Information on EC 1.14.14.25 - cholesterol 24-hydroxylase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.14.14.25
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RECOMMENDED NAME
GeneOntology No.
cholesterol 24-hydroxylase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
cholesterol + [reduced NADPH-hemoprotein reductase] + O2 = (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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redox reaction
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reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Primary bile acid biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
cholesterol,NADPH-hemoprotein reductase:oxygen oxidoreductase (24-hydroxylating)
A P-450 heme-thiolate protein. The enzyme can also produce 25-hydroxycholesterol. In addition, it can further hydroxylate the product to 24,25-dihydroxycholesterol and 24,27-dihydroxycholesterol [2]. This reaction is the first step in the enzymic degradation of cholesterol in the brain as hydroxycholesterol can pass the blood---brain barrier whereas cholesterol cannot [3]. The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase [3].
CAS REGISTRY NUMBER
COMMENTARY hide
213327-78-7
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50812-30-1
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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-
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
zebra
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
APP23 mouse
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Manually annotated by BRENDA team
C57/B6-J mice
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Manually annotated by BRENDA team
and R6/2 mutant mice
SwissProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(24S)-24-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,25-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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-
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-
?
(24S)-24-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,27-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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-
-
-
?
(24S)-hydroxycholesterol + [reduced NADPH-hemoprotein reductase] + O2
24,25-dihydroxycholesterol + 24,27-dihydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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preferred substrate in vitro
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-
?
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
show the reaction diagram
cholesterol + reduced adrenodoxin + O2
24-hydroxycholesterol + oxidized adrenodoxin + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
cholesterol 3-sulfate + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol 3-sulfate + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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-
-
-
?
dextromethorphan + [reduced NADPH-hemoprotein reductase] + O2
?
show the reaction diagram
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O- and N-demethylation
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-
?
diclofenac + [reduced NADPH-hemoprotein reductase] + O2
?
show the reaction diagram
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4'-hydroxylation
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-
?
phenacetin + [reduced NADPH-hemoprotein reductase] + O2
?
show the reaction diagram
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O-deethylation
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-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
cholesterol + NADPH + O2
(24S)-hydroxycholesterol + NADP+ + H2O
show the reaction diagram
cholesterol + reduced adrenodoxin + O2
24-hydroxycholesterol + oxidized adrenodoxin + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + H+ + O2
(24S)-24-hydroxycholesterol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P-450
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cytochrome P450
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NADPH
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
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
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(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
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(4-benzyl-4-hydroxypiperidin-1-yl)([2,4'-bipyridin]-3-yl)methanone
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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
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2-[5-methyl-1-(pyridine-4-carbonyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl]benzonitrile
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8-(1,3-oxazol-5-yl)-N-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide
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clobenpropit
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complete inhibition
N-benzyl-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide
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shRNA
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knockdown
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siRNA
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reduction of the cholesterol 24-hydroxylase, which results in lower levels of Trk phosphorylation
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thioperamide
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66% inhibition
Tranylcypromine
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complete inhibition
voriconazole
[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
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[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
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additional information
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generation of a series of imidazo[1,2-a]pyridine analogues that effectively inhibit cholesterol 24-hydroxylase (CYP46A1), synthesis and evaluation, overview
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cholesterol 3-sulfate
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i.e. CH-35
efavirenz
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EFV, activates the enzyme pharmacologically as a potential target for Alzheimers disease
lovastatin
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induces and activates the enzyme, acts neuroprotectively in hippocampus after kainate injury, overview
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0015 - 0.0039
(24S)-24-hydroxycholesterol
0.0053 - 0.0077
cholesterol
0.0033 - 0.0049
cholesterol 3-sulfate
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00117 - 0.0153
(24S)-24-hydroxycholesterol
0.0018 - 0.11
cholesterol
0.0076 - 0.042
cholesterol 3-sulfate
additional information
additional information
Homo sapiens
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turnover-numbers of truncated enzyme forms
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000011
voriconazole
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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cerebellar interneurons and Purkinje cells
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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in the cerebellum
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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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
Manually annotated by BRENDA team
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of liver
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
53000
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immunoblotting
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
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1 * 49000, truncated enzyme form, SDS-PAGE
additional information
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structure-function relationship
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
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analysis of the crystal structure of cholesterol sulfate-bound CYP46A1, PDB ID 2Q9F
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial
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recombinant His-tagged enzyme by nickel affinity chromatography
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truncated enzyme forms
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5'-upstream region of human CYP46 gene
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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
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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
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DNA sequence determination and analysis
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DNA sequence determination and analysis, located on chromosome14q32.1
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expressed in 293 cells
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expressed in Escherichia coli
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expressed in Escherichia coli GC5 cells
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expressed in Mus musculus
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expression Escherichia coli, HEK293 cells transfected with CYP46A1
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expression in Escherichia coli
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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
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full ORF expression clone p46+ including the full cyp46A1 mouse open reading frame. Cyp46A1 overexpressed in 10 days in vitro hippocampal neurons
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full-length and truncated (DELTA2-50) CYP46A1 expressed in Escherichia coli membranes
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gene CYP46A1, CYP46A1 restoration protects from Exp-HTT-induced striatal dysfunctions in vitro. CYP46A1 restoration in the striatum improves the motor phenotype of R6/2 mice
gene CYP46A1, expression analysis
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gene CYP46A1, expressionin CHO-K1 cells and HEK-293 cells
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gene CYP46A1, quantitative expression analysis
gene CYP46A1, recombinant expression of wild-type full-length and mutant truncated forms of enzyme CYP46A1 in Escherichia coli
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His-tagged enzyme
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
ablation of the sensorimotor cortex induces an increase of Cyp46 immunoreactivity in the ipsilateral cortex in the brain
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ablation of the sensorimotor cortex induces an increase of Cyp46 immunoreactivity in the ipsilateral cortex in the brain; CYP46A1 expression is increased in the retina of voriconazole-treated rats
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age-associated increase in TrkB activity correlates with a mild yet progressive loss of cholesterol, which, in turn, correlates with increased expression of the cholesterol catabolic enzyme cholesterol 24-hydroxylase. Increased expression of cholesterol-24-hydroxylase in the hippocampus of aged mice
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Cyp46 is upregulated in traumatic brain injury, specifically in microglia
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CYP46A1 expression is increased in the retina of voriconazole-treated rats
expression of the gene in the mouse embryo as early as day 11.5 and gradual increase in mRNA and protein in postnatal brain. Over a 14-day culture period, during which the neurons extend processes and form increasing numbers of synapses but do not divide, there is a gradual increase in cholesterol 24-hydroxylase mRNA and protein
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gradual increase in mRNA and protein in postnatal brain
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intraperitoneal injection of a high dose of valproate (700 mg/kg) results in a modest induction of the mRNA expression of CYP46A1 in the liver, and CYP46A1 in the brain. Intraperitoneal injection of trichostatin A to male mice results in dose dependent increases in the expression of brain and liver CYP46A1
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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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A1309C
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destroys its heme structure, resulting in the complete lack of cholesterol 24-hydroxylase activity
K422A
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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
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site-directed mutagenesis, the K94A replacement produces inactive P420 protein
R138A
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site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
R139A
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site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type
R147A
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site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is unaltered compared to the wild-type
R424A
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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
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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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