CYP46A1

Summary

CYP46A1 (cytochrome P450 family 46 subfamily A member 1, HGNC:2641) is a protein-coding gene on chromosome 14q32.2, encoding Cholesterol 24-hydroxylase (Q9Y6A2). P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein is expressed in the brain, where it converts cholesterol to 24S-hydroxycholesterol. While cholesterol cannot pass the blood-brain barrier, 24S-hydroxycholesterol can be secreted in the brain into the circulation to be returned to the liver for catabolism.

Source: NCBI Gene 10858 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 40 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006668

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2641
Approved symbol	CYP46A1
Name	cytochrome P450 family 46 subfamily A member 1
Location	14q32.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000036530
Ensembl biotype	protein_coding
OMIM	604087
Entrez	10858

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000261835, ENST00000380228, ENST00000554176, ENST00000554611, ENST00000554917, ENST00000556313, ENST00000556822, ENST00000900093, ENST00000900094, ENST00000900095, ENST00000900096, ENST00000900097, ENST00000941881

RefSeq mRNA: 1 — MANE Select: NM_006668 NM_006668

CCDS: CCDS9954

Canonical transcript exons

ENST00000261835 — 15 exons

Exon	Start	End
ENSE00000660303	99721956	99722066
ENSE00000660305	99726190	99726256
ENSE00000941498	99707568	99707678
ENSE00002228051	99684298	99684536
ENSE00002521196	99726557	99727301
ENSE00003461591	99691081	99691161
ENSE00003492395	99716137	99716199
ENSE00003496585	99691780	99691861
ENSE00003518507	99725391	99725479
ENSE00003535628	99715810	99715960
ENSE00003550580	99699466	99699539
ENSE00003563420	99721239	99721323
ENSE00003565465	99706647	99706785
ENSE00003574464	99718054	99718126
ENSE00003579073	99700015	99700101

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 98.95.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1519 / max 130.3071, expressed in 368 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141396	2.0531	361
141395	0.0517	31
141394	0.0471	26

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	98.95	gold quality
putamen	UBERON:0001874	98.28	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.20	gold quality
caudate nucleus	UBERON:0001873	98.18	gold quality
CA1 field of hippocampus	UBERON:0003881	98.17	gold quality
nucleus accumbens	UBERON:0001882	97.81	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.81	gold quality
entorhinal cortex	UBERON:0002728	97.79	gold quality
superior frontal gyrus	UBERON:0002661	97.48	gold quality
orbitofrontal cortex	UBERON:0004167	96.98	gold quality
postcentral gyrus	UBERON:0002581	96.56	gold quality
parietal lobe	UBERON:0001872	96.24	gold quality
prefrontal cortex	UBERON:0000451	96.15	gold quality
frontal cortex	UBERON:0001870	96.11	gold quality
endothelial cell	CL:0000115	95.96	gold quality
right frontal lobe	UBERON:0002810	95.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.95	gold quality
primary visual cortex	UBERON:0002436	95.91	gold quality
temporal lobe	UBERON:0001871	95.65	gold quality
anterior cingulate cortex	UBERON:0009835	95.49	gold quality
telencephalon	UBERON:0001893	95.48	gold quality
cingulate cortex	UBERON:0003027	95.48	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.43	gold quality
neocortex	UBERON:0001950	95.12	gold quality
cerebral cortex	UBERON:0000956	95.00	gold quality
Ammon’s horn	UBERON:0001954	94.88	gold quality
forebrain	UBERON:0001890	94.74	gold quality
occipital lobe	UBERON:0002021	94.54	gold quality
amygdala	UBERON:0001876	94.39	gold quality
cranial nerve II	UBERON:0000941	93.59	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.71
E-MTAB-6678	no	3.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3, SP4

miRNA regulators (miRDB)

34 targeting CYP46A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3152-3P	99.10	66.35	678
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-432-5P	98.00	68.13	989
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-1293	96.16	64.69	916

Literature-anchored findings (GeneRIF, showing 40)

• In addition to its involvement in cholesterol homeostasis in the brain, CYP46A1 has a broad substrate specificity and is able to metabolize neurosteroids and drugs that can cross the blood-brain barrier and are targeted to the central nervous system. (PMID:14640697)
• Polymorphisms in the CYP46 gene are found not to be risk factors for Alzheimer’s disease nor are they associated with parenchymal or vascular accumulation of amyloid-beta protein. (PMID:15106838)
• The distribution of CYP46 genotypes was significantly different in AD compared to controls and the CYP46 and ApoE polymorphisms synergically increase the risk for AD development. (PMID:15165699)
• In contrast to two previous reports but in accordance with one other, we were unable to detect an association between an intron 2 polymorphism of CYP46 and Alzheimer disease. (PMID:15172102)
• the polymorphism of CYP46 intron 2 is implicated in the susceptibility to late-onset Alzheimer’s disease and a strong synergistic interaction between CYP46 TT homozoygots (PMID:15450677)
• The GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. (PMID:15936520)
• Based on the results of genome-wide screens, along with biological studies, we selected three genes as candidates for AD risk factors: ATP-binding cassette transporter A1 (ABCA1), cholesterol 25-hydroxylase (CH25H) and cholesterol 24-hydroxylase (CH24H). (PMID:16157450)
• Polymorphism was associated with the risk of Alzheimer disease(AD) but subjects homozygous for the C alleles were protected from AD with an adjusted odds ratio. (PMID:16734927)
• here was no significant difference in the genotype or allele frequencies for CYP46 gene between AD patients and controls. (PMID:17335784)
• substantial substrate-induced conformational changes in CYP46A1 suggest that structurally distinct compounds could bind in the enzyme active site (PMID:18621681)
• The expression of CYP46A1, as well as other cytochrome P450s involved in cholesterol homeostasis, are potently regulated by histone acetylation status. (PMID:19059217)
• the substrate, cholesterol, enters CYP46A1 from the membrane (PMID:19161969)
• Cholesterol 24-hydroxylase (CYP46A1) polymorphisms are associated with faster cognitive deterioration in Chinese older persons (PMID:19212968)
• From the logistic regression ananlsis of this stidy showed that the highest risk for was found for Alzheimer’s disease individuals who co-inherited APOE epsilon4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46 rs754203 g allele. (PMID:19363267)
• The rs754203 SNP in CYP46A1 was associated with a risk for POAG. This polymorphism was not associated with changes in plasma 24S-hydroxycholesterol. (PMID:19553612)
• The data of this study suggested that CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects. (PMID:19647891)
• These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD. (PMID:20193040)
• Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. (PMID:20667828)
• Study of two independent Chinese data sets indicates individuals with CYP46A1 promoter bearing the CG haplotype are genetically more susceptible to Alzheimer’s disease than those with TA haplotype. (PMID:20693622)
• The average P450 concentrations/mg of total tissue protein were 345 fmol of CYP46A1 and 110 fmol of CYP27A1 in the temporal lobe, and 60 fmol of CYP46A1 and 490 fmol of CYP27A1 in the retina. (PMID:21049985)
• The rs754203 polymorphism itself is unlikely a genetic risk factor for primary open angle glaucoma in Caucasian individuals. (PMID:21386929)
• There was no association between the CYP46 genotype and measures of cognitive event-related potentials. (PMID:21729100)
• Differentiated Ntera2/clone D1 (NT2) cells express the key genes involved in brain cholesterol homeostasis including CYP46A1. (PMID:22185844)
• The intronic polymorphism in CYP46A1 is associated with Alzheimer disease in a Chinese Han population, and the CYP46A1 T allele might be a risk factor. (PMID:22528464)
• The rs754203 C allele in the CYP46A1 gene may confer a higher risk for exudative age-related macular degeneration in patients who carry no risk alleles in the CFH and LOC387715 genes. (PMID:22977134)
• An meta-analysis has successfully proved that CC genotype of the CYP46A1 T/C polymorphism could increase the risk of Alzheimer’s disease. (PMID:23070465)
• A meta-analysis indicates that the CYP46 gene SNP rs754203 is not significantly associated with sporadic Alzheimer’s disease susceptibility in Chinese Han populations. (PMID:23167762)
• analysis of binding of the cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1 (PMID:23288837)
• To identify the determinants of tight azole binding to CYP46A1. (PMID:23604141)
• results of meta-analysis suggested that CYP46A1 rs754203 is a minor risk factor for Alzheimer’s disease (PMID:23792195)
• While there were no differences in cognitive performance between participants with and those without metabolic syndrome, ApoE and CYP46 genotypes did correlate with mental manipulation scores. (PMID:24924840)
• Human CYP46A1 oxidizes 7-dehydrocholesterol to 24-hydroxy-7-dehydrocholesterol and 25-hydroxy-7-dehydrocholesterol. (PMID:25017465)
• under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in liver X receptor activity (PMID:25084760)
• hippocampal CYP46A1 protein and 24S-hydroxycholesterol levels were reduced in a mouse model of Alzheimer’s Disease-like Tau neuropathology (PMID:26358780)
• CYP46A1 rs4900442 genetic polymorphism was associated with increased risk of Alzheimer disease in the Chinese population, but no evidences were detected in Caucasian population. (PMID:27026489)
• Findings of this study suggest that CYP46A1 gene and PPARgamma2 gene polymorphisms can be a predictive marker for early identification of population at risk of primary open angle glaucoma (POAG). (PMID:27162448)
• Polymorphism within the CYP46A1 gene is a positive risk factor for type 2 diabetes mellitus. (PMID:28206854)
• Data suggest that CYP46A1, the enzyme responsible for the majority of cholesterol elimination from the brain, exhibits activation by neurotransmitters, L-glutamate, L-aspartate, gamma-aminobutyric acid, and acetylcholine; L-glutamate-induced CYP46A1 activation may be of physiological relevance. (PMID:28642370)
• the APOEepsilon4 alleles were significantly higher in patients with Alzheimer’s disease (AD) and there was a potential synergistic interaction between the CYP46A1 C allele and APOEepsilon4 allele in AD. (PMID:29516283)
• Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma. (PMID:31777202)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyp46a1.2	ENSDARG00000004262
danio_rerio	cyp46a1.1	ENSDARG00000012137
danio_rerio	cyp46a1.3	ENSDARG00000089177
danio_rerio	cyp46a1.5	ENSDARG00000093477
danio_rerio	cyp46a1.4	ENSDARG00000113820
mus_musculus	Cyp46a1	ENSMUSG00000021259
rattus_norvegicus	Cyp46a1	ENSRNOG00000007147

Protein

Protein identifiers

Cholesterol 24-hydroxylase — Q9Y6A2 (reviewed: Q9Y6A2)

Alternative names: Cholesterol 24-monooxygenase, Cholesterol 24S-hydroxylase, Cytochrome P450 46A1

All UniProt accessions (4): Q9Y6A2, G3V366, H0YJI0, H0YJU5

UniProt curated annotations — full annotation on UniProt →

Function. P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation. By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning. Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis. Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain. May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane. Postsynapse. Presynapse. Cell projection. Dendrite.

Tissue specificity. Expressed in brain. The mRNA was broadly distributed with higher levels in gray matter zones and lower levels in regions rich in white matter. Not detected in fetal sample but its expression increases linearly with age.

Pathway. Steroid metabolism; cholesterol degradation. Lipid metabolism; C21-steroid hormone metabolism.

Similarity. Belongs to the cytochrome P450 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y6A2-1	1	yes
Q9Y6A2-2	2
Q9Y6A2-3	3

RefSeq proteins (1): NP_006659* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002401	Cyt_P450_E_grp-I	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily
IPR039983	CYP46A1	Family

Pfam: PF00067

Enzyme classification (BRENDA):

• EC 1.14.14.25 — cholesterol 24-hydroxylase (BRENDA: 16 organisms, 44 substrates, 69 inhibitors, 10 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(24S)-24-HYDROXYCHOLESTEROL	0.0015–0.0039	3
CHOLESTEROL	0.0053–0.0077	3
CHOLESTEROL 3-SULFATE	0.0033–0.0049	2

Catalyzed reactions (Rhea), 12 shown:

• cholesterol + reduced [NADPH–hemoprotein reductase] + O2 = (24S)-hydroxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:22716)
• testosterone + reduced [NADPH–hemoprotein reductase] + O2 = 6beta,17beta-dihydroxyandrost-4-en-3-one + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46296)
• testosterone + reduced [NADPH–hemoprotein reductase] + O2 = 2-hydroxytestosterone + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46300)
• testosterone + reduced [NADPH–hemoprotein reductase] + O2 = 16beta,17beta-dihydroxyandrost-4-en-3-one + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46304)
• progesterone + reduced [NADPH–hemoprotein reductase] + O2 = 17alpha-hydroxyprogesterone + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46308)
• 7alpha-hydroxycholesterol + reduced [NADPH–hemoprotein reductase] + O2 = (24S)-7alpha-dihydroxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46380)
• (24S)-hydroxycholesterol + reduced [NADPH–hemoprotein reductase] + O2 = 24S,25-dihydroxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46384)
• (24S)-hydroxycholesterol + reduced [NADPH–hemoprotein reductase] + O2 = (24S,25R)-24,26-dihydroxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46388)
• 4beta-hydroxycholesterol + reduced [NADPH–hemoprotein reductase] + O2 = 4beta,24S-dihydroxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46392)
• desmosterol + reduced [NADPH–hemoprotein reductase] + O2 = (24S)-25-epoxycholesterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:53232)
• desmosterol + reduced [NADPH–hemoprotein reductase] + O2 = (24Z),26-hydroxydesmosterol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:53236)
• 7-dehydrocholesterol + reduced [NADPH–hemoprotein reductase] + O2 = cholesta-5,7-dien-3beta,25-diol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:53240)

UniProt features (49 total): helix 23, strand 14, turn 6, splice variant 3, chain 1, transmembrane region 1, binding site 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
7N6F	X-RAY DIFFRACTION	1.4
3MDM	X-RAY DIFFRACTION	1.6
7N3L	X-RAY DIFFRACTION	1.63
9NNA	X-RAY DIFFRACTION	1.67
7N3M	X-RAY DIFFRACTION	1.7
9NNI	X-RAY DIFFRACTION	1.7
9NNM	X-RAY DIFFRACTION	1.7
9NNO	X-RAY DIFFRACTION	1.8
2Q9F	X-RAY DIFFRACTION	1.9
9NNE	X-RAY DIFFRACTION	1.95
7LRL	X-RAY DIFFRACTION	2
3MDR	X-RAY DIFFRACTION	2
7LS4	X-RAY DIFFRACTION	2.05
4FIA	X-RAY DIFFRACTION	2.1
7LS3	X-RAY DIFFRACTION	2.15
9NNJ	X-RAY DIFFRACTION	2.29
3MDT	X-RAY DIFFRACTION	2.3
2Q9G	X-RAY DIFFRACTION	2.4
3MDV	X-RAY DIFFRACTION	2.4
4ENH	X-RAY DIFFRACTION	2.5
4J14	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6A2-F1	94.90	0.88

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 437 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-193775	Synthesis of bile acids and bile salts via 24-hydroxycholesterol
R-HSA-211976	Endogenous sterols

MSigDB gene sets: 129 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, REACTOME_ENDOGENOUS_STEROLS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CELL_CELL_SIGNALING, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GTGTTGA_MIR505

GO Biological Process (13): bile acid biosynthetic process (GO:0006699), cholesterol catabolic process (GO:0006707), xenobiotic metabolic process (GO:0006805), nervous system development (GO:0007399), sterol metabolic process (GO:0016125), progesterone metabolic process (GO:0042448), regulation of long-term synaptic potentiation (GO:1900271), protein localization to membrane raft (GO:1903044), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), C21-steroid hormone metabolic process (GO:0008207), regulation of biological quality (GO:0065008)

GO Molecular Function (10): iron ion binding (GO:0005506), steroid hydroxylase activity (GO:0008395), heme binding (GO:0020037), cholesterol 24-hydroxylase activity (GO:0033781), testosterone 6-beta-hydroxylase activity (GO:0050649), testosterone 16-beta-hydroxylase activity (GO:0062184), monooxygenase activity (GO:0004497), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872)

GO Cellular Component (8): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), dendrite (GO:0030425), presynapse (GO:0098793), postsynapse (GO:0098794), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Synthesis of bile acids and bile salts	1
Cytochrome P450 - arranged by substrate type	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
steroid metabolic process	2
steroid hydroxylase activity	2
oxidoreductase activity	2
synapse	2
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
cholesterol metabolic process	1
sterol catabolic process	1
alcohol catabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
system development	1
C21-steroid hormone metabolic process	1
ketone metabolic process	1
olefinic compound metabolic process	1
regulation of synaptic plasticity	1
long-term synaptic potentiation	1
protein localization to membrane	1
primary metabolic process	1
lipid metabolic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
hormone metabolic process	1
biological regulation	1
transition metal ion binding	1
monooxygenase activity	1
tetrapyrrole binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
neuron projection	1
dendritic tree	1
cell junction	1

Protein interactions and networks

STRING

1934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYP46A1	APOE	P02649	740
CYP46A1	CH25H	O95992	686
CYP46A1	CYP7B1	O75881	682
CYP46A1	CYP39A1	Q9NYL5	676
CYP46A1	APP	P05067	643
CYP46A1	AMACR	Q9UHK6	642
CYP46A1	ABCA1	O95477	641
CYP46A1	CYP7A1	P22680	632
CYP46A1	ABCG1	P45844	632
CYP46A1	HMGCR	P04035	622
CYP46A1	ABCA2	Q9BZC7	622
CYP46A1	HSD3B7	Q9H2F3	579
CYP46A1	CYP8B1	Q9UNU6	537
CYP46A1	HSD11B1	P28845	531
CYP46A1	DHCR24	Q15392	531

IntAct

6 interactions, top by confidence:

A	B	Type	Score
	CYP46A1	psi-mi:“MI:0915”(physical association)	0.540
	CYP46A1	psi-mi:“MI:0407”(direct interaction)	0.540
	CYP46A1	psi-mi:“MI:0407”(direct interaction)	0.440
	CYP46A1	psi-mi:“MI:0414”(enzymatic reaction)	0.440
CYP46A1	RIN3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (4): CYP46A1 (Two-hybrid), CYP46A1 (Biochemical Activity), CYP46A1 (Two-hybrid), CYP46A1 (Two-hybrid)

ESM2 similar proteins: O42231, O42430, O42457, O77809, O77810, P00184, P00185, P00186, P00187, P04798, P04799, P05176, P05177, P14581, P24453, P33616, P56590, P56591, P56592, P79716, P79760, P79761, Q00557, Q06367, Q0IIF9, Q3LFT9, Q3LFU0, Q4H4C3, Q4V8D1, Q5KQT6, Q5KQT7, Q5RBQ1, Q5TCH4, Q64391, Q6GUR1, Q6JZS3, Q7Z449, Q8SPK0, Q92039, Q92095

Diamond homologs: A0A0A2J1Z6, A0A0C3HJL3, A0A0G4P2K0, A0A100IM63, A0A101MN42, A0A165U5Z9, A0A3G9HRC2, A0A455R5H4, A2QLV1, A2RRT9, B0XZV0, B1B557, B2RML6, B3FWR7, B8QHP1, B8QHP5, C8V0D4, C9K1X6, D4AY62, F4IK45, G5EJN7, G7XMT1, G9MLG2, H2DH17, I3V6B7, I7ZK32, L8AXV5, O08336, O08394, O16805, O49394, O61309, O70537, P04800, P05183, P10615, P14779, P24462, P30607, P30609

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

40 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3171 predictions. Top by Δscore:

Variant	Effect	Δscore
14:99684533:CCAGG:C	donor_loss	1.0000
14:99684535:AGG:A	donor_loss	1.0000
14:99684537:G:GA	donor_loss	1.0000
14:99684538:T:A	donor_loss	1.0000
14:99691774:TTCCA:T	acceptor_loss	1.0000
14:99691775:TCCAG:T	acceptor_loss	1.0000
14:99691777:CAGGG:C	acceptor_loss	1.0000
14:99691778:A:AG	acceptor_gain	1.0000
14:99691778:AG:A	acceptor_gain	1.0000
14:99691779:G:GA	acceptor_loss	1.0000
14:99691779:G:GG	acceptor_gain	1.0000
14:99691779:GG:G	acceptor_gain	1.0000
14:99707567:GGCA:G	acceptor_gain	1.0000
14:99715924:G:GT	donor_gain	1.0000
14:99716135:A:AG	acceptor_gain	1.0000
14:99716136:G:GA	acceptor_gain	1.0000
14:99716136:GCT:G	acceptor_gain	1.0000
14:99716626:G:T	donor_gain	1.0000
14:99721234:CACA:C	acceptor_loss	1.0000
14:99721236:CAG:C	acceptor_loss	1.0000
14:99721237:A:AG	acceptor_gain	1.0000
14:99721237:AGG:A	acceptor_loss	1.0000
14:99721238:G:GG	acceptor_gain	1.0000
14:99721310:A:AG	donor_gain	1.0000
14:99721311:G:GG	donor_gain	1.0000
14:99721330:G:GT	donor_gain	1.0000
14:99721330:G:T	donor_gain	1.0000
14:99721341:G:T	donor_gain	1.0000
14:99725389:A:AG	acceptor_gain	1.0000
14:99725390:G:GA	acceptor_gain	1.0000

AlphaMissense

3252 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:99721975:G:C	R362T	0.999
14:99721975:G:T	R362M	0.999
14:99721976:G:C	R362S	0.999
14:99721976:G:T	R362S	0.999
14:99726212:T:C	F430L	0.999
14:99726214:C:A	F430L	0.999
14:99726214:C:G	F430L	0.999
14:99691833:T:A	V85D	0.998
14:99700071:G:C	R138P	0.998
14:99721966:A:T	E359V	0.998
14:99722044:T:A	V385D	0.998
14:99725394:A:C	S394R	0.998
14:99725396:C:A	S394R	0.998
14:99725396:C:G	S394R	0.998
14:99725413:G:C	R400P	0.998
14:99725460:T:C	F416L	0.998
14:99725462:C:A	F416L	0.998
14:99725462:C:G	F416L	0.998
14:99700091:T:C	F145L	0.997
14:99700093:C:A	F145L	0.997
14:99700093:C:G	F145L	0.997
14:99721965:G:A	E359K	0.997
14:99699495:G:C	K104N	0.996
14:99699495:G:T	K104N	0.996
14:99718099:T:C	L318P	0.996
14:99721972:T:C	L361P	0.996
14:99722004:C:A	R372S	0.996
14:99725427:T:C	F405L	0.996
14:99725429:T:A	F405L	0.996
14:99725429:T:G	F405L	0.996

dbSNP variants (sampled 300 via entrez): RS1000000792 (14:99701376 A>G), RS1000210437 (14:99719747 CT>C,CTT), RS1000264443 (14:99699227 C>A,T), RS1000302677 (14:99725922 G>A), RS1000308057 (14:99688244 A>C,G), RS1000374434 (14:99723132 G>A), RS1000386742 (14:99705333 A>G), RS1000501709 (14:99697449 T>G), RS1000510732 (14:99708757 T>C), RS1000530880 (14:99714339 C>T), RS1000688070 (14:99713909 A>G), RS1001003965 (14:99697758 C>A), RS1001010892 (14:99723411 C>A,T), RS1001102603 (14:99711197 C>A), RS1001104683 (14:99717263 G>A)

Disease associations

OMIM: gene MIM:604087 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): pulmonary disease, chronic obstructive, susceptibility to (MONDO:0100167)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002938_29	Copper levels	5.000000e-06
GCST003474_8	Scalp hair shape	1.000000e-07
GCST005194_176	Coronary artery disease	5.000000e-16
GCST005195_2	Coronary artery disease	3.000000e-16
GCST007096_151	Pulse pressure	7.000000e-10
GCST007097_162	Pulse pressure	2.000000e-06
GCST007097_163	Pulse pressure	3.000000e-08
GCST010767_2	Coronary atherosclerosis (time to event)	6.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004918	age at diagnosis
EFO:0007938	coronary atherosclerosis measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523510 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 807,132 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL223228	EFAVIRENZ	4	35,999
CHEMBL638	VORICONAZOLE	4	23,088
CHEMBL4298172	SOTICLESTAT	3	88
CHEMBL112570	CHOLESTEROL	2	747,957

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CYP39, CYP46 and CYP51 families

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
soticlestat	Inhibition	8.35	pIC50

Binding affinities (BindingDB)

13 measured of 13 human assays (13 total across all organisms); most potent 13 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3-fluoroazetidin-1-yl)-[1-[4-(5-methyl-1,3-thiazol-2-yl)-3-pyridinyl]piperidin-4-yl]methanone	IC50	4.9 nM	US-9963443: Radiolabeled compounds
N-cyclopropyl-1-[4-(4-fluorophenyl)pyrimidin-5-yl]-N-methylpiperidine-4-carboxamide	IC50	5.4 nM	US-9963443: Radiolabeled compounds
[1-[4-(4-bromopyrazol-1-yl)-3-pyridinyl]piperidin-4-yl]-(3-fluoroazetidin-1-yl)methanone	IC50	6.9 nM	US-9963443: Radiolabeled compounds
(3-fluoroazetidin-1-yl)-[1-[4-(4-methylpyrazol-1-yl)-3-pyridinyl]piperidin-4-yl]methanone	IC50	7.1 nM	US-9963443: Radiolabeled compounds
1-[4-(4-chloropyrazol-1-yl)-3-pyridinyl]-N-methyl-N-(oxan-4-yl)piperidine-4-carboxamide	IC50	7.4 nM	US-9963443: Radiolabeled compounds
(3-fluoroazetidin-1-yl)-[1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl]methanone	IC50	8.8 nM	US-9963443: Radiolabeled compounds
[1-[4-(4-cyclopropylpyrazol-1-yl)-3-pyridinyl]piperidin-4-yl]-(3-fluoroazetidin-1-yl)methanone	IC50	10 nM	US-9963443: Radiolabeled compounds
[1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl]-[(3R)-3-fluoropyrrolidin-1-yl]methanone	IC50	16 nM	US-9963443: Radiolabeled compounds
1-[4-(4-chloropyrazol-1-yl)-3-pyridinyl]-N-methyl-N-[(3R)-oxolan-3-yl]piperidine-4-carboxamide	IC50	17 nM	US-9963443: Radiolabeled compounds
N-(2-fluoroethyl)-N-[(4-fluorophenyl)methyl]-4-[4-(4-methylpyrazol-1-yl)-3-pyridinyl]piperazine-1-carboxamide	IC50	17 nM	US-9963443: Radiolabeled compounds
[1-[4-(4-chloropyrazol-1-yl)-3-pyridinyl]piperidin-4-yl]-(3-fluoroazetidin-1-yl)methanone	IC50	19 nM	US-9963443: Radiolabeled compounds
[1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl]-[(3S)-3-fluoropyrrolidin-1-yl]methanone	IC50	20 nM	US-9963443: Radiolabeled compounds
N-[(3S)-2-[[4-(4-chloropyrazol-1-yl)-3-pyridinyl]methyl]oxolan-3-yl]piperidine-4-carboxamide	IC50	20 nM	US-9963443: Radiolabeled compounds

ChEMBL bioactivities

87 potent at pChembl≥5 of 93 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5279173
8.62	IC50	2.4	nM	CHEMBL5288661
8.57	IC50	2.7	nM	CHEMBL5276973
8.37	IC50	4.3	nM	CHEMBL5282804
8.36	IC50	4.4	nM	CHEMBL5271033
8.33	IC50	4.7	nM	CHEMBL5269674
8.31	IC50	4.9	nM	CHEMBL5289771
8.31	IC50	4.9	nM	CHEMBL4547685
8.27	IC50	5.4	nM	CHEMBL4587543
8.21	IC50	6.1	nM	CHEMBL5284673
8.16	IC50	6.9	nM	CHEMBL4517530
8.15	IC50	7.1	nM	CHEMBL4522732
8.14	IC50	7.3	nM	CHEMBL5093928
8.13	IC50	7.4	nM	SOTICLESTAT
8.13	IC50	7.4	nM	CHEMBL4521254
8.11	IC50	7.8	nM	CHEMBL5275089
8.10	IC50	7.9	nM	CHEMBL5275183
8.09	IC50	8.1	nM	CHEMBL4594072
8.07	IC50	8.5	nM	CHEMBL4532699
8.06	IC50	8.8	nM	CHEMBL4558147
8.02	IC50	9.5	nM	CHEMBL4527933
8.00	IC50	10	nM	CHEMBL4587383
7.96	Ki	11	nM	VORICONAZOLE
7.92	IC50	12	nM	CHEMBL4538165
7.92	IC50	12	nM	CHEMBL5083867
7.89	Ki	12.89	nM	CHEMBL5195220
7.85	IC50	14	nM	CHEMBL5076011
7.80	IC50	16	nM	CHEMBL5082831
7.80	IC50	16	nM	CHEMBL5286208
7.80	IC50	16	nM	CHEMBL4537955
7.77	IC50	17	nM	CHEMBL5274224
7.77	IC50	17	nM	CHEMBL4578812
7.77	IC50	17	nM	CHEMBL4538659
7.72	IC50	19	nM	CHEMBL4568019
7.70	IC50	20	nM	CHEMBL4522699
7.70	IC50	20	nM	CHEMBL5893119
7.68	IC50	21	nM	CHEMBL5269081
7.66	IC50	22	nM	VORICONAZOLE
7.62	IC50	24	nM	CHEMBL4580834
7.55	IC50	28	nM	CHEMBL5087082
7.44	IC50	36	nM	CHEMBL5272679
7.36	IC50	44	nM	CHEMBL4561003
7.33	IC50	47	nM	VORICONAZOLE
7.32	IC50	48	nM	CHEMBL5083692
7.30	Kd	50	nM	CHEMBL1231592
7.30	Kd	50	nM	VORICONAZOLE
7.28	IC50	52	nM	CHEMBL4555625
7.24	IC50	58	nM	CHEMBL5094350
7.22	IC50	60	nM	CHEMBL5285548
7.19	IC50	65	nM	CHEMBL5082660

PubChem BioAssay actives

66 with measured affinity, of 120 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyrimidin-4-yl-3-pyridinyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0010	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(5-chloro-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0024	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0027	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyrimidin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0043	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(4-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0044	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(5-methoxy-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0047	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-[5-methyl-2-(3-methyl-4-pyridinyl)phenyl]methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0049	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(5-fluoro-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0061	uM
1-[4-(4-fluorophenyl)pyrimidin-5-yl]-N,N-dimethylpiperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0073	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyridin-4-yl-3-pyridinyl)methanone	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0074	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-methyl-6-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0078	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0079	uM
N-cyclopropyl-1-(4-phenyl-3-pyridinyl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0081	uM
N,N-dimethyl-1-[4-(4-methylpyrazol-1-yl)-3-pyridinyl]piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0085	uM
1-[4-(4-bromopyrazol-1-yl)-3-pyridinyl]-N,N-dimethylpiperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0095	uM
N,N-dimethyl-1-[4-(5-methyl-1,3-thiazol-2-yl)-3-pyridinyl]piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0120	uM
1-[4-(4-cyclopropylpyrazol-1-yl)-3-pyridinyl]-N,N-dimethylpiperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0120	uM
3-(3,4-dihydroxyphenyl)-N-[4-[3-[[(E)-3-[4-hydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]prop-2-enoyl]amino]propylamino]butyl]propanamide	1854433: Inhibition of CYP46A1 (unknown origin)	ki	0.0129	uM
N-ethyl-N-methyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0140	uM
N,N-dimethyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0160	uM
(4-benzyl-3-hydroxypiperidin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0160	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-[2-(3-fluoro-4-pyridinyl)-5-methylphenyl]methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0170	uM
[4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl]-(2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0210	uM
1-[4-(4-chloropyrazol-1-yl)-3-pyridinyl]-N,N-dimethylpiperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0240	uM
N-phenyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0280	uM
[4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl]-(2-pyrimidin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0360	uM
N-cyclopropyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0440	uM
N,N-dimethyl-1-(4-pyrazol-1-yl-3-pyridinyl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0480	uM
N-cyclopropyl-4-(4-phenyl-3-pyridinyl)piperazine-1-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0520	uM
N-ethyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0580	uM
[5,5-dimethyl-3-(2-methylphenyl)-4H-pyrazol-1-yl]-pyridin-4-ylmethanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0600	uM
N,N-dimethyl-1-[4-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0650	uM
N,N-dimethyl-1-(4-pyridin-2-yl-3-pyridinyl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0680	uM
N-methyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0720	uM
N-cyclopropyl-4-(4-phenyl-3-pyridinyl)benzamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.0740	uM
(4-benzyl-4-methoxypiperidin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0740	uM
1-benzyl-4-(5-methyl-2-pyridin-4-ylbenzoyl)piperazin-2-one	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0890	uM
(4-benzylpiperazin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.0930	uM
[4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl]-(2-pyridin-4-yl-3-pyridinyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.1000	uM
3-(3,4-dihydroxyphenyl)-N-[4-[3-[[(E)-3-[3-hydroxy-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]prop-2-enoyl]amino]propylamino]butyl]propanamide	1854433: Inhibition of CYP46A1 (unknown origin)	ki	0.1063	uM
(4-benzylpiperidin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.1100	uM
(4-benzyl-4-hydroxypiperidin-1-yl)-(3-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.1300	uM
N-cyclopropyl-1-(4-pyridin-2-yl-3-pyridinyl)piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.1600	uM
N-[4-[3-[[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]amino]propylamino]butyl]-3-[3-hydroxy-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]propanamide	1854433: Inhibition of CYP46A1 (unknown origin)	ki	0.2584	uM
[5-hydroxy-3-phenyl-5-(trifluoromethyl)-4H-pyrazol-1-yl]-pyridin-4-ylmethanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.3500	uM
N-cyclohexyl-4-(1H-imidazol-5-yl)piperidine-1-carbothioamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.4300	uM
(4-ethyl-4-hydroxypiperidin-1-yl)-(5-methyl-2-pyridin-4-ylphenyl)methanone	1933895: Inhibition of full length N-terminal his6-tagged human CH24H (28 to 494 residues) expressed in Escherichia coli DH5alpha using [14C] cholesterol as substrate preincubated for 15 mins followed by substrate addition and measured after 5 min in presence of beta-NADPH	ic50	0.5400	uM
Efavirenz	1653622: Binding affinity to recombinant human C-terminal 4His-tagged CYP46A1 delta(2 to 50) mutant expressed in Escherichia coli in absence of substrate by UV-spectrophotometric method	kd	0.8000	uM
N-cyclopropyl-4-(4-phenyl-3-pyridinyl)piperidine-1-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	0.9500	uM
N,N-dimethyl-1-[4-(3-methylpyrazol-1-yl)-3-pyridinyl]piperidine-4-carboxamide	1819613: Inhibition of CH24H expressing human 293-F cells for 15 minutes using [14C] cholesterol as substrate and measured after 5 hrs by trypan blue staining based thin-layer chromatography	ic50	1.1000	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
24-hydroxycholesterol	affects abundance, increases chemical synthesis, increases metabolic processing	2
Cholesterol	affects metabolic processing, increases hydroxylation, affects abundance	2
Particulate Matter	increases abundance, increases expression	2
methyleugenol	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
cholest-5-en-3 beta,7 alpha-diol	increases hydroxylation	1
fipronil	affects cotreatment, decreases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
6-methyl-2-(phenylethynyl)pyridine	increases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
DEET	affects cotreatment, decreases expression	1
Dextromethorphan	decreases methylation	1
Diclofenac	increases hydroxylation	1
Diethylhexyl Phthalate	decreases expression	1
Cholestanol	increases hydroxylation	1
Estradiol	affects binding, increases expression	1
Lead	affects expression	1
Phenacetin	decreases ethylation	1
Progesterone	increases hydroxylation	1
Rotenone	increases expression	1
Sodium Glutamate	decreases reaction, increases expression	1
Testosterone	increases hydroxylation	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

27 unique, capped per target: 24 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4417815	Binding	Inhibition of full-length recombinant human CYP46A1 assessed as cholesterol hydroxylation at 43 uM using cholesterol as substrate in presence of NADPH cytochrome P450 oxidoreductase by gas chromatography-mass spectrometry (Rvb = 100%)	Post-Translational Regulation of Catalytic Activities of Cytochrome P450 46A1 and Uses Thereof
CHEMBL4613993	ADMET	Inhibition of recombinant human C-terminal 4His-tagged CYP46A1 delta(2 to 50) mutant expressed in Escherichia coli at 60 to 100 uM using cholesterol as substrate measured after 30 mins in presence of cytochrome P450 oxidoreductase by gas ch	In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.