ID   CH25H_HUMAN             Reviewed;         272 AA.
AC   O95992; B2RBY3;
DT   07-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   24-JAN-2024, entry version 159.
DE   RecName: Full=Cholesterol 25-hydroxylase {ECO:0000305};
DE            EC=1.14.99.38 {ECO:0000269|PubMed:33239446, ECO:0000269|PubMed:9852097};
DE   AltName: Full=Cholesterol 25-monooxygenase;
DE            Short=h25OH;
GN   Name=CH25H {ECO:0000312|HGNC:HGNC:1907};
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 [GENOMIC DNA / MRNA], FUNCTION, GLYCOSYLATION, AND
RP   CATALYTIC ACTIVITY.
RC   TISSUE=Lung;
RX   PubMed=9852097; DOI=10.1074/jbc.273.51.34316;
RA   Lund E.G., Kerr T.A., Sakai J., Li W.-P., Russell D.W.;
RT   "cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic
RT   membrane proteins that synthesize a potent oxysterol regulator of lipid
RT   metabolism.";
RL   J. Biol. Chem. 273:34316-34327(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Heart;
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=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung, and Ovary;
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   [6]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=15465627; DOI=10.1016/j.neurobiolaging.2004.01.001;
RA   Riemenschneider M., Mahmoodzadeh S., Eisele T., Klopp N., Schwarz S.,
RA   Wagenpfeil S., Diehl J., Mueller U., Foerstl H., Illig T., Kurz A.;
RT   "Association analysis of genes involved in cholesterol metabolism located
RT   within the linkage region on chromosome 10 and Alzheimer's disease.";
RL   Neurobiol. Aging 25:1305-1308(2004).
RN   [7]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=16157450; DOI=10.1016/j.neulet.2005.08.048;
RA   Shibata N., Kawarai T., Lee J.H., Lee H.-S., Shibata E., Sato C., Liang Y.,
RA   Duara R., Mayeux R.P., St George-Hyslop P.H., Rogaeva E.;
RT   "Association studies of cholesterol metabolism genes (CH25H, ABCA1 and
RT   CH24H) in Alzheimer's disease.";
RL   Neurosci. Lett. 391:142-146(2006).
RN   [8]
RP   FUNCTION, AND INDUCTION BY IFN.
RX   PubMed=32944968; DOI=10.15252/embj.2020106057;
RA   Wang S., Li W., Hui H., Tiwari S.K., Zhang Q., Croker B.A., Rawlings S.,
RA   Smith D., Carlin A.F., Rana T.M.;
RT   "Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by
RT   depleting membrane cholesterol.";
RL   EMBO J. 39:e106057-e106057(2020).
RN   [9]
RP   FUNCTION, MUTAGENESIS OF 242-HIS-HIS-243, AND CATALYTIC ACTIVITY.
RX   PubMed=33239446; DOI=10.1073/pnas.2012197117;
RA   Zang R., Case J.B., Yutuc E., Ma X., Shen S., Gomez Castro M.F., Liu Z.,
RA   Zeng Q., Zhao H., Son J., Rothlauf P.W., Kreutzberger A.J.B., Hou G.,
RA   Zhang H., Bose S., Wang X., Vahey M.D., Mani K., Griffiths W.J.,
RA   Kirchhausen T., Fremont D.H., Guo H., Diwan A., Wang Y., Diamond M.S.,
RA   Whelan S.P.J., Ding S.;
RT   "Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking
RT   membrane fusion.";
RL   Proc. Natl. Acad. Sci. U.S.A. 117:32105-32113(2020).
CC   -!- FUNCTION: Catalyzes the formation of 25-hydroxycholesterol from
CC       cholesterol, leading to repress cholesterol biosynthetic enzymes
CC       (PubMed:9852097). Plays a key role in cell positioning and movement in
CC       lymphoid tissues: 25-hydroxycholesterol is an intermediate in
CC       biosynthesis of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC), an
CC       oxysterol that acts as a ligand for the G protein-coupled receptor
CC       GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells (By
CC       similarity). May play an important role in regulating lipid metabolism
CC       by synthesizing a corepressor that blocks sterol regulatory element
CC       binding protein (SREBP) processing (PubMed:9852097). As an interferon-
CC       stimulated gene, has broad antiviral activities against a wide range of
CC       enveloped viruses, such as vesicular stomatitis virus (VSV) and SARS
CC       coronavirus-2 (SARS-CoV-2). Its product, 25-hydroxycholesterol,
CC       activates the ER-localized enzyme ACAT to induce internalization of
CC       accessible cholesterol on the plasma membrane and restricts SARS-CoV-2
CC       S protein-mediated fusion which inhibits virus replication
CC       (PubMed:33239446, PubMed:32944968). In testis, production of 25-
CC       hydroxycholesterol by macrophages plays a role in Leydig cell
CC       differentiation (By similarity). Required to restrain inflammation in
CC       macrophages: production of 25-hydroxycholesterol protects macrophages
CC       from cholesterol overload, thereby preventing mitochondrial DNA release
CC       and subsequent activation of the AIM2 inflammasome (By similarity).
CC       {ECO:0000250|UniProtKB:Q4QQV7, ECO:0000250|UniProtKB:Q9Z0F5,
CC       ECO:0000269|PubMed:32944968, ECO:0000269|PubMed:33239446,
CC       ECO:0000269|PubMed:9852097}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=AH2 + cholesterol + O2 = 25-hydroxycholesterol + A + H2O;
CC         Xref=Rhea:RHEA:21104, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15379, ChEBI:CHEBI:16113, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:42977; EC=1.14.99.38;
CC         Evidence={ECO:0000269|PubMed:33239446, ECO:0000269|PubMed:9852097};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21105;
CC         Evidence={ECO:0000269|PubMed:33239446, ECO:0000305|PubMed:9852097};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cholesterol + H(+) + NADPH + O2 = 25-hydroxycholesterol + H2O
CC         + NADP(+); Xref=Rhea:RHEA:46132, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16113,
CC         ChEBI:CHEBI:42977, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC         Evidence={ECO:0000269|PubMed:9852097};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46133;
CC         Evidence={ECO:0000305|PubMed:9852097};
CC   -!- COFACTOR:
CC       Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC         Evidence={ECO:0000250|UniProtKB:Q9Z0F5};
CC   -!- INTERACTION:
CC       O95992; P60329: KRTAP12-4; NbExp=3; IntAct=EBI-12820943, EBI-10176396;
CC       O95992; P32242: OTX1; NbExp=3; IntAct=EBI-12820943, EBI-740446;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:Q9Z0F5}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:Q9Z0F5}.
CC   -!- INDUCTION: Induced by interferon (IFN) upon infection by virus like
CC       SARS-CoV-2. {ECO:0000269|PubMed:32944968}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:9852097}.
CC   -!- SIMILARITY: Belongs to the sterol desaturase family. {ECO:0000305}.
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DR   EMBL; AF059212; AAC97481.1; -; Genomic_DNA.
DR   EMBL; AF059214; AAC97483.1; -; mRNA.
DR   EMBL; AK314865; BAG37380.1; -; mRNA.
DR   EMBL; AL513533; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471066; EAW50146.1; -; Genomic_DNA.
DR   EMBL; BC017843; AAH17843.1; -; mRNA.
DR   EMBL; BC072430; AAH72430.1; -; mRNA.
DR   CCDS; CCDS7400.1; -.
DR   RefSeq; NP_003947.1; NM_003956.3.
DR   AlphaFoldDB; O95992; -.
DR   BioGRID; 114490; 4.
DR   IntAct; O95992; 4.
DR   MINT; O95992; -.
DR   STRING; 9606.ENSP00000360918; -.
DR   SwissLipids; SLP:000001483; -.
DR   GlyCosmos; O95992; 3 sites, No reported glycans.
DR   GlyGen; O95992; 3 sites.
DR   BioMuta; CH25H; -.
DR   PaxDb; 9606-ENSP00000360918; -.
DR   PeptideAtlas; O95992; -.
DR   Antibodypedia; 30238; 137 antibodies from 16 providers.
DR   DNASU; 9023; -.
DR   Ensembl; ENST00000371852.4; ENSP00000360918.2; ENSG00000138135.7.
DR   GeneID; 9023; -.
DR   KEGG; hsa:9023; -.
DR   MANE-Select; ENST00000371852.4; ENSP00000360918.2; NM_003956.4; NP_003947.1.
DR   UCSC; uc001kfz.4; human.
DR   AGR; HGNC:1907; -.
DR   CTD; 9023; -.
DR   DisGeNET; 9023; -.
DR   GeneCards; CH25H; -.
DR   HGNC; HGNC:1907; CH25H.
DR   HPA; ENSG00000138135; Tissue enhanced (lymphoid).
DR   MIM; 604551; gene.
DR   neXtProt; NX_O95992; -.
DR   OpenTargets; ENSG00000138135; -.
DR   PharmGKB; PA26443; -.
DR   VEuPathDB; HostDB:ENSG00000138135; -.
DR   eggNOG; KOG0873; Eukaryota.
DR   GeneTree; ENSGT00940000162142; -.
DR   HOGENOM; CLU_047036_5_1_1; -.
DR   InParanoid; O95992; -.
DR   OMA; VPWLYKT; -.
DR   OrthoDB; 2732776at2759; -.
DR   PhylomeDB; O95992; -.
DR   TreeFam; TF353265; -.
DR   BioCyc; MetaCyc:HS06462-MONOMER; -.
DR   BRENDA; 1.14.99.38; 2681.
DR   PathwayCommons; O95992; -.
DR   Reactome; R-HSA-192105; Synthesis of bile acids and bile salts.
DR   SignaLink; O95992; -.
DR   BioGRID-ORCS; 9023; 13 hits in 1145 CRISPR screens.
DR   GenomeRNAi; 9023; -.
DR   Pharos; O95992; Tbio.
DR   PRO; PR:O95992; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; O95992; Protein.
DR   Bgee; ENSG00000138135; Expressed in mucosa of paranasal sinus and 157 other cell types or tissues.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR   GO; GO:0000254; F:C-4 methylsterol oxidase activity; IBA:GO_Central.
DR   GO; GO:0001567; F:cholesterol 25-hydroxylase activity; IDA:UniProtKB.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0008395; F:steroid hydroxylase activity; IBA:GO_Central.
DR   GO; GO:0035754; P:B cell chemotaxis; ISS:UniProtKB.
DR   GO; GO:0008203; P:cholesterol metabolic process; IDA:UniProtKB.
DR   GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR   GO; GO:0090206; P:negative regulation of cholesterol metabolic process; IEA:Ensembl.
DR   GO; GO:1903914; P:negative regulation of fusion of virus membrane with host plasma membrane; IDA:UniProtKB.
DR   GO; GO:0034340; P:response to type I interferon; IDA:UniProtKB.
DR   GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR   InterPro; IPR006694; Fatty_acid_hydroxylase.
DR   PANTHER; PTHR11863:SF213; CHOLESTEROL 25-HYDROXYLASE; 1.
DR   PANTHER; PTHR11863; STEROL DESATURASE; 1.
DR   Pfam; PF04116; FA_hydroxylase; 1.
DR   Genevisible; O95992; HS.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum; Glycoprotein; Iron; Lipid biosynthesis;
KW   Lipid metabolism; Membrane; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW   Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix.
FT   CHAIN           1..272
FT                   /note="Cholesterol 25-hydroxylase"
FT                   /id="PRO_0000226801"
FT   TRANSMEM        38..58
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        84..104
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        121..141
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          129..263
FT                   /note="Fatty acid hydroxylase"
FT                   /evidence="ECO:0000255"
FT   MOTIF           142..146
FT                   /note="Histidine box-1"
FT   MOTIF           157..161
FT                   /note="Histidine box-2"
FT   MOTIF           238..244
FT                   /note="Histidine box-3"
FT   CARBOHYD        5
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        163
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        189
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         133
FT                   /note="L -> P (in dbSNP:rs17117295)"
FT                   /id="VAR_048899"
FT   MUTAGEN         242..243
FT                   /note="HH->QQ: Loss of cholesterol 25-hydroxylase activity.
FT                   Loss of inhibition of infection by SARS-COV-2."
FT                   /evidence="ECO:0000269|PubMed:33239446"
SQ   SEQUENCE   272 AA;  31745 MW;  0DF46BC21802008B CRC64;
     MSCHNCSDPQ VLCSSGQLFL QPLWDHLRSW EALLQSPFFP VIFSITTYVG FCLPFVVLDI
     LCSWVPALRR YKIHPDFSPS AQQLLPCLGQ TLYQHVMFVF PVTLLHWARS PALLPHEAPE
     LLLLLHHILF CLLLFDMEFF VWHLLHHKVP WLYRTFHKVH HQNSSSFALA TQYMSVWELF
     SLGFFDMMNV TLLGCHPLTT LTFHVVNIWL SVEDHSGYNF PWSTHRLVPF GWYGGVVHHD
     LHHSHFNCNF APYFTHWDKI LGTLRTASVP AR
//