ID CP39A_HUMAN Reviewed; 469 AA. AC Q9NYL5; Q5VTT0; Q96FW5; DT 23-JAN-2002, integrated into UniProtKB/Swiss-Prot. DT 17-APR-2007, sequence version 2. DT 24-JAN-2024, entry version 184. DE RecName: Full=24-hydroxycholesterol 7-alpha-hydroxylase {ECO:0000303|PubMed:10748047}; DE EC=1.14.14.26 {ECO:0000305|PubMed:25201972}; DE AltName: Full=Cytochrome P450 39A1; DE Short=hCYP39A1; DE AltName: Full=Oxysterol 7-alpha-hydroxylase; DE Flags: Precursor; GN Name=CYP39A1 {ECO:0000303|PubMed:25201972, GN ECO:0000312|HGNC:HGNC:17449}; 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], FUNCTION, AND VARIANT LYS-324. RC TISSUE=Liver; RX PubMed=10748047; DOI=10.1074/jbc.m001810200; RA Li-Hawkins J., Lund E.G., Bronson A.D., Russell D.W.; RT "Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24- RT hydroxycholesterol."; RL J. Biol. Chem. 275:16543-16549(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Testis; 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=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS PRO-23 AND HIS-288. RC TISSUE=Skin; 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, CATALYTIC ACTIVITY, POLYMORPHISM, VARIANTS PRO-23; HIS-103; RP HIS-288; LYS-324 AND GLN-329, AND PATHWAY. RX PubMed=25201972; DOI=10.1073/pnas.1413561111; RA Stiles A.R., Kozlitina J., Thompson B.M., McDonald J.G., King K.S., RA Russell D.W.; RT "Genetic, anatomic, and clinical determinants of human serum sterol and RT vitamin D levels."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E4006-E4014(2014). CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in neural CC cholesterol clearance through bile acid synthesis (PubMed:25201972, CC PubMed:10748047). Catalyzes 7-alpha hydroxylation of (24S)- CC hydroxycholesterol, a neural oxysterol that is metabolized to bile CC acids in the liver (PubMed:25201972, PubMed:10748047). Mechanistically, CC uses molecular oxygen inserting one oxygen atom into a substrate, and CC reducing the second into a water molecule, with two electrons provided CC by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein CC reductase) (PubMed:25201972, PubMed:10748047). CC {ECO:0000269|PubMed:10748047, ECO:0000269|PubMed:25201972}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(24S)-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein CC reductase] = (24S)-7alpha-dihydroxycholesterol + H(+) + H2O + CC oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46124, 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:37640, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; CC EC=1.14.14.26; Evidence={ECO:0000269|PubMed:25201972}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46125; CC Evidence={ECO:0000305|PubMed:25201972}; CC -!- COFACTOR: CC Name=heme; Xref=ChEBI:CHEBI:30413; CC Evidence={ECO:0000250|UniProtKB:Q16850}; CC -!- PATHWAY: Steroid metabolism; cholesterol degradation. CC {ECO:0000305|PubMed:25201972}. CC -!- PATHWAY: Lipid metabolism; bile acid biosynthesis. CC {ECO:0000305|PubMed:25201972}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Multi-pass membrane protein CC {ECO:0000255}. Microsome membrane {ECO:0000250|UniProtKB:Q64654}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Liver specific. {ECO:0000269|PubMed:10748047}. CC -!- POLYMORPHISM: Variations in CYP39A1 are associated with elevated serum CC (24S)-hydroxycholesterol levels among a cohort of American residents. CC {ECO:0000269|PubMed:25201972}. CC -!- SIMILARITY: Belongs to the cytochrome P450 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; AF237982; AAF63329.1; -; mRNA. DR EMBL; AK292263; BAF84952.1; -; mRNA. DR EMBL; AL591242; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL035670; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC010358; AAH10358.1; -; mRNA. DR CCDS; CCDS4916.1; -. DR RefSeq; NP_001265667.1; NM_001278738.1. DR RefSeq; NP_001265668.1; NM_001278739.1. DR RefSeq; NP_057677.2; NM_016593.4. DR AlphaFoldDB; Q9NYL5; -. DR SMR; Q9NYL5; -. DR BioGRID; 119453; 7. DR IntAct; Q9NYL5; 5. DR STRING; 9606.ENSP00000275016; -. DR SwissLipids; SLP:000001229; -. DR iPTMnet; Q9NYL5; -. DR PhosphoSitePlus; Q9NYL5; -. DR BioMuta; CYP39A1; -. DR DMDM; 145559458; -. DR MassIVE; Q9NYL5; -. DR PaxDb; 9606-ENSP00000275016; -. DR PeptideAtlas; Q9NYL5; -. DR ProteomicsDB; 83251; -. DR Antibodypedia; 30714; 276 antibodies from 28 providers. DR DNASU; 51302; -. DR Ensembl; ENST00000275016.3; ENSP00000275016.2; ENSG00000146233.8. DR GeneID; 51302; -. DR KEGG; hsa:51302; -. DR MANE-Select; ENST00000275016.3; ENSP00000275016.2; NM_016593.5; NP_057677.2. DR UCSC; uc003oyf.3; human. DR AGR; HGNC:17449; -. DR CTD; 51302; -. DR DisGeNET; 51302; -. DR GeneCards; CYP39A1; -. DR HGNC; HGNC:17449; CYP39A1. DR HPA; ENSG00000146233; Tissue enriched (liver). DR MIM; 605994; gene. DR neXtProt; NX_Q9NYL5; -. DR OpenTargets; ENSG00000146233; -. DR PharmGKB; PA38452; -. DR VEuPathDB; HostDB:ENSG00000146233; -. DR eggNOG; KOG0684; Eukaryota. DR GeneTree; ENSGT00940000153141; -. DR HOGENOM; CLU_558065_0_0_1; -. DR InParanoid; Q9NYL5; -. DR OMA; EYLLRNW; -. DR OrthoDB; 1537669at2759; -. DR PhylomeDB; Q9NYL5; -. DR TreeFam; TF105090; -. DR BioCyc; MetaCyc:HS07335-MONOMER; -. DR PathwayCommons; Q9NYL5; -. DR Reactome; R-HSA-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol. DR Reactome; R-HSA-211976; Endogenous sterols. DR SignaLink; Q9NYL5; -. DR UniPathway; UPA00221; -. DR UniPathway; UPA01058; -. DR BioGRID-ORCS; 51302; 17 hits in 1153 CRISPR screens. DR GeneWiki; CYP39A1; -. DR GenomeRNAi; 51302; -. DR Pharos; Q9NYL5; Tbio. DR PRO; PR:Q9NYL5; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q9NYL5; Protein. DR Bgee; ENSG00000146233; Expressed in parotid gland and 144 other cell types or tissues. DR ExpressionAtlas; Q9NYL5; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; TAS:UniProtKB. DR GO; GO:0033782; F:24-hydroxycholesterol 7alpha-hydroxylase activity; IEA:UniProtKB-EC. DR GO; GO:0020037; F:heme binding; IEA:InterPro. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0008396; F:oxysterol 7-alpha-hydroxylase activity; IDA:UniProtKB. DR GO; GO:0008387; F:steroid 7-alpha-hydroxylase activity; IBA:GO_Central. DR GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB. DR GO; GO:0006707; P:cholesterol catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0042632; P:cholesterol homeostasis; IBA:GO_Central. DR GO; GO:0007586; P:digestion; TAS:UniProtKB. DR GO; GO:0016125; P:sterol metabolic process; TAS:Reactome. DR CDD; cd20635; CYP39A1; 1. DR Gene3D; 1.10.630.10; Cytochrome P450; 1. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR024204; Cyt_P450_CYP7A1-type. DR InterPro; IPR002403; Cyt_P450_E_grp-IV. DR InterPro; IPR036396; Cyt_P450_sf. DR PANTHER; PTHR24304:SF2; 24-HYDROXYCHOLESTEROL 7-ALPHA-HYDROXYLASE; 1. DR PANTHER; PTHR24304; CYTOCHROME P450 FAMILY 7; 1. DR Pfam; PF00067; p450; 1. DR PIRSF; PIRSF000047; Cytochrome_CYPVIIA1; 1. DR PRINTS; PR00465; EP450IV. DR SUPFAM; SSF48264; Cytochrome P450; 1. DR Genevisible; Q9NYL5; HS. PE 1: Evidence at protein level; KW Cholesterol metabolism; Endoplasmic reticulum; Heme; Iron; KW Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase; KW Oxidoreductase; Reference proteome; Signal; Steroid metabolism; KW Sterol metabolism; Transmembrane; Transmembrane helix. FT SIGNAL 1..23 FT /evidence="ECO:0000255" FT CHAIN 24..469 FT /note="24-hydroxycholesterol 7-alpha-hydroxylase" FT /evidence="ECO:0000255" FT /id="PRO_0000051992" FT TRANSMEM 267..287 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 352..372 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 412..432 FT /note="Helical" FT /evidence="ECO:0000255" FT BINDING 414 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:0000250|UniProtKB:Q16850" FT VARIANT 23 FT /note="R -> P (60% decrease of 7-alpha hydroxylase FT activity; dbSNP:rs12192544)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:25201972" FT /id="VAR_031609" FT VARIANT 103 FT /note="R -> H (correlated with elevated serum FT (24S)-hydroxycholesterol levels; 30% decrease of 7-alpha FT hydroxylase activity; dbSNP:rs2277119)" FT /evidence="ECO:0000269|PubMed:25201972" FT /id="VAR_031610" FT VARIANT 288 FT /note="Y -> H (10% decrease of 7-alpha hydroxylase FT activity; dbSNP:rs17856332)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:25201972" FT /id="VAR_031611" FT VARIANT 324 FT /note="N -> K (correlated with elevated serum FT (24S)-hydroxycholesterol levels; impairs 7-alpha FT hydroxylase activity; dbSNP:rs7761731)" FT /evidence="ECO:0000269|PubMed:10748047, FT ECO:0000269|PubMed:25201972" FT /id="VAR_031612" FT VARIANT 329 FT /note="K -> Q (impairs 7-alpha hydroxylase activity; FT dbSNP:rs41273654)" FT /evidence="ECO:0000269|PubMed:25201972" FT /id="VAR_083092" SQ SEQUENCE 469 AA; 54116 MW; 74B013055257275C CRC64; MELISPTVII ILGCLALFLL LQRKNLRRPP CIKGWIPWIG VGFEFGKAPL EFIEKARIKY GPIFTVFAMG NRMTFVTEEE GINVFLKSKK VDFELAVQNI VYRTASIPKN VFLALHEKLY IMLKGKMGTV NLHQFTGQLT EELHEQLENL GTHGTMDLNN LVRHLLYPVT VNMLFNKSLF STNKKKIKEF HQYFQVYDED FEYGSQLPEC LLRNWSKSKK WFLELFEKNI PDIKACKSAK DNSMTLLQAT LDIVETETSK ENSPNYGLLL LWASLSNAVP VAFWTLAYVL SHPDIHKAIM EGISSVFGKA GKDKIKVSED DLENLLLIKW CVLETIRLKA PGVITRKVVK PVEILNYIIP SGDLLMLSPF WLHRNPKYFP EPELFKPERW KKANLEKHSF LDCFMAFGSG KFQCPARWFA LLEVQMCIIL ILYKYDCSLL DPLPKQSYLH LVGVPQPEGQ CRIEYKQRI //