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Q9Y6A2 (CP46A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cholesterol 24-hydroxylase

Short name=CH24H
EC=1.14.13.98
Alternative name(s):
Cytochrome P450 46A1
Gene names
Name:CYP46A1
Synonyms:CYP46
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length500 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol. Has also activity with xenobiotic compounds, such as clotrimazole. Ref.6 Ref.7

Catalytic activity

Cholesterol + NADPH + O2 = (24S)-24-hydroxycholesterol + NADP+ + H2O. Ref.6

Cofactor

Heme group. Ref.6 Ref.7 Ref.8

Subcellular location

Endoplasmic reticulum membrane; Single-pass membrane protein. Microsome membrane; Single-pass membrane protein.

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.

Sequence similarities

Belongs to the cytochrome P450 family.

Biophysicochemical properties

Kinetic parameters:

KM=2.2 µM for 24(S)-hydroxycholesterol Ref.5

Ontologies

Keywords
   Biological processCholesterol metabolism
Lipid metabolism
Steroid metabolism
Sterol metabolism
   Cellular componentEndoplasmic reticulum
Membrane
Microsome
   Coding sequence diversityAlternative splicing
   DomainTransmembrane
Transmembrane helix
   LigandHeme
Iron
Metal-binding
NADP
   Molecular functionMonooxygenase
Oxidoreductase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbile acid biosynthetic process

Traceable author statement. Source: Reactome

bile acid metabolic process

Traceable author statement. Source: Reactome

cholesterol catabolic process

Inferred from direct assay Ref.6. Source: UniProtKB

nervous system development

Traceable author statement Ref.1. Source: ProtInc

small molecule metabolic process

Traceable author statement. Source: Reactome

sterol metabolic process

Traceable author statement. Source: Reactome

xenobiotic metabolic process

Inferred from direct assay Ref.7. Source: UniProtKB

   Cellular_componentendoplasmic reticulum

Traceable author statement Ref.1. Source: ProtInc

endoplasmic reticulum membrane

Traceable author statement. Source: Reactome

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functioncholesterol 24-hydroxylase activity

Inferred from direct assay Ref.6. Source: UniProtKB

heme binding

Inferred from electronic annotation. Source: InterPro

iron ion binding

Inferred from electronic annotation. Source: InterPro

monooxygenase activity

Inferred from electronic annotation. Source: UniProtKB-KW

oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen

Inferred from electronic annotation. Source: InterPro

steroid hydroxylase activity

Traceable author statement Ref.1. Source: ProtInc

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9Y6A2-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q9Y6A2-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-97: Missing.
Note: No experimental confirmation available.
Isoform 3 (identifier: Q9Y6A2-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-153: Missing.
     383-392: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 500500Cholesterol 24-hydroxylase
PRO_0000051994

Regions

Transmembrane3 – 2321Helical; Potential
Compositional bias493 – 4997Poly-Pro

Sites

Metal binding4371Iron (heme axial ligand)

Natural variations

Alternative sequence1 – 153153Missing in isoform 3.
VSP_053858
Alternative sequence1 – 9797Missing in isoform 2.
VSP_053859
Alternative sequence383 – 39210Missing in isoform 3.
VSP_053860

Secondary structure

............................................................................ 500
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: AB9307749D9E5FDA

FASTA50056,821
        10         20         30         40         50         60 
MSPGLLLLGS AVLLAFGLCC TFVHRARSRY EHIPGPPRPS FLLGHLPCFW KKDEVGGRVL 

        70         80         90        100        110        120 
QDVFLDWAKK YGPVVRVNVF HKTSVIVTSP ESVKKFLMST KYNKDSKMYR ALQTVFGERL 

       130        140        150        160        170        180 
FGQGLVSECN YERWHKQRRV IDLAFSRSSL VSLMETFNEK AEQLVEILEA KADGQTPVSM 

       190        200        210        220        230        240 
QDMLTYTAMD ILAKAAFGME TSMLLGAQKP LSQAVKLMLE GITASRNTLA KFLPGKRKQL 

       250        260        270        280        290        300 
REVRESIRFL RQVGRDWVQR RREALKRGEE VPADILTQIL KAEEGAQDDE GLLDNFVTFF 

       310        320        330        340        350        360 
IAGHETSANH LAFTVMELSR QPEIVARLQA EVDEVIGSKR YLDFEDLGRL QYLSQVLKES 

       370        380        390        400        410        420 
LRLYPPAWGT FRLLEEETLI DGVRVPGNTP LLFSTYVMGR MDTYFEDPLT FNPDRFGPGA 

       430        440        450        460        470        480 
PKPRFTYFPF SLGHRSCIGQ QFAQMEVKVV MAKLLQRLEF RLVPGQRFGL QEQATLKPLD 

       490        500 
PVLCTLRPRG WQPAPPPPPC 

« Hide

Isoform 2 [UniParc].

Checksum: E47E531F99EAA940
Show »

FASTA40345,976
Isoform 3 [UniParc].

Checksum: 43E23CB22A230FD7
Show »

FASTA33738,315

References

« Hide 'large scale' references
[1]"cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain."
Lund E.G., Guileyardo J.M., Russell D.W.
Proc. Natl. Acad. Sci. U.S.A. 96:7238-7243(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Fetal brain.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
Tissue: Amygdala and Caudate nucleus.
[3]"The DNA sequence and analysis of human chromosome 14."
Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H. expand/collapse author list , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J.
Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[5]"Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain."
Mast N., Norcross R., Andersson U., Shou M., Nakayama K., Bjoerkhem I., Pikuleva I.A.
Biochemistry 42:14284-14292(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION, BIOPHYSICOCHEMICAL PROPERTIES.
[6]"Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain."
Mast N., White M.A., Bjorkhem I., Johnson E.F., Stout C.D., Pikuleva I.A.
Proc. Natl. Acad. Sci. U.S.A. 105:9546-9551(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 51-500 IN COMPLEX WITH HEME AND CHOLESTEROL 3-SULFATE, FUNCTION, CATALYTIC ACTIVITY, COFACTOR.
[7]"Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain."
Mast N., Charvet C., Pikuleva I.A., Stout C.D.
J. Biol. Chem. 285:31783-31795(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 51-500 IN COMPLEXES WITH HEME AND INHIBITORS, FUNCTION, COFACTOR.
[8]"Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response."
Mast N., Zheng W., Stout C.D., Pikuleva I.A.
J. Biol. Chem. 288:4613-4624(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 51-500 IN COMPLEXES WITH HEME AND THE INHIBITOR BICALUTAMIDE, COFACTOR.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF094480 mRNA. Translation: AAD41244.1.
AK090886 mRNA. Translation: BAC03539.1.
AK295216 mRNA. Translation: BAG58210.1.
AL136000 Genomic DNA. No translation available.
AL160313 Genomic DNA. No translation available.
BC022539 mRNA. Translation: AAH22539.1.
RefSeqNP_006659.1. NM_006668.1.
UniGeneHs.25121.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2Q9FX-ray1.90A51-500[»]
2Q9GX-ray2.40A51-500[»]
3MDMX-ray1.60A51-500[»]
3MDRX-ray2.00A/B51-500[»]
3MDTX-ray2.30A/B51-500[»]
3MDVX-ray2.40A/B51-500[»]
4ENHX-ray2.50A51-500[»]
4FIAX-ray2.10A51-500[»]
4J14X-ray2.50A51-500[»]
ProteinModelPortalQ9Y6A2.
SMRQ9Y6A2. Positions 33-491.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING9606.ENSP00000261835.

PTM databases

PhosphoSiteQ9Y6A2.

Polymorphism databases

DMDM12585217.

Proteomic databases

PaxDbQ9Y6A2.
PRIDEQ9Y6A2.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000261835; ENSP00000261835; ENSG00000036530.
ENST00000423126; ENSP00000405779; ENSG00000036530.
ENST00000554176; ENSP00000450553; ENSG00000036530.
GeneID10858.
KEGGhsa:10858.
UCSCuc001ygo.3. human. [Q9Y6A2-1]

Organism-specific databases

CTD10858.
GeneCardsGC14P100150.
HGNCHGNC:2641. CYP46A1.
HPAHPA040702.
MIM604087. gene.
neXtProtNX_Q9Y6A2.
PharmGKBPA27117.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG2124.
HOGENOMHOG000290190.
HOVERGENHBG102502.
InParanoidQ9Y6A2.
KOK07440.
OMATYFEDPL.
PhylomeDBQ9Y6A2.
TreeFamTF352037.

Enzyme and pathway databases

BRENDA1.14.13.98. 2681.
ReactomeREACT_111217. Metabolism.
SABIO-RKQ9Y6A2.

Gene expression databases

ArrayExpressQ9Y6A2.
BgeeQ9Y6A2.
CleanExHS_CYP46A1.
GenevestigatorQ9Y6A2.

Family and domain databases

Gene3D1.10.630.10. 1 hit.
InterProIPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]
PfamPF00067. p450. 1 hit.
[Graphical view]
PRINTSPR00463. EP450I.
PR00385. P450.
SUPFAMSSF48264. SSF48264. 1 hit.
PROSITEPS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCYP46A1. human.
EvolutionaryTraceQ9Y6A2.
GeneWikiCYP46A1.
GenomeRNAi10858.
NextBio35472068.
PROQ9Y6A2.
SOURCESearch...

Entry information

Entry nameCP46A_HUMAN
AccessionPrimary (citable) accession number: Q9Y6A2
Secondary accession number(s): B4DHP8, E7EQG9, Q8N2B0
Entry history
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: November 1, 1999
Last modified: April 16, 2014
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM