CP46A_HUMAN
ID CP46A_HUMAN Reviewed; 500 AA.
AC Q9Y6A2; B4DHP8; E7EQG9; Q8N2B0;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Cholesterol 24-hydroxylase {ECO:0000305|PubMed:14640697};
DE Short=CH24H;
DE EC=1.14.14.25 {ECO:0000269|PubMed:10377398, ECO:0000269|PubMed:14640697, ECO:0000269|PubMed:25017465};
DE AltName: Full=Cholesterol 24-monooxygenase;
DE AltName: Full=Cholesterol 24S-hydroxylase {ECO:0000303|PubMed:10377398};
DE AltName: Full=Cytochrome P450 46A1 {ECO:0000303|PubMed:14640697};
GN Name=CYP46A1 {ECO:0000303|PubMed:20667828, ECO:0000312|HGNC:HGNC:2641};
GN Synonyms=CYP46;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=10377398; DOI=10.1073/pnas.96.13.7238;
RA Lund E.G., Guileyardo J.M., Russell D.W.;
RT "cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol
RT homeostasis in the brain.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:7238-7243(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Amygdala, and Caudate nucleus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12077124; DOI=10.1074/jbc.m201712200;
RA Bodin K., Andersson U., Rystedt E., Ellis E., Norlin M., Pikuleva I.,
RA Eggertsen G., Bjoerkhem I., Diczfalusy U.;
RT "Metabolism of 4 beta -hydroxycholesterol in humans.";
RL J. Biol. Chem. 277:31534-31540(2002).
RN [6]
RP CHARACTERIZATION, BIOPHYSICOCHEMICAL PROPERTIES, FUNCTION, CATALYTIC
RP ACTIVITY, AND PATHWAY.
RX PubMed=14640697; DOI=10.1021/bi035512f;
RA Mast N., Norcross R., Andersson U., Shou M., Nakayama K., Bjoerkhem I.,
RA Pikuleva I.A.;
RT "Broad substrate specificity of human cytochrome P450 46A1 which initiates
RT cholesterol degradation in the brain.";
RL Biochemistry 42:14284-14292(2003).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=25017465; DOI=10.1194/jlr.m051508;
RA Goyal S., Xiao Y., Porter N.A., Xu L., Guengerich F.P.;
RT "Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450
RT 46A1.";
RL J. Lipid Res. 55:1933-1943(2014).
RN [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=28190002; DOI=10.1074/jbc.m116.774760;
RA Mast N., Anderson K.W., Lin J.B., Li Y., Turko I.V., Tatsuoka C.,
RA Bjorkhem I., Pikuleva I.A.;
RT "Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol
RT Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum.";
RL J. Biol. Chem. 292:4913-4924(2017).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 51-500 IN COMPLEX WITH HEME AND
RP CHOLESTEROL 3-SULFATE, CATALYTIC ACTIVITY, FUNCTION, AND COFACTOR.
RX PubMed=18621681; DOI=10.1073/pnas.0803717105;
RA Mast N., White M.A., Bjorkhem I., Johnson E.F., Stout C.D., Pikuleva I.A.;
RT "Crystal structures of substrate-bound and substrate-free cytochrome P450
RT 46A1, the principal cholesterol hydroxylase in the brain.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:9546-9551(2008).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 51-500 IN COMPLEXES WITH HEME AND
RP INHIBITORS, FUNCTION, AND COFACTOR.
RX PubMed=20667828; DOI=10.1074/jbc.m110.143313;
RA Mast N., Charvet C., Pikuleva I.A., Stout C.D.;
RT "Structural basis of drug binding to CYP46A1, an enzyme that controls
RT cholesterol turnover in the brain.";
RL J. Biol. Chem. 285:31783-31795(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 51-500 IN COMPLEXES WITH HEME AND
RP THE INHIBITOR BICALUTAMIDE, AND COFACTOR.
RX PubMed=23288837; DOI=10.1074/jbc.m112.438754;
RA Mast N., Zheng W., Stout C.D., Pikuleva I.A.;
RT "Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome
RT P450 46A1: unusual features and spectral response.";
RL J. Biol. Chem. 288:4613-4624(2013).
CC -!- FUNCTION: P450 monooxygenase that plays a major role in cholesterol
CC homeostasis in the brain. Primarily catalyzes the hydroxylation (with S
CC stereochemistry) at C-24 of cholesterol side chain, triggering
CC cholesterol diffusion out of neurons and its further degradation
CC (PubMed:10377398, PubMed:14640697, PubMed:25017465, PubMed:18621681).
CC By promoting constant cholesterol elimination in neurons, may activate
CC the mevalonate pathway and coordinate the synthesis of new cholesterol
CC and nonsterol isoprenoids involved in synaptic activity and learning
CC (By similarity). Further hydroxylates cholesterol derivatives and
CC hormone steroids on both the ring and side chain of these molecules,
CC converting them into active oxysterols involved in lipid signaling and
CC biosynthesis (PubMed:12077124, PubMed:14640697, PubMed:28190002). Acts
CC as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into
CC (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2
CC and NR1H3 receptors shown to promote neurogenesis in developing brain
CC (PubMed:25017465). May also catalyze the oxidative metabolism of
CC xenobiotics, such as clotrimazole (PubMed:20667828).
CC {ECO:0000250|UniProtKB:Q9WVK8, ECO:0000269|PubMed:10377398,
CC ECO:0000269|PubMed:12077124, ECO:0000269|PubMed:14640697,
CC ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:20667828,
CC ECO:0000269|PubMed:25017465, ECO:0000269|PubMed:28190002}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol + O2 + reduced [NADPH--hemoprotein reductase] =
CC (24S)-hydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:22716, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:34310, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; EC=1.14.14.25;
CC Evidence={ECO:0000269|PubMed:10377398, ECO:0000269|PubMed:14640697,
CC ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:25017465};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22717;
CC Evidence={ECO:0000250|UniProtKB:Q9WVK8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholestanol + O2 + reduced [NADPH--hemoprotein reductase] =
CC (24S)-hydroxycholestanol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:53808, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86570,
CC ChEBI:CHEBI:137687; Evidence={ECO:0000269|PubMed:28190002};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53809;
CC Evidence={ECO:0000250|UniProtKB:Q9WVK8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7-dehydrocholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = cholesta-5,7-dien-3beta,24S-diol + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53244, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17759,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:137061;
CC Evidence={ECO:0000269|PubMed:25017465};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53245;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7-dehydrocholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = cholesta-5,7-dien-3beta,25-diol + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53240, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17759,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:137057;
CC Evidence={ECO:0000269|PubMed:25017465};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53241;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=desmosterol + O2 + reduced [NADPH--hemoprotein reductase] =
CC (24Z),26-hydroxydesmosterol + H(+) + H2O + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:53236, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:17737, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:137053;
CC Evidence={ECO:0000269|PubMed:25017465};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53237;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=desmosterol + O2 + reduced [NADPH--hemoprotein reductase] =
CC (24S)-25-epoxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:53232, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:17737, ChEBI:CHEBI:41633, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:25017465};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53233;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4beta-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = 4beta,24S-dihydroxycholesterol + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46392, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:85778, ChEBI:CHEBI:86087;
CC Evidence={ECO:0000269|PubMed:12077124};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46393;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(24S)-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = (24S,25R)-24,26-dihydroxycholesterol + H(+) + H2O +
CC oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46388,
CC Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:34310,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86165;
CC Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46389;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(24S)-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = 24S,25-dihydroxycholesterol + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46384, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:34310,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86074;
CC Evidence={ECO:0000269|PubMed:14640697, ECO:0000269|PubMed:18621681};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46385;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7alpha-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein
CC reductase] = (24S)-7alpha-dihydroxycholesterol + H(+) + H2O +
CC oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46380,
CC Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17500,
CC ChEBI:CHEBI:37640, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46381;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + progesterone + reduced [NADPH--hemoprotein reductase] =
CC 17alpha-hydroxyprogesterone + H(+) + H2O + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:46308, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:17026, ChEBI:CHEBI:17252,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46309;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone =
CC 16beta,17beta-dihydroxyandrost-4-en-3-one + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46304, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17347,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:83027;
CC Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46305;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone =
CC 2-hydroxytestosterone + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:46300, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:17347, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:86013; Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46301;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone =
CC 6beta,17beta-dihydroxyandrost-4-en-3-one + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46296, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17347,
CC ChEBI:CHEBI:34477, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:14640697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46297;
CC Evidence={ECO:0000305};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:20667828,
CC ECO:0000269|PubMed:23288837};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.2 uM for 24(S)-hydroxycholesterol {ECO:0000269|PubMed:14640697};
CC KM=7 uM for cholesterol {ECO:0000269|PubMed:25017465};
CC KM=2.8 uM for cholesta-5,7-dien-3beta-ol/7-dehydrocholesterol
CC {ECO:0000269|PubMed:25017465};
CC KM=9.4 uM for cholesta-5,24-dien-3beta-ol/desmosterol
CC {ECO:0000269|PubMed:25017465};
CC Note=kcat/KM=8.4 mM/min for cholesterol, kcat/KM=8.5 mM/min for
CC cholesta-5,7-dien-3beta-ol/7-dehydrocholesterol and kcat/KM=3.5
CC mM/min for cholesta-5,24-dien-3beta-ol/desmosterol.
CC {ECO:0000269|PubMed:25017465};
CC -!- PATHWAY: Steroid metabolism; cholesterol degradation.
CC {ECO:0000305|PubMed:14640697}.
CC -!- PATHWAY: Lipid metabolism; C21-steroid hormone metabolism.
CC {ECO:0000305|PubMed:14640697}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q9WVK8}; Single-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9WVK8}. Microsome membrane
CC {ECO:0000250|UniProtKB:Q9WVK8}; Single-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9WVK8}. Postsynapse
CC {ECO:0000250|UniProtKB:Q9WVK8}. Presynapse
CC {ECO:0000250|UniProtKB:Q9WVK8}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q9WVK8}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9Y6A2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y6A2-2; Sequence=VSP_053859;
CC Name=3;
CC IsoId=Q9Y6A2-3; Sequence=VSP_053858, VSP_053860;
CC -!- TISSUE SPECIFICITY: Expressed in brain. The mRNA was broadly
CC distributed with higher levels in gray matter zones and lower levels in
CC regions rich in white matter. Not detected in fetal sample but its
CC expression increases linearly with age. {ECO:0000269|PubMed:10377398}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AF094480; AAD41244.1; -; mRNA.
DR EMBL; AK090886; BAC03539.1; -; mRNA.
DR EMBL; AK295216; BAG58210.1; -; mRNA.
DR EMBL; AL136000; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL160313; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC022539; AAH22539.1; -; mRNA.
DR CCDS; CCDS9954.1; -. [Q9Y6A2-1]
DR RefSeq; NP_006659.1; NM_006668.1. [Q9Y6A2-1]
DR PDB; 2Q9F; X-ray; 1.90 A; A=51-500.
DR PDB; 2Q9G; X-ray; 2.40 A; A=51-500.
DR PDB; 3MDM; X-ray; 1.60 A; A=51-500.
DR PDB; 3MDR; X-ray; 2.00 A; A/B=51-500.
DR PDB; 3MDT; X-ray; 2.30 A; A/B=51-500.
DR PDB; 3MDV; X-ray; 2.40 A; A/B=51-500.
DR PDB; 4ENH; X-ray; 2.50 A; A=51-500.
DR PDB; 4FIA; X-ray; 2.10 A; A=51-500.
DR PDB; 4J14; X-ray; 2.50 A; A=51-500.
DR PDB; 7LRL; X-ray; 2.00 A; A=28-494.
DR PDB; 7LS3; X-ray; 2.15 A; A=28-494.
DR PDB; 7LS4; X-ray; 2.05 A; A=28-494.
DR PDB; 7N3L; X-ray; 1.63 A; A=28-494.
DR PDB; 7N3M; X-ray; 1.70 A; AAA=28-494.
DR PDBsum; 2Q9F; -.
DR PDBsum; 2Q9G; -.
DR PDBsum; 3MDM; -.
DR PDBsum; 3MDR; -.
DR PDBsum; 3MDT; -.
DR PDBsum; 3MDV; -.
DR PDBsum; 4ENH; -.
DR PDBsum; 4FIA; -.
DR PDBsum; 4J14; -.
DR PDBsum; 7LRL; -.
DR PDBsum; 7LS3; -.
DR PDBsum; 7LS4; -.
DR PDBsum; 7N3L; -.
DR PDBsum; 7N3M; -.
DR AlphaFoldDB; Q9Y6A2; -.
DR SMR; Q9Y6A2; -.
DR BioGRID; 116069; 4.
DR IntAct; Q9Y6A2; 1.
DR STRING; 9606.ENSP00000261835; -.
DR BindingDB; Q9Y6A2; -.
DR ChEMBL; CHEMBL4523510; -.
DR GuidetoPHARMACOLOGY; 1373; -.
DR SwissLipids; SLP:000001220; -. [Q9Y6A2-1]
DR SwissLipids; SLP:000001720; -.
DR iPTMnet; Q9Y6A2; -.
DR PhosphoSitePlus; Q9Y6A2; -.
DR BioMuta; CYP46A1; -.
DR DMDM; 12585217; -.
DR MassIVE; Q9Y6A2; -.
DR PaxDb; Q9Y6A2; -.
DR PeptideAtlas; Q9Y6A2; -.
DR PRIDE; Q9Y6A2; -.
DR ProteomicsDB; 4238; -.
DR ProteomicsDB; 71672; -.
DR ProteomicsDB; 86640; -. [Q9Y6A2-1]
DR Antibodypedia; 14316; 304 antibodies from 31 providers.
DR DNASU; 10858; -.
DR Ensembl; ENST00000261835.8; ENSP00000261835.3; ENSG00000036530.9. [Q9Y6A2-1]
DR Ensembl; ENST00000380228.6; ENSP00000369577.3; ENSG00000036530.9. [Q9Y6A2-2]
DR GeneID; 10858; -.
DR KEGG; hsa:10858; -.
DR MANE-Select; ENST00000261835.8; ENSP00000261835.3; NM_006668.2; NP_006659.1.
DR UCSC; uc001ygo.4; human. [Q9Y6A2-1]
DR CTD; 10858; -.
DR DisGeNET; 10858; -.
DR GeneCards; CYP46A1; -.
DR HGNC; HGNC:2641; CYP46A1.
DR HPA; ENSG00000036530; Tissue enriched (brain).
DR MIM; 604087; gene.
DR neXtProt; NX_Q9Y6A2; -.
DR OpenTargets; ENSG00000036530; -.
DR PharmGKB; PA27117; -.
DR VEuPathDB; HostDB:ENSG00000036530; -.
DR eggNOG; KOG0157; Eukaryota.
DR GeneTree; ENSGT00940000156927; -.
DR InParanoid; Q9Y6A2; -.
DR OMA; IAGRTMF; -.
DR OrthoDB; 825914at2759; -.
DR PhylomeDB; Q9Y6A2; -.
DR TreeFam; TF352037; -.
DR BRENDA; 1.14.14.25; 2681.
DR PathwayCommons; Q9Y6A2; -.
DR Reactome; R-HSA-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
DR Reactome; R-HSA-211976; Endogenous sterols.
DR SABIO-RK; Q9Y6A2; -.
DR SignaLink; Q9Y6A2; -.
DR UniPathway; UPA00229; -.
DR UniPathway; UPA01058; -.
DR BioGRID-ORCS; 10858; 4 hits in 1066 CRISPR screens.
DR ChiTaRS; CYP46A1; human.
DR EvolutionaryTrace; Q9Y6A2; -.
DR GeneWiki; CYP46A1; -.
DR GenomeRNAi; 10858; -.
DR Pharos; Q9Y6A2; Tchem.
DR PRO; PR:Q9Y6A2; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9Y6A2; protein.
DR Bgee; ENSG00000036530; Expressed in middle temporal gyrus and 126 other tissues.
DR ExpressionAtlas; Q9Y6A2; baseline and differential.
DR Genevisible; Q9Y6A2; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; TAS:ProtInc.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0098794; C:postsynapse; ISS:UniProtKB.
DR GO; GO:0098793; C:presynapse; ISS:UniProtKB.
DR GO; GO:0033781; F:cholesterol 24-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0008395; F:steroid hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0062184; F:testosterone 16-beta-hydroxylase activity; IEA:RHEA.
DR GO; GO:0006699; P:bile acid biosynthetic process; TAS:Reactome.
DR GO; GO:0006707; P:cholesterol catabolic process; IDA:UniProtKB.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0042448; P:progesterone metabolic process; IDA:UniProtKB.
DR GO; GO:1903044; P:protein localization to membrane raft; ISS:ARUK-UCL.
DR GO; GO:1900271; P:regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR GO; GO:0016125; P:sterol metabolic process; TAS:Reactome.
DR GO; GO:0006805; P:xenobiotic metabolic process; IDA:UniProtKB.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR039983; CYP46A1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR PANTHER; PTHR24293; PTHR24293; 1.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell projection;
KW Cholesterol metabolism; Endoplasmic reticulum; Heme; Iron;
KW Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase;
KW Oxidoreductase; Reference proteome; Steroid metabolism; Sterol metabolism;
KW Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..500
FT /note="Cholesterol 24-hydroxylase"
FT /id="PRO_0000051994"
FT TRANSMEM 3..23
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 437
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:18621681,
FT ECO:0000269|PubMed:20667828, ECO:0000269|PubMed:23288837,
FT ECO:0007744|PDB:2Q9F, ECO:0007744|PDB:2Q9G,
FT ECO:0007744|PDB:3MDR, ECO:0007744|PDB:3MDT,
FT ECO:0007744|PDB:3MDV, ECO:0007744|PDB:4ENH,
FT ECO:0007744|PDB:4FIA, ECO:0007744|PDB:4J14"
FT VAR_SEQ 1..153
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_053858"
FT VAR_SEQ 1..97
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_053859"
FT VAR_SEQ 383..392
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_053860"
FT TURN 29..32
FT /evidence="ECO:0007829|PDB:7LS4"
FT HELIX 60..71
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 73..79
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 82..87
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 90..97
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 106..113
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 118..121
FT /evidence="ECO:0007829|PDB:3MDM"
FT TURN 125..127
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 131..141
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 142..145
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 147..151
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 154..170
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 173..176
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 180..197
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 203..205
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 209..227
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 230..232
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 234..236
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 237..266
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 275..282
FT /evidence="ECO:0007829|PDB:3MDM"
FT TURN 283..285
FT /evidence="ECO:0007829|PDB:2Q9F"
FT STRAND 287..289
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 290..302
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 305..318
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 322..335
FT /evidence="ECO:0007829|PDB:3MDM"
FT TURN 336..338
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 344..349
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 351..363
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 370..374
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 378..380
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 383..385
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 387..393
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 395..399
FT /evidence="ECO:0007829|PDB:3MDM"
FT TURN 402..404
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 405..407
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 413..416
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 424..426
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 433..435
FT /evidence="ECO:0007829|PDB:3MDM"
FT HELIX 440..457
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 458..462
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 470..480
FT /evidence="ECO:0007829|PDB:3MDM"
FT STRAND 483..488
FT /evidence="ECO:0007829|PDB:3MDM"
SQ SEQUENCE 500 AA; 56821 MW; AB9307749D9E5FDA CRC64;
MSPGLLLLGS AVLLAFGLCC TFVHRARSRY EHIPGPPRPS FLLGHLPCFW KKDEVGGRVL
QDVFLDWAKK YGPVVRVNVF HKTSVIVTSP ESVKKFLMST KYNKDSKMYR ALQTVFGERL
FGQGLVSECN YERWHKQRRV IDLAFSRSSL VSLMETFNEK AEQLVEILEA KADGQTPVSM
QDMLTYTAMD ILAKAAFGME TSMLLGAQKP LSQAVKLMLE GITASRNTLA KFLPGKRKQL
REVRESIRFL RQVGRDWVQR RREALKRGEE VPADILTQIL KAEEGAQDDE GLLDNFVTFF
IAGHETSANH LAFTVMELSR QPEIVARLQA EVDEVIGSKR YLDFEDLGRL QYLSQVLKES
LRLYPPAWGT FRLLEEETLI DGVRVPGNTP LLFSTYVMGR MDTYFEDPLT FNPDRFGPGA
PKPRFTYFPF SLGHRSCIGQ QFAQMEVKVV MAKLLQRLEF RLVPGQRFGL QEQATLKPLD
PVLCTLRPRG WQPAPPPPPC
