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-JUL-2024, entry version 161. 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:32944968, PubMed:33239446). 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 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; 117 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 InterPro; IPR050307; Sterol_Desaturase_Related. DR PANTHER; PTHR11863:SF213; CHOLESTEROL 25-HYDROXYLASE; 1. DR PANTHER; PTHR11863; STEROL DESATURASE; 1. DR Pfam; PF04116; FA_hydroxylase; 1. 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 //