CP4FN_HUMAN
ID CP4FN_HUMAN Reviewed; 531 AA.
AC Q6NT55; Q8N8H4;
DT 10-JUL-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Ultra-long-chain fatty acid omega-hydroxylase {ECO:0000305};
DE EC=1.14.14.177 {ECO:0000269|PubMed:26056268};
DE AltName: Full=Cytochrome P450 4F22 {ECO:0000303|PubMed:26056268};
GN Name=CYP4F22 {ECO:0000303|PubMed:26056268, ECO:0000312|HGNC:HGNC:26820};
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 [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS ARCI5 LEU-59; HIS-243; TRP-372;
RP TYR-435 AND ASP-436, SUBCELLULAR LOCATION, TOPOLOGY, AND CAUTION.
RX PubMed=26056268; DOI=10.1073/pnas.1503491112;
RA Ohno Y., Nakamichi S., Ohkuni A., Kamiyama N., Naoe A., Tsujimura H.,
RA Yokose U., Sugiura K., Ishikawa J., Akiyama M., Kihara A.;
RT "Essential role of the cytochrome P450 CYP4F22 in the production of
RT acylceramide, the key lipid for skin permeability barrier formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:7707-7712(2015).
RN [4]
RP VARIANTS ARCI5 LEU-59; HIS-243; TRP-372; TYR-435 AND ASP-436.
RX PubMed=16436457; DOI=10.1093/hmg/ddi491;
RA Lefevre C., Bouadjar B., Ferrand V., Tadini G., Megarbane A., Lathrop M.,
RA Prud'homme J.-F., Fischer J.;
RT "Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3.";
RL Hum. Mol. Genet. 15:767-776(2006).
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in epidermal
CC ceramide biosynthesis. Hydroxylates the terminal carbon (omega-
CC hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to
CC ceramide synthesis (PubMed:26056268). Contributes to the synthesis of
CC three classes of omega-hydroxy-ultra-long chain fatty acylceramides
CC having sphingosine, 6-hydroxysphingosine and phytosphingosine bases,
CC all major lipid components that underlie the permeability barrier of
CC the stratum corneum (PubMed:26056268). Mechanistically, uses molecular
CC oxygen inserting one oxygen atom into a substrate, and reducing the
CC second into a water molecule, with two electrons provided by NADPH via
CC cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
CC (PubMed:26056268). {ECO:0000269|PubMed:26056268}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + triacontanoate =
CC H(+) + H2O + omega-hydroxy-triacontanoate + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:50336, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:31004, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:76044;
CC Evidence={ECO:0000269|PubMed:26056268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50337;
CC Evidence={ECO:0000305|PubMed:26056268};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an omega-methyl-ultra-long-chain fatty acid + O2 + reduced
CC [NADPH--hemoprotein reductase] = an omega-hydroxy-ultra-long-chain
CC fatty acid + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:63376, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:147288,
CC ChEBI:CHEBI:147293; EC=1.14.14.177;
CC Evidence={ECO:0000269|PubMed:26056268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63377;
CC Evidence={ECO:0000305|PubMed:26056268};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P51869};
CC -!- INTERACTION:
CC Q6NT55; Q13520: AQP6; NbExp=3; IntAct=EBI-17509525, EBI-13059134;
CC Q6NT55; Q15800: MSMO1; NbExp=3; IntAct=EBI-17509525, EBI-949102;
CC Q6NT55; Q9BRK0: REEP2; NbExp=3; IntAct=EBI-17509525, EBI-11337973;
CC Q6NT55; Q96MV1: TLCD4; NbExp=3; IntAct=EBI-17509525, EBI-12947623;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:26056268}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:26056268}. Microsome membrane
CC {ECO:0000269|PubMed:26056268}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:26056268}.
CC -!- DISEASE: Ichthyosis, congenital, autosomal recessive 5 (ARCI5)
CC [MIM:604777]: A form of autosomal recessive congenital ichthyosis, a
CC disorder of keratinization with abnormal differentiation and
CC desquamation of the epidermis, resulting in abnormal skin scaling over
CC the whole body. The main skin phenotypes are lamellar ichthyosis (LI)
CC and non-bullous congenital ichthyosiform erythroderma (NCIE), although
CC phenotypic overlap within the same patient or among patients from the
CC same family can occur. Lamellar ichthyosis is a condition often
CC associated with an embedment in a collodion-like membrane at birth;
CC skin scales later develop, covering the entire body surface. Non-
CC bullous congenital ichthyosiform erythroderma characterized by fine
CC whitish scaling on an erythrodermal background; larger brownish scales
CC are present on the buttocks, neck and legs.
CC {ECO:0000269|PubMed:16436457, ECO:0000269|PubMed:26056268}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC -!- CAUTION: A second transmembrane domain at positions 95-115 is predicted
CC by three programs ESKW, MEMSAT and Phobius. However experimental
CC evidence supports the presence of a single signal-anchor transmembrane
CC domain at the N-terminus. {ECO:0000305|PubMed:26056268}.
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DR EMBL; AK096820; BAC04868.1; -; mRNA.
DR EMBL; BC069351; AAH69351.1; -; mRNA.
DR EMBL; BC093894; AAH93894.1; -; mRNA.
DR EMBL; BC093896; AAH93896.1; -; mRNA.
DR CCDS; CCDS12331.1; -.
DR RefSeq; NP_775754.2; NM_173483.3.
DR RefSeq; XP_011525994.1; XM_011527692.2.
DR RefSeq; XP_011525995.1; XM_011527693.2.
DR AlphaFoldDB; Q6NT55; -.
DR SMR; Q6NT55; -.
DR BioGRID; 125990; 32.
DR IntAct; Q6NT55; 4.
DR STRING; 9606.ENSP00000269703; -.
DR SwissLipids; SLP:000001622; -.
DR iPTMnet; Q6NT55; -.
DR PhosphoSitePlus; Q6NT55; -.
DR BioMuta; CYP4F22; -.
DR DMDM; 74748981; -.
DR jPOST; Q6NT55; -.
DR MassIVE; Q6NT55; -.
DR MaxQB; Q6NT55; -.
DR PaxDb; Q6NT55; -.
DR PeptideAtlas; Q6NT55; -.
DR PRIDE; Q6NT55; -.
DR ProteomicsDB; 66660; -.
DR Antibodypedia; 27086; 86 antibodies from 18 providers.
DR DNASU; 126410; -.
DR Ensembl; ENST00000269703.8; ENSP00000269703.1; ENSG00000171954.13.
DR Ensembl; ENST00000601005.2; ENSP00000469866.1; ENSG00000171954.13.
DR GeneID; 126410; -.
DR KEGG; hsa:126410; -.
DR MANE-Select; ENST00000269703.8; ENSP00000269703.1; NM_173483.4; NP_775754.2.
DR UCSC; uc002nbh.5; human.
DR CTD; 126410; -.
DR DisGeNET; 126410; -.
DR GeneCards; CYP4F22; -.
DR HGNC; HGNC:26820; CYP4F22.
DR HPA; ENSG00000171954; Tissue enhanced (esophagus, skin, vagina).
DR MalaCards; CYP4F22; -.
DR MIM; 604777; phenotype.
DR MIM; 611495; gene.
DR neXtProt; NX_Q6NT55; -.
DR OpenTargets; ENSG00000171954; -.
DR Orphanet; 313; Lamellar ichthyosis.
DR PharmGKB; PA162383112; -.
DR VEuPathDB; HostDB:ENSG00000171954; -.
DR eggNOG; KOG0157; Eukaryota.
DR GeneTree; ENSGT00940000161507; -.
DR HOGENOM; CLU_001570_5_1_1; -.
DR InParanoid; Q6NT55; -.
DR OMA; IAYTNMF; -.
DR OrthoDB; 1247045at2759; -.
DR PhylomeDB; Q6NT55; -.
DR TreeFam; TF105088; -.
DR BioCyc; MetaCyc:ENSG00000171954-MON; -.
DR BRENDA; 1.14.14.177; 2681.
DR PathwayCommons; Q6NT55; -.
DR Reactome; R-HSA-211935; Fatty acids.
DR Reactome; R-HSA-211958; Miscellaneous substrates.
DR Reactome; R-HSA-211979; Eicosanoids.
DR Reactome; R-HSA-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR Reactome; R-HSA-5579005; Defective CYP4F22 causes ARCI5.
DR SignaLink; Q6NT55; -.
DR BioGRID-ORCS; 126410; 8 hits in 1065 CRISPR screens.
DR ChiTaRS; CYP4F22; human.
DR GeneWiki; CYP4F22; -.
DR GenomeRNAi; 126410; -.
DR Pharos; Q6NT55; Tbio.
DR PRO; PR:Q6NT55; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q6NT55; protein.
DR Bgee; ENSG00000171954; Expressed in lower esophagus mucosa and 71 other tissues.
DR Genevisible; Q6NT55; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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; IDA:UniProtKB.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0046513; P:ceramide biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006690; P:icosanoid metabolic process; TAS:Reactome.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Heme; Ichthyosis; Iron; Lipid metabolism; Membrane;
KW Metal-binding; Microsome; Monooxygenase; Oxidoreductase;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..531
FT /note="Ultra-long-chain fatty acid omega-hydroxylase"
FT /id="PRO_0000293731"
FT TOPO_DOM 1..22
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:26056268"
FT TRANSMEM 23..43
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:26056268"
FT TOPO_DOM 44..531
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:26056268"
FT BINDING 335
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /note="covalent"
FT /evidence="ECO:0000250|UniProtKB:P51869"
FT BINDING 475
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:P51869"
FT VARIANT 59
FT /note="F -> L (in ARCI5; results in decreased synthesis of
FT omega-hydroxyceramides; dbSNP:rs118091316)"
FT /evidence="ECO:0000269|PubMed:16436457,
FT ECO:0000269|PubMed:26056268"
FT /id="VAR_037441"
FT VARIANT 178
FT /note="S -> C (in dbSNP:rs16980531)"
FT /id="VAR_033118"
FT VARIANT 243
FT /note="R -> H (in ARCI5; results in decreased synthesis of
FT omega-hydroxyceramides; dbSNP:rs118203937)"
FT /evidence="ECO:0000269|PubMed:16436457,
FT ECO:0000269|PubMed:26056268"
FT /id="VAR_037442"
FT VARIANT 372
FT /note="R -> W (in ARCI5; results in decreased synthesis of
FT omega-hydroxyceramides; dbSNP:rs201129618)"
FT /evidence="ECO:0000269|PubMed:16436457,
FT ECO:0000269|PubMed:26056268"
FT /id="VAR_037443"
FT VARIANT 435
FT /note="H -> Y (in ARCI5; results in impaired synthesis of
FT omega-hydroxyceramides; dbSNP:rs118203935)"
FT /evidence="ECO:0000269|PubMed:16436457,
FT ECO:0000269|PubMed:26056268"
FT /id="VAR_037444"
FT VARIANT 436
FT /note="H -> D (in ARCI5; results in impaired synthesis of
FT omega-hydroxyceramides; dbSNP:rs118203936)"
FT /evidence="ECO:0000269|PubMed:16436457,
FT ECO:0000269|PubMed:26056268"
FT /id="VAR_037445"
FT VARIANT 505
FT /note="K -> Q (in dbSNP:rs7256787)"
FT /id="VAR_033119"
FT CONFLICT 125
FT /note="I -> T (in Ref. 1; BAC04868)"
FT /evidence="ECO:0000305"
FT CONFLICT 288
FT /note="Q -> R (in Ref. 1; BAC04868)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 531 AA; 61958 MW; 32E801893EB8C536 CRC64;
MLPITDRLLH LLGLEKTAFR IYAVSTLLLF LLFFLFRLLL RFLRLCRSFY ITCRRLRCFP
QPPRRNWLLG HLGMYLPNEA GLQDEKKVLD NMHHVLLVWM GPVLPLLVLV HPDYIKPLLG
ASAAIAPKDD LFYGFLKPWL GDGLLLSKGD KWSRHRRLLT PAFHFDILKP YMKIFNQSAD
IMHAKWRHLA EGSAVSLDMF EHISLMTLDS LQKCVFSYNS NCQEKMSDYI SAIIELSALS
VRRQYRLHHY LDFIYYRSAD GRRFRQACDM VHHFTTEVIQ ERRRALRQQG AEAWLKAKQG
KTLDFIDVLL LARDEDGKEL SDEDIRAEAD TFMFEGHDTT SSGISWMLFN LAKYPEYQEK
CREEIQEVMK GRELEELEWD DLTQLPFTTM CIKESLRQYP PVTLVSRQCT EDIKLPDGRI
IPKGIICLVS IYGTHHNPTV WPDSKVYNPY RFDPDNPQQR SPLAYVPFSA GPRNCIGQSF
AMAELRVVVA LTLLRFRLSV DRTRKVRRKP ELILRTENGL WLKVEPLPPR A
