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Information on EC 1.14.14.25 - cholesterol 24-hydroxylase and Organism(s) Homo sapiens
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1.14.14.25 cholesterol 24-hydroxylaseIUBMB 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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Word Map
- 1.14.14.25
- alzheimer
- 24s-hydroxycholesterol
- oxysterols
- cyp27a1
- efavirenz
-
24-hydroxylation
- medicine
-
27-hydroxylase
-
24s-ohc
-
epsilon4
- lathosterol
- desmosterol
-
cholesterol-metabolizing
- drug development
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
cyp46a1, cyp46, cholesterol 24-hydroxylase, cytochrome p450 46a1, cholesterol 24s-hydroxylase, cholesterol-24s-hydroxylase, ch24h, 24s-hydroxylase, cyp46a, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CYP46
CYP46A1
cytochrome P450 46A1
CYP46A1
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cholesterol + [reduced NADPH-hemoprotein reductase] + O2 = (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
structure-function relationship
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
213327-78-7
-
50812-30-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(24S)-24-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,25-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
(24S)-24-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,27-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
(24S)-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,25-dihydroxycholesterol + 24,27-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
preferred substrate in vitro
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
cholesterol 3-sulfate + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol 3-sulfate + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
dextromethorphan + [reduced NADPH-hemoprotein reductase] + O2
?
-
O- and N-demethylation
-
-
?
diclofenac + [reduced NADPH-hemoprotein reductase] + O2
?
-
4'-hydroxylation
-
-
?
phenacetin + [reduced NADPH-hemoprotein reductase] + O2
?
-
O-deethylation
-
-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
-
-
-
-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
-
the enzyme is important in cholesterol metabolism in the 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 + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
-
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
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
r
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
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] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
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
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
a major pathway for excretion of excess cholesterol from the brain, polymorphisms within the CYP46A1 gene are associated with Alzheimers disease incidence. The ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain, overview
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
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)
-
-
?
additional information
?
-
-
CYP46A1 affects the pathophysiology of Alzheimers' disease and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease
-
-
?
additional information
?
-
-
regulation of cholesterol synthesis is more important for maintenance of cholesterol homeostasis in brain than is the corresponding regulation of cholesterol removal
-
-
?
additional information
?
-
the enzyme is a mediator of cholesterol homeostasis in the brain
-
-
?
additional information
?
-
-
the enzyme is a mediator of cholesterol homeostasis in the brain
-
-
?
additional information
?
-
-
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
-
-
?
additional information
?
-
-
(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
-
-
?
additional information
?
-
-
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
-
-
?
additional information
?
-
-
(24S)-24-hydroxycholesterol activates alpha- and beta-secretases, while (27S)-27-hydroxycholesterol inhibits them, overview
-
-
?
additional information
?
-
active site structure and substrate binding, overview
-
-
?
additional information
?
-
coupled assay with recombinant Rattus norvegicus NADPH cytochrome P450 oxidoreductase
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
-
the enzyme is important in cholesterol metabolism in the 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 + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
-
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
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
r
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
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] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
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
-
-
?
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
-
a major pathway for excretion of excess cholesterol from the brain, polymorphisms within the CYP46A1 gene are associated with Alzheimers disease incidence. The ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain, overview
-
-
?
additional information
?
-
-
CYP46A1 affects the pathophysiology of Alzheimers' disease and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease
-
-
?
additional information
?
-
-
regulation of cholesterol synthesis is more important for maintenance of cholesterol homeostasis in brain than is the corresponding regulation of cholesterol removal
-
-
?
additional information
?
-
the enzyme is a mediator of cholesterol homeostasis in the brain
-
-
?
additional information
?
-
-
the enzyme is a mediator of cholesterol homeostasis in the brain
-
-
?
additional information
?
-
-
(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
-
-
?
additional information
?
-
-
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
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADPH
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)[8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone
-
(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)[8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]methanone
-
1-[3-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]-4H-1,2,4-triazol-1-ium
-
2-[5-methyl-1-(pyridine-4-carbonyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl]benzonitrile
-
8-(1,3-oxazol-5-yl)-N-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide
-
N-benzyl-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide
-
[6-cyclopropyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl](3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methanone
-
[6-fluoro-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl](3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methanone
-
additional information
generation of a series of imidazo[1,2-a]pyridine analogues that effectively inhibit cholesterol 24-hydroxylase (CYP46A1), synthesis and evaluation, overview
-
voriconazole
-
binds with high affinity to CYP46A1 in vitro and efficiently inhibits CYP46A1-catalyzed cholesterol hydroxylations in the reconstituted system
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
efavirenz
EFV, activates the enzyme pharmacologically as a potential target for Alzheimers disease
additional information
pharmaceuticals activate CYP46A1 allosterically through binding to the site on the cytosolic protein surface, which is different from the enzyme active site facing the membrane
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
-
Km-value of truncated enzyme forms
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
turnover-numbers of truncated enzyme forms
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
in neurons and some astrocytes in the normal brain, in Alzheimer's disease the enzyme shows prominent expression in astrocytes and around amyloid plaques
predominantly expressed in. The 24-hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate with age
-
expression of Cyp46 in the brain is altered during normal development but is relatively stable in normal adult brain
quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview
-
quantitative RT-PCR and real-time PCR CYP46 expression analysis, overview
neuronal-specific CYP46A1 protein levels are decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls
-
abnormal induction of the enzyme in patients with Alzheimers disease
quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview
-
contains cholesterol 24-hydroxylase mRNA but does not synthesize 24S-hydroxycholesterol
additional information
-
quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview
additional information
quantification of membrane-associated CYP46A1 in brain and retina, and analysis of tissue-dependent enzyme-product relationships, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
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
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
-
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
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
metabolism
-
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
-
cholesterol 24S-hydroxylase is a cholesterol metabolic enzyme with regulatory function in traumatic brain injury, overview
physiological function
-
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
-
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
-
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
-
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
-
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
-
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
mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site, overview
additional information
-
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
-
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CP46A_HUMAN
500
0
56821
Swiss-Prot
Secretory Pathway (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
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
analysis of the crystal structure of cholesterol sulfate-bound CYP46A1, PDB ID 2Q9F
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A1309C
-
destroys its heme structure, resulting in the complete lack of cholesterol 24-hydroxylase activity
K422A
site-directed mutagenesis, the K422A mutant retains the ability to be activated by EFV, although to a slightly lower extent than wild-type CYP46A1. The cholesterol-bound K422A mutant also shows cooperativity similar to cholesterol-bound wild-type CYP46A1. Binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
K94A
site-directed mutagenesis, the K94A replacement produces inactive P420 protein
R138A
site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
R139A
site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
R147A
site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is unaltered compared to the wild-type
R424A
site-directed mutagenesis, the R424A mutant shows a total loss of the ability to be activated by EFV. The R424A replacement affects EFV binding to the allosteric site and cholesterol binding to the CYP46A1 active site. Binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
additional information
additional information
-
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
additional information
-
determination of single nucleotide polymorphisms in North American Caucasians and Caribbean Hispanic Alzheimer patients, overview
additional information
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
additional information
-
polymorphisms within the CYP46A1 gene are associated with Alzheimers disease incidence
additional information
construction of truncated enzyme mutant DELTA(3-27)CYP46A1
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
-
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
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DNA and amino acid sequence determnination and analysis, determination of single nucleotide polymorphisms in North American Caucasians and Caribbean Hispanic Alzheimer patients, overview
-
expression in Escherichia coli, wild-type and trucation mutatants. All four mutants lack the N-terminal transmembrane region (residues 327), 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 494499), and DELTA46A1DELTA lacks the C-terminal proline-rich region
-
full-length and truncated (DELTA2-50) CYP46A1 expressed in Escherichia coli membranes
gene CYP46A1, recombinant expression of wild-type full-length and mutant truncated forms of enzyme CYP46A1 in Escherichia coli
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
generation of imidazo[1,2-a]pyridine analogues that effectively inhibit cholesterol 24-hydroxylase (CYP46A1). They can be used for prophylactic treatment of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease
medicine
medicine
-
CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease
medicine
-
genotyping of CYP46A1 gene polymorphisms (associated with the risk of Alzheimer's disease in Chinese)
medicine
-
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
medicine
restoring CYP46A1 activity in the striatum promises a therapeutic approach in Huntington's disease
medicine
the enzyme is a potential target for Alzheimers disease as it can be activated pharmacologically by some of the marketed drugs as exemplified by efavirenz (EFV), the anti-HIV medication
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
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
Russell, D.W.
Oxysterol biosynthetic enzymes
Biochim. Biophys. Acta
1529
126-135
2000
Mus musculus (Q9WVK8), Homo sapiens (Q9Y6A2)
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
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
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
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
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
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
Pikuleva, I.A.
Cholesterol-metabolizing cytochromes P450
Drug Metab. Dispos.
34
513-520
2006
Homo sapiens
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
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 (Q9Y6A2)
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 (Q9Y6A2), Homo sapiens
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
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)
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
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
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
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
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
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
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
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
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, Homo sapiens (Q9Y6A2)
Fourgeux, C.; Bron, A.; Acar, N.; Creuzot-Garcher, C.; Bretillon, L.
24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma
Chem. Phys. Lipids
164
496-499
2011
Homo sapiens
Maioli, S.; Bavner, A.; Ali, Z.; Heverin, M.; Ismail, M.A.; Puerta, E.; Olin, M.; Saeed, A.; Shafaati, M.; Parini, P.; Cedazo-Minguez, A.; Bjoerkhem, I.
Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain?
PLoS ONE
8
e68534
2013
Homo sapiens
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)
Uto, Y.
Imidazo[1,2-a]pyridines as cholesterol 24-hydroxylase (CYP46A1) inhibitors: a patent evaluation (WO2014061676)
Expert Opin. Ther. Pat.
25
373-377
2015
Homo sapiens (Q9Y6A2)
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