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Q9Y6A2

- CP46A_HUMAN

UniProt

Q9Y6A2 - CP46A_HUMAN

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Protein
Cholesterol 24-hydroxylase
Gene
CYP46A1, CYP46
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.2 Publications

Catalytic activityi

Cholesterol + NADPH + O2 = (24S)-24-hydroxycholesterol + NADP+ + H2O.1 Publication

Cofactori

Heme group.3 Publications

Kineticsi

  1. KM=2.2 µM for 24(S)-hydroxycholesterol1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi437 – 4371Iron (heme axial ligand)

GO - Molecular functioni

  1. cholesterol 24-hydroxylase activity Source: UniProtKB
  2. heme binding Source: UniProtKB
  3. iron ion binding Source: InterPro
  4. steroid hydroxylase activity Source: ProtInc

GO - Biological processi

  1. bile acid biosynthetic process Source: Reactome
  2. bile acid metabolic process Source: Reactome
  3. cholesterol catabolic process Source: UniProtKB
  4. nervous system development Source: ProtInc
  5. small molecule metabolic process Source: Reactome
  6. sterol metabolic process Source: Reactome
  7. xenobiotic metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Monooxygenase, Oxidoreductase

Keywords - Biological processi

Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Keywords - Ligandi

Heme, Iron, Metal-binding, NADP

Enzyme and pathway databases

BRENDAi1.14.13.98. 2681.
ReactomeiREACT_11053. Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
REACT_13812. Endogenous sterols.
SABIO-RKQ9Y6A2.

Names & Taxonomyi

Protein namesi
Recommended name:
Cholesterol 24-hydroxylase (EC:1.14.13.98)
Short name:
CH24H
Alternative name(s):
Cytochrome P450 46A1
Gene namesi
Name:CYP46A1
Synonyms:CYP46
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 14

Organism-specific databases

HGNCiHGNC:2641. CYP46A1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei3 – 2321Helical; Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. endoplasmic reticulum Source: ProtInc
  2. endoplasmic reticulum membrane Source: Reactome
  3. integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Microsome

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA27117.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 500500Cholesterol 24-hydroxylase
PRO_0000051994Add
BLAST

Proteomic databases

PaxDbiQ9Y6A2.
PRIDEiQ9Y6A2.

PTM databases

PhosphoSiteiQ9Y6A2.

Expressioni

Tissue specificityi

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.

Gene expression databases

ArrayExpressiQ9Y6A2.
BgeeiQ9Y6A2.
CleanExiHS_CYP46A1.
GenevestigatoriQ9Y6A2.

Organism-specific databases

HPAiHPA040702.

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000261835.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi60 – 7112
Beta strandi73 – 797
Beta strandi82 – 876
Helixi90 – 978
Helixi106 – 1138
Beta strandi118 – 1214
Turni125 – 1273
Helixi131 – 14111
Helixi142 – 1454
Helixi147 – 1515
Helixi154 – 17017
Beta strandi173 – 1764
Helixi180 – 19718
Helixi203 – 2053
Helixi209 – 22719
Helixi230 – 2323
Helixi234 – 2363
Helixi237 – 26630
Helixi275 – 2828
Turni283 – 2853
Beta strandi287 – 2893
Helixi290 – 30213
Helixi305 – 31814
Helixi322 – 33514
Turni336 – 3383
Helixi344 – 3496
Helixi351 – 36313
Beta strandi370 – 3745
Beta strandi378 – 3803
Beta strandi383 – 3853
Beta strandi387 – 3937
Helixi395 – 3995
Turni402 – 4043
Beta strandi405 – 4073
Helixi413 – 4164
Beta strandi424 – 4263
Helixi433 – 4353
Helixi440 – 45718
Beta strandi458 – 4625
Beta strandi470 – 48011
Beta strandi483 – 4886

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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[»]
ProteinModelPortaliQ9Y6A2.
SMRiQ9Y6A2. Positions 57-491.

Miscellaneous databases

EvolutionaryTraceiQ9Y6A2.

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi493 – 4997Poly-Pro

Sequence similaritiesi

Belongs to the cytochrome P450 family.

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG2124.
HOGENOMiHOG000290190.
HOVERGENiHBG102502.
InParanoidiQ9Y6A2.
KOiK07440.
OMAiRPRGWQP.
PhylomeDBiQ9Y6A2.
TreeFamiTF352037.

Family and domain databases

Gene3Di1.10.630.10. 1 hit.
InterProiIPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]
PfamiPF00067. p450. 1 hit.
[Graphical view]
PRINTSiPR00463. EP450I.
PR00385. P450.
SUPFAMiSSF48264. SSF48264. 1 hit.
PROSITEiPS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q9Y6A2-1) [UniParc]FASTAAdd to Basket

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.

« Hide

MSPGLLLLGS AVLLAFGLCC TFVHRARSRY EHIPGPPRPS FLLGHLPCFW    50
KKDEVGGRVL QDVFLDWAKK YGPVVRVNVF HKTSVIVTSP ESVKKFLMST 100
KYNKDSKMYR ALQTVFGERL FGQGLVSECN YERWHKQRRV IDLAFSRSSL 150
VSLMETFNEK AEQLVEILEA KADGQTPVSM QDMLTYTAMD ILAKAAFGME 200
TSMLLGAQKP LSQAVKLMLE GITASRNTLA KFLPGKRKQL REVRESIRFL 250
RQVGRDWVQR RREALKRGEE VPADILTQIL KAEEGAQDDE GLLDNFVTFF 300
IAGHETSANH LAFTVMELSR QPEIVARLQA EVDEVIGSKR YLDFEDLGRL 350
QYLSQVLKES LRLYPPAWGT FRLLEEETLI DGVRVPGNTP LLFSTYVMGR 400
MDTYFEDPLT FNPDRFGPGA PKPRFTYFPF SLGHRSCIGQ QFAQMEVKVV 450
MAKLLQRLEF RLVPGQRFGL QEQATLKPLD PVLCTLRPRG WQPAPPPPPC 500
Length:500
Mass (Da):56,821
Last modified:November 1, 1999 - v1
Checksum:iAB9307749D9E5FDA
GO
Isoform 2 (identifier: Q9Y6A2-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-97: Missing.

Note: No experimental confirmation available.

Show »
Length:403
Mass (Da):45,976
Checksum:iE47E531F99EAA940
GO
Isoform 3 (identifier: Q9Y6A2-3) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-153: Missing.
     383-392: Missing.

Note: No experimental confirmation available.

Show »
Length:337
Mass (Da):38,315
Checksum:i43E23CB22A230FD7
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 153153Missing in isoform 3.
VSP_053858Add
BLAST
Alternative sequencei1 – 9797Missing in isoform 2.
VSP_053859Add
BLAST
Alternative sequencei383 – 39210Missing in isoform 3.
VSP_053860

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
CCDSiCCDS9954.1. [Q9Y6A2-1]
RefSeqiNP_006659.1. NM_006668.1. [Q9Y6A2-1]
UniGeneiHs.25121.

Genome annotation databases

EnsembliENST00000261835; ENSP00000261835; ENSG00000036530.
ENST00000423126; ENSP00000405779; ENSG00000036530.
ENST00000554176; ENSP00000450553; ENSG00000036530.
GeneIDi10858.
KEGGihsa:10858.
UCSCiuc001ygo.3. human. [Q9Y6A2-1]

Polymorphism databases

DMDMi12585217.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
CCDSi CCDS9954.1. [Q9Y6A2-1 ]
RefSeqi NP_006659.1. NM_006668.1. [Q9Y6A2-1 ]
UniGenei Hs.25121.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2Q9F X-ray 1.90 A 51-500 [» ]
2Q9G X-ray 2.40 A 51-500 [» ]
3MDM X-ray 1.60 A 51-500 [» ]
3MDR X-ray 2.00 A/B 51-500 [» ]
3MDT X-ray 2.30 A/B 51-500 [» ]
3MDV X-ray 2.40 A/B 51-500 [» ]
4ENH X-ray 2.50 A 51-500 [» ]
4FIA X-ray 2.10 A 51-500 [» ]
4J14 X-ray 2.50 A 51-500 [» ]
ProteinModelPortali Q9Y6A2.
SMRi Q9Y6A2. Positions 57-491.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

STRINGi 9606.ENSP00000261835.

PTM databases

PhosphoSitei Q9Y6A2.

Polymorphism databases

DMDMi 12585217.

Proteomic databases

PaxDbi Q9Y6A2.
PRIDEi Q9Y6A2.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000261835 ; ENSP00000261835 ; ENSG00000036530 .
ENST00000423126 ; ENSP00000405779 ; ENSG00000036530 .
ENST00000554176 ; ENSP00000450553 ; ENSG00000036530 .
GeneIDi 10858.
KEGGi hsa:10858.
UCSCi uc001ygo.3. human. [Q9Y6A2-1 ]

Organism-specific databases

CTDi 10858.
GeneCardsi GC14P100150.
HGNCi HGNC:2641. CYP46A1.
HPAi HPA040702.
MIMi 604087. gene.
neXtProti NX_Q9Y6A2.
PharmGKBi PA27117.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG2124.
HOGENOMi HOG000290190.
HOVERGENi HBG102502.
InParanoidi Q9Y6A2.
KOi K07440.
OMAi RPRGWQP.
PhylomeDBi Q9Y6A2.
TreeFami TF352037.

Enzyme and pathway databases

BRENDAi 1.14.13.98. 2681.
Reactomei REACT_11053. Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
REACT_13812. Endogenous sterols.
SABIO-RK Q9Y6A2.

Miscellaneous databases

ChiTaRSi CYP46A1. human.
EvolutionaryTracei Q9Y6A2.
GeneWikii CYP46A1.
GenomeRNAii 10858.
NextBioi 35472068.
PROi Q9Y6A2.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q9Y6A2.
Bgeei Q9Y6A2.
CleanExi HS_CYP46A1.
Genevestigatori Q9Y6A2.

Family and domain databases

Gene3Di 1.10.630.10. 1 hit.
InterProi IPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view ]
Pfami PF00067. p450. 1 hit.
[Graphical view ]
PRINTSi PR00463. EP450I.
PR00385. P450.
SUPFAMi SSF48264. SSF48264. 1 hit.
PROSITEi PS00086. CYTOCHROME_P450. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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.
    , 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.
    , 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.

Entry informationi

Entry nameiCP46A_HUMAN
AccessioniPrimary (citable) accession number: Q9Y6A2
Secondary accession number(s): B4DHP8, E7EQG9, Q8N2B0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: November 1, 1999
Last modified: September 3, 2014
This is version 131 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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