Alzheimer Disease	Chromatin-Modifying Agents Increase Transcription of CYP46A1, a Key Player in Brain Cholesterol Elimination.	PubMed
Alzheimer Disease	Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease.	PubMed
Alzheimer Disease	Cyp46 polymorphisms in Alzheimer's disease: a review.	PubMed
Alzheimer Disease	CYP46: a risk factor for Alzheimer's disease or a coincidence?	PubMed
Alzheimer Disease	CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism.	PubMed
Alzheimer Disease	Differential expression of cholesterol hydroxylases in Alzheimer's disease.	PubMed
Alzheimer Disease	Earlier Onset of Alzheimer's Disease: Risk Polymorphisms Within PRNP, PRND, CYP46, and APOE Genes.	PubMed
Alzheimer Disease	Exclusion of CYP46 and APOM as candidate genes for Alzheimer's disease in a French population.	PubMed
Alzheimer Disease	Genetic association of CYP46 and risk for Alzheimer's disease.	PubMed
Alzheimer Disease	Genetic variation in the cholesterol 24-hydroxylase (CYP46) gene and the risk of Alzheimer's disease.	PubMed
Alzheimer Disease	Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism.	PubMed
Alzheimer Disease	Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease.	PubMed
Alzheimer Disease	Intron 2 (T/C) CYP46 Polymorphism Is Associated with Alzheimer's Disease in Chinese Patients.	PubMed
Alzheimer Disease	Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators.	PubMed
Alzheimer Disease	Lack of association between the CYP46 gene polymorphism and Italian late-onset sporadic Alzheimer's disease.	PubMed
Alzheimer Disease	Lack of association of the cholesterol 24-hydroxylase (CYP46) intron 2 polymorphism with Alzheimer's disease.	PubMed
Alzheimer Disease	On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells.	PubMed
Alzheimer Disease	Plasma 24S hydroxycholesterol response to statins in Alzheimer's disease patients: effects of gender, CYP46, and ApoE polymorphisms.	PubMed
Alzheimer Disease	Polymorphism in the cholesterol 24S-hydroxylase gene (CYP46A1) associated with the APOEpsilon3 allele increases the risk of Alzheimer's disease and of mild cognitive impairment progressing to Alzheimer's disease.	PubMed
Alzheimer Disease	Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease.	PubMed
Alzheimer Disease	Polymorphisms of cholesterol metabolism genes CYP46 and ABCA1 and the risk of sporadic Alzheimer's disease in Chinese.	PubMed
Alzheimer Disease	Polymorphisms of the cholesterol 24-hydroxylase (CYP46A1) gene and the risk of Alzheimer's disease in a Chinese population.	PubMed
Alzheimer Disease	Primary Open Angle Glaucoma: Association with Cholesterol 24S-Hydroxylase (CYP46A1) Gene Polymorphism and Plasma 24-Hydroxycholesterol Levels.	PubMed
Alzheimer Disease	Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan.	PubMed
Alzheimer Disease	Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway.	PubMed
Alzheimer Disease	The effects of gender and CYP46 and apo E polymorphism on 24S-hydroxycholesterol levels in Alzheimer's patients treated with statins.	PubMed
Alzheimer Disease	Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease.	PubMed
Alzheimer Disease	[Cholesterol and Alzheimer's disease]	PubMed
Alzheimer Disease	[Cholesterol and statins in Alzheimer disease]	PubMed
Alzheimer Disease	[Correlation of cholesterol 24-hydroxylase and ATP-binding cassette transporter A1 polymorphisms with Alzheimer's disease]	PubMed
Brain Injuries	Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner.	PubMed
Dementia	CYP46 T/C polymorphism is not associated with Alzheimer's dementia in a population from Hungary.	PubMed
Glaucoma	24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma.	PubMed
Glaucoma	Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina.	PubMed
Glaucoma	Primary Open Angle Glaucoma: Association with Cholesterol 24S-Hydroxylase (CYP46A1) Gene Polymorphism and Plasma 24-Hydroxycholesterol Levels.	PubMed
Glaucoma	Role of cholesterol 24S-hydroxylase gene polymorphism (rs754203) in primary open angle glaucoma.	PubMed
Glaucoma, Open-Angle	Primary Open Angle Glaucoma: Association with Cholesterol 24S-Hydroxylase (CYP46A1) Gene Polymorphism and Plasma 24-Hydroxycholesterol Levels.	PubMed
Glaucoma, Open-Angle	Role of cholesterol 24S-hydroxylase gene polymorphism (rs754203) in primary open angle glaucoma.	PubMed
Glaucoma, Open-Angle	SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma.	PubMed
Herpes Zoster	SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma.	PubMed
Macular Degeneration	Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina.	PubMed
Nervous System Diseases	Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina.	PubMed
Neuroblastoma	Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway.	PubMed
Neurodegenerative Diseases	Rediscovery of cerebrosterol.	PubMed
Obesity	A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease.	PubMed
Retinal Degeneration	Oxysterols: functional significance in fetal development and the maintenance of normal retinal function.	PubMed

REF.	AUTHORS	TITLE	JOURNAL	VOL.	PAGES	YEAR	ORGANISM	LINK TO PUBMED	SOURCE
657671	Mast, N.; Andersson, U.; Nakayama, K.; Bjorkhem, I.; Pikuleva, I.A.	Expression of human cytochrome P450 46A1 in Escherichia coli: effects of N- and C-terminal modifications	Arch. Biochem. Biophys.	428	99-108	2004	Homo sapiens	PubMed
657971	Mast, N.; Norcross, R.; Andersson, U.; Shou, M.; Nakayama, K.; Bjorkhem, I.; Pikuleva, I.A.	Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain	Biochemistry	42	14284-14292	2003	Homo sapiens	PubMed
658159	Russell, D.W.	Oxysterol biosynthetic enzymes	Biochim. Biophys. Acta	1529	126-135	2000	Homo sapiens, Mus musculus	PubMed
659216	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	PubMed
659374	Brown, J.3rd.; Theisler, C.; Silberman, S.; Magnuson, D.; Gottardi-Littell, N.; Lee, J.M.; Yager, D.; Crowley, J.; Sambamurti, K.; Rahman, M.M.; Reiss, A.B.; Eckman, C.B.; Wolozin, B.	Differential expression of cholesterol hydroxylases in Alzheimer's disease	J. Biol. Chem.	279	34674-34681	2004	Homo sapiens	PubMed
659516	Ohyama, Y.; Meaney, S.; Heverin, M.; Ekstrom, L.; Brafman, A.; Shafir, M.; Andersson, U.; Olin, M.; Eggertsen, G.; Diczfalusy, U.; Feinstein, E.; Bjorkhem, I.	Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): Marked insensitivity towards different regulatory axes	J. Biol. Chem.	281	3810-3820	2006	Homo sapiens	PubMed
660011	Bogdanovic, N.; Bretillon, L.; Lund, E.G.; Diczfalusy, U.; Lannfelt, L.; Winblad, B.; Russell, D.W.; Bjorkhem, I.	On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells	Neurosci. Lett.	314	45-48	2001	Homo sapiens	PubMed
660012	Shibata, N.; Kawarai, T.; Lee, J.H.; Lee, H.S.; Shibata, E.; Sato, C.; Liang, Y.; Duara, R.; Mayeux, R.P.; St George-Hyslop, P.H.; Rogaeva, E.	Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer's disease	Neurosci. Lett.	391	142-146	2006	Homo sapiens	PubMed
660401	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, Mus musculus	PubMed
671173	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	PubMed
673298	Pikuleva, I.A.	Cholesterol-metabolizing cytochromes P450	Drug Metab. Dispos.	34	513-520	2006	Homo sapiens	PubMed
675535	He, X.; Jenner, A.M.; Ong, W.Y.; Farooqui, A.A.; Patel, S.C.	Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury	J. Neuropathol. Exp. Neurol.	65	652-663	2006	Rattus norvegicus	PubMed
676852	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	PubMed
684856	Famer, D.; Meaney, S.; Mousavi, M.; Nordberg, A.; Bjoerkhem, I.; Crisby, M.	Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway	Biochem. Biophys. Res. Commun.	359	46-50	2007	Homo sapiens	PubMed
686258	Bretillon, L.; Diczfalusy, U.; Bjoerkhem, I.; Maire, M.A.; Martine, L.; Joffre, C.; Acar, N.; Bron, A.; Creuzot-Garcher, C.	Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina	Curr. Eye Res.	32	361-366	2007	Bos taurus, Rattus norvegicus	PubMed
687987	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	PubMed
688555	Cartagena, C.M.; Ahmed, F.; Burns, M.P.; Pajoohesh-Ganji, A.; Pak, D.T.; Faden, A.I.; Rebeck, G.W.	Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain	J. Neurotrauma	25	1087-1098	2008	Rattus norvegicus	PubMed
689814	Mast, N.; White, M.A.; Bjorkhem, I.; Johnson, E.F.; Stout, C.D.; Pikuleva, I.A.	Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain	Proc. Natl. Acad. Sci. USA	105	9546-9551	2008	Homo sapiens	PubMed
695874	Mast, N.; Liao, W.L.; Pikuleva, I.A.; Turko, I.V.	Combined use of mass spectrometry and heterologous expression for identification of membrane-interacting peptides in cytochrome P450 46A1 and NADPH-cytochrome P450 oxidoreductase	Arch. Biochem. Biophys.	483	81-89	2009	Homo sapiens	PubMed
698342	Fu, B.Y.; Ma, S.L.; Tang, N.L.; Tam, C.W.; Lui, V.W.; Chiu, H.F.; Lam, L.C.	Cholesterol 24-hydroxylase (CYP46A1) polymorphisms are associated with faster cognitive deterioration in Chinese older persons: a two-year follow up study	Int. J. Geriatr. Psychiatry	24	921-926	2009	Homo sapiens	-
701715	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, Equus caballus, Equus sp., Gallus gallus, Homo sapiens, Macaca mulatta, Mus musculus, Ornithorhynchus anatinus, Oryctolagus cuniculus, Pan troglodytes, Rattus norvegicus, Xenopus laevis	PubMed
702028	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	PubMed
703580	Koelsch, H.; Luetjohann, D.; Jessen, F.; Popp, J.; Hentschel, F.; Kelemen, P.; Schmitz, S.; Maier, W.; Heun, R.	CYP46A1 variants influence Alzheimers disease risk and brain cholesterol metabolism	Eur. Psychiatry	24	183-190	2009	Homo sapiens	PubMed
704109	Fourgeux, C.; Martine, L.; Bjoerkhem, I.; Diczfalusy, U.; Joffre, C.; Acar, N.; Creuzot-Garcher, C.; Bron, A.; Bretillon, L.	Primary open angle glaucoma: Association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and pPlasma 24-hydroxycholesterol levels	Invest. Ophthalmol. Vis. Sci.	50	5712-5717	2009	Homo sapiens	PubMed
705008	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	PubMed
705612	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	PubMed
705825	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	PubMed
705920	Solomon, A.; Leoni, V.; Kivipelto, M.; Besga, A.; Oksengard, A.R.; Julin, P.; Svensson, L.; Wahlund, L.O.; Andreasen, N.; Winblad, B.; Soininen, H.; Bjoerkhem, I.	Plasma levels of 24S-hydroxycholesterol reflect brain volumes in patients without objective cognitive impairment but not in those with Alzheimers disease	Neurosci. Lett.	462	89-93	2009	Homo sapiens	PubMed
706536	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	PubMed
711641	Cartagena, C.M.; Burns, M.P.; Rebeck, G.W.	24S-hydroxycholesterol effects on lipid metabolism genes are modeled in traumatic brain injury	Brain Res.	1319	1-12	2010	Homo sapiens	PubMed
712120	Smiljanic, K.; Lavrnja, I.; Mladenovic Djordjevic, A.; Ruzdijic, S.; Stojiljkovic, M.; Pekovic, S.; Kanazir, S.	Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner	Histochem. Cell Biol.	134	159-169	2010	Rattus norvegicus	PubMed
712816	Tian, G.; Kong, Q.; Lai, L.; Ray-Chaudhury, A.; Lin, C.L.	Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimers disease	J. Neurochem.	113	978-989	2010	Homo sapiens	PubMed
712869	Liao, W.L.; Heo, G.Y.; Dodder, N.G.; Reem, R.E.; Mast, N.; Huang, S.; Dipatre, P.L.; Turko, I.V.; Pikuleva, I.A.	Quantification of cholesterol-metabolizing P450s CYP27A1 and CYP46A1 in neural tissues reveals a lack of enzyme-product correlations in human retina but not human brain	J. Proteome Res.	10	241-248	2011	Homo sapiens	PubMed

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