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 27-MAR-2024, entry version 164. 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, GN 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 CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:50336, Rhea:RHEA- CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:31004, CC ChEBI:CHEBI:57618, 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}. 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; 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; 9606-ENSP00000269703; -. DR PeptideAtlas; Q6NT55; -. DR ProteomicsDB; 66660; -. DR Antibodypedia; 27086; 99 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 AGR; HGNC:26820; -. 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; QQMHLFS; -. DR OrthoDB; 1611592at2759; -. DR PhylomeDB; Q6NT55; -. DR TreeFam; TF105088; -. DR BioCyc; MetaCyc:ENSG00000171954-MONOMER; -. 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 1145 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 73 other cell types or tissues. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. 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 CDD; cd20679; CYP4F; 1. DR Gene3D; 1.10.630.10; Cytochrome P450; 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 PANTHER; PTHR24291; CYTOCHROME P450 FAMILY 4; 1. DR PANTHER; PTHR24291:SF53; ULTRA-LONG-CHAIN FATTY ACID OMEGA-HYDROXYLASE; 1. DR Pfam; PF00067; p450; 1. DR PRINTS; PR00463; EP450I. DR PRINTS; PR00385; P450. DR SUPFAM; SSF48264; Cytochrome P450; 1. DR PROSITE; PS00086; CYTOCHROME_P450; 1. DR Genevisible; Q6NT55; HS. 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 //