CP39A_HUMAN
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 03-AUG-2022, entry version 176.
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, 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; 6.
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; Q9NYL5; -.
DR PeptideAtlas; Q9NYL5; -.
DR PRIDE; Q9NYL5; -.
DR ProteomicsDB; 83251; -.
DR Antibodypedia; 30714; 253 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 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; RPPCIKG; -.
DR OrthoDB; 572303at2759; -.
DR PhylomeDB; Q9NYL5; -.
DR TreeFam; TF105090; -.
DR BioCyc; MetaCyc:HS07335-MON; -.
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 1073 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 142 other tissues.
DR ExpressionAtlas; Q9NYL5; baseline and differential.
DR Genevisible; Q9NYL5; HS.
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: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:0008395; F:steroid 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 Gene3D; 1.10.630.10; -; 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 Pfam; PF00067; p450; 1.
DR PIRSF; PIRSF000047; Cytochrome_CYPVIIA1; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
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 (associated with elevated serum (24S)-
FT 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 (associated with elevated serum (24S)-
FT hydroxycholesterol levels; impairs 7-alpha hydroxylase
FT 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
