ID   CP26C_HUMAN             Reviewed;         522 AA.
AC   Q6V0L0; Q5VXH6;
DT   19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT   19-JUL-2005, sequence version 2.
DT   24-JAN-2024, entry version 158.
DE   RecName: Full=Cytochrome P450 26C1;
DE            Short=CYP26C1 {ECO:0000303|PubMed:14532297};
DE            EC=1.14.14.1 {ECO:0000269|PubMed:14532297};
GN   Name=CYP26C1;
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], TISSUE SPECIFICITY, INDUCTION, FUNCTION, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=14532297; DOI=10.1074/jbc.m308337200;
RA   Taimi M., Helvig C., Wisniewski J., Ramshaw H., White J., Amad M.,
RA   Korczak B., Petkovich M.;
RT   "A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis
RT   and all-trans isomers of retinoic acid.";
RL   J. Biol. Chem. 279:77-85(2004).
RN   [2]
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   [3]
RP   INVOLVEMENT IN FFDD4.
RX   PubMed=23161670; DOI=10.1093/hmg/dds477;
RA   Slavotinek A.M., Mehrotra P., Nazarenko I., Tang P.L., Lao R., Cameron D.,
RA   Li B., Chu C., Chou C., Marqueling A.L., Yahyavi M., Cordoro K.,
RA   Frieden I., Glaser T., Prescott T., Morren M.A., Devriendt K., Kwok P.Y.,
RA   Petkovich M., Desnick R.J.;
RT   "Focal facial dermal dysplasia, type IV, is caused by mutations in
RT   CYP26C1.";
RL   Hum. Mol. Genet. 22:696-703(2013).
CC   -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC       retinoates (RAs), the active metabolites of vitamin A, and critical
CC       signaling molecules in animals (PubMed:14532297). RAs exist as at least
CC       four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and
CC       9,13-dicis-RA, where atRA is considered to be the biologically active
CC       isomer, although 9-cis-RA and 13-cis-RA also have activity (Probable).
CC       Catalyzes the oxidation of atRA primarily at C-4 (PubMed:14532297).
CC       Oxidation of atRA limits its biological activity and initiates a
CC       degradative process leading to its eventual elimination, thereby
CC       contributes to the regulation of atRA homeostasis and signaling
CC       (Probable). Able to metabolize other RAs such as 9-cis with high
CC       efficiency (PubMed:14532297). Can oxidize all-trans-13,14-
CC       dihydroretinoate (DRA) to metabolites which could include all-trans-4-
CC       oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-
CC       trans-18-hydroxy-DRA (By similarity). Shares sequence similarity with
CC       other CYP26 family members, but has higher affinity to 9-cis-RA and is
CC       much less sensitive to the inhibitory effects of ketoconazole
CC       (PubMed:14532297). In cooperation with Cyp26a1, contributes to the CNS
CC       patterning and the development of regions of higher visual acuity (By
CC       similarity). {ECO:0000250|UniProtKB:B2RXA7,
CC       ECO:0000269|PubMed:14532297, ECO:0000305|PubMed:14532297}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an organic molecule + O2 + reduced [NADPH--hemoprotein
CC         reductase] = an alcohol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:17149, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:30879, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC         ChEBI:CHEBI:142491; EC=1.14.14.1;
CC         Evidence={ECO:0000269|PubMed:14532297};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17150;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=all-trans-retinoate + O2 + reduced [NADPH--hemoprotein
CC         reductase] = all-trans-4-hydroxyretinoate + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:51984, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:35291,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:134178;
CC         Evidence={ECO:0000269|PubMed:14532297};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51985;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=all-trans-4-hydroxyretinoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = all-trans-4-oxoretinoate + H(+) + 2
CC         H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75851,
CC         Rhea:RHEA-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:134178, ChEBI:CHEBI:134186;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75852;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=9-cis-retinoate + O2 + reduced [NADPH--hemoprotein reductase]
CC         = 9-cis-4-hydroxyretinoate + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75847, 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:78630, ChEBI:CHEBI:139253;
CC         Evidence={ECO:0000269|PubMed:14532297};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75848;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=9-cis-4-hydroxyretinoate + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 9-cis-4-oxoretinoate + H(+) + 2 H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75855, 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:139253, ChEBI:CHEBI:139254;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75856;
CC         Evidence={ECO:0000305|PubMed:14532297};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=all-trans-4-hydroxy-13,14-dihydroretinoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = all-trans-4-oxo-13,14-
CC         dihydroretinoate + H(+) + 2 H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:75859, 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:194184,
CC         ChEBI:CHEBI:194478; Evidence={ECO:0000250|UniProtKB:B2RXA7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75860;
CC         Evidence={ECO:0000250|UniProtKB:B2RXA7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=all-trans-13,14-dihydroretinoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = all-trans-4-hydroxy-13,14-
CC         dihydroretinoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:75863, 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:194183,
CC         ChEBI:CHEBI:194478; Evidence={ECO:0000250|UniProtKB:B2RXA7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75864;
CC         Evidence={ECO:0000250|UniProtKB:B2RXA7};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:B2RXA7};
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass membrane
CC       protein {ECO:0000305}.
CC   -!- TISSUE SPECIFICITY: Detected in most tissues at very low level.
CC       {ECO:0000269|PubMed:14532297}.
CC   -!- INDUCTION: By retinoic acid. {ECO:0000269|PubMed:14532297}.
CC   -!- DISEASE: Focal facial dermal dysplasia 4 (FFDD4) [MIM:614974]: A form
CC       of focal facial dermal dysplasia, a group of developmental defects
CC       characterized by bitemporal or preauricular skin lesions resembling
CC       aplasia cutis congenita. Skin defects occur at the sites of facial
CC       fusion during embryogenesis, with temporal lesions situated at the
CC       junction between the frontonasal and maxillary facial prominences, and
CC       preauricular lesions at the meeting point of the maxillary and
CC       mandibular prominences. The ectodermal lesions show consistent
CC       histologic abnormalities: atrophy and flattening of the epidermis,
CC       replacement of the dermis by loose connective tissue, reduced levels of
CC       fragmented elastic tissue and absence of the subcutaneous tissues and
CC       adnexal structures. FFDD4 is characterized by isolated, preauricular
CC       skin lesions. {ECO:0000269|PubMed:23161670}. Note=The disease is caused
CC       by variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; AY356349; AAQ55485.1; -; mRNA.
DR   EMBL; AL358613; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS7425.1; -.
DR   RefSeq; NP_899230.2; NM_183374.2.
DR   AlphaFoldDB; Q6V0L0; -.
DR   SMR; Q6V0L0; -.
DR   IntAct; Q6V0L0; 1.
DR   STRING; 9606.ENSP00000498424; -.
DR   DrugBank; DB00523; Alitretinoin.
DR   DrugBank; DB00755; Tretinoin.
DR   iPTMnet; Q6V0L0; -.
DR   PhosphoSitePlus; Q6V0L0; -.
DR   BioMuta; CYP26C1; -.
DR   DMDM; 71153209; -.
DR   PaxDb; 9606-ENSP00000285949; -.
DR   PeptideAtlas; Q6V0L0; -.
DR   ProteomicsDB; 67704; -.
DR   Antibodypedia; 45703; 184 antibodies from 25 providers.
DR   DNASU; 340665; -.
DR   Ensembl; ENST00000651965.1; ENSP00000498424.1; ENSG00000187553.10.
DR   GeneID; 340665; -.
DR   KEGG; hsa:340665; -.
DR   MANE-Select; ENST00000651965.1; ENSP00000498424.1; NM_183374.3; NP_899230.2.
DR   UCSC; uc010qns.2; human.
DR   AGR; HGNC:20577; -.
DR   CTD; 340665; -.
DR   DisGeNET; 340665; -.
DR   GeneCards; CYP26C1; -.
DR   HGNC; HGNC:20577; CYP26C1.
DR   HPA; ENSG00000187553; Not detected.
DR   MalaCards; CYP26C1; -.
DR   MIM; 608428; gene.
DR   MIM; 614974; phenotype.
DR   neXtProt; NX_Q6V0L0; -.
DR   OpenTargets; ENSG00000187553; -.
DR   Orphanet; 398189; Focal facial dermal dysplasia type IV.
DR   PharmGKB; PA134913464; -.
DR   VEuPathDB; HostDB:ENSG00000187553; -.
DR   eggNOG; KOG0157; Eukaryota.
DR   GeneTree; ENSGT00800000124060; -.
DR   HOGENOM; CLU_001570_15_6_1; -.
DR   InParanoid; Q6V0L0; -.
DR   OMA; MIIHSTR; -.
DR   OrthoDB; 758626at2759; -.
DR   PhylomeDB; Q6V0L0; -.
DR   TreeFam; TF105093; -.
DR   PathwayCommons; Q6V0L0; -.
DR   Reactome; R-HSA-211916; Vitamins.
DR   Reactome; R-HSA-5365859; RA biosynthesis pathway.
DR   Reactome; R-HSA-5579004; Defective CYP26C1 causes FFDD4.
DR   SignaLink; Q6V0L0; -.
DR   BioGRID-ORCS; 340665; 11 hits in 1143 CRISPR screens.
DR   GeneWiki; CYP26C1; -.
DR   GenomeRNAi; 340665; -.
DR   Pharos; Q6V0L0; Tbio.
DR   PRO; PR:Q6V0L0; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q6V0L0; Protein.
DR   Bgee; ENSG00000187553; Expressed in primordial germ cell in gonad and 11 other cell types or tissues.
DR   ExpressionAtlas; Q6V0L0; baseline and differential.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0070330; F:aromatase activity; IEA:RHEA.
DR   GO; GO:0020037; F:heme binding; IEA:InterPro.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0004497; F:monooxygenase activity; IBA:GO_Central.
DR   GO; GO:0008401; F:retinoic acid 4-hydroxylase activity; IDA:BHF-UCL.
DR   GO; GO:0001972; F:retinoic acid binding; IDA:BHF-UCL.
DR   GO; GO:0009952; P:anterior/posterior pattern specification; ISS:BHF-UCL.
DR   GO; GO:0007417; P:central nervous system development; ISS:BHF-UCL.
DR   GO; GO:0048387; P:negative regulation of retinoic acid receptor signaling pathway; NAS:BHF-UCL.
DR   GO; GO:0014032; P:neural crest cell development; ISS:BHF-UCL.
DR   GO; GO:0048284; P:organelle fusion; ISS:BHF-UCL.
DR   GO; GO:0034653; P:retinoic acid catabolic process; IDA:BHF-UCL.
DR   GO; GO:0016125; P:sterol metabolic process; IBA:GO_Central.
DR   GO; GO:0006766; P:vitamin metabolic process; TAS:Reactome.
DR   CDD; cd20636; CYP26C1; 1.
DR   Gene3D; 1.10.630.10; Cytochrome P450; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   PANTHER; PTHR24286; CYTOCHROME P450 26; 1.
DR   PANTHER; PTHR24286:SF100; CYTOCHROME P450 26C1; 1.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00465; EP450IV.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; Cytochrome P450; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   1: Evidence at protein level;
KW   Disease variant; Ectodermal dysplasia; Heme; Iron; Lipid metabolism;
KW   Membrane; Metal-binding; Monooxygenase; Oxidoreductase; Reference proteome;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..522
FT                   /note="Cytochrome P450 26C1"
FT                   /id="PRO_0000051987"
FT   TRANSMEM        9..29
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         459
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:0000255"
FT   VARIANT         245
FT                   /note="R -> Q (in dbSNP:rs11187265)"
FT                   /id="VAR_022886"
FT   CONFLICT        447
FT                   /note="F -> L (in Ref. 1; AAQ55485)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   522 AA;  57111 MW;  5401DF5646E51060 CRC64;
     MFPWGLSCLS VLGAAGTALL CAGLLLSLAQ HLWTLRWMLS RDRASTLPLP KGSMGWPFFG
     ETLHWLVQGS RFHSSRRERY GTVFKTHLLG RPVIRVSGAE NVRTILLGEH RLVRSQWPQS
     AHILLGSHTL LGAVGEPHRR RRKVLARVFS RAALERYVPR LQGALRHEVR SWCAAGGPVS
     VYDASKALTF RMAARILLGL RLDEAQCATL ARTFEQLVEN LFSLPLDVPF SGLRKGIRAR
     DQLHRHLEGA ISEKLHEDKA AEPGDALDLI IHSARELGHE PSMQELKESA VELLFAAFFT
     TASASTSLVL LLLQHPAAIA KIREELVAQG LGRACGCAPG AAGGSEGPPP DCGCEPDLSL
     AALGRLRYVD CVVKEVLRLL PPVSGGYRTA LRTFELDGYQ IPKGWSVMYS IRDTHETAAV
     YRSPPEGFDP ERFGAAREDS RGASSRFHYI PFGGGARSCL GQELAQAVLQ LLAVELVRTA
     RWELATPAFP AMQTVPIVHP VDGLRLFFHP LTPSVAGNGL CL
//