title: Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation.
abstract: A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid ω-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the ω-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (≥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production.
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan;
authors.forename: Shota
authors.initials: S
authors.lastname: Nakamichi
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan;
authors.forename: Aya
authors.initials: A
authors.lastname: Ohkuni
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan;
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kamiyama
authors.affiliation: Kao Corporation, Haga-gun, Tochigi 321-3497, Japan;
authors.forename: Ayano
authors.initials: A
authors.lastname: Naoe
authors.affiliation: Kao Corporation, Haga-gun, Tochigi 321-3497, Japan;
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsujimura
authors.affiliation: Kao Corporation, Haga-gun, Tochigi 321-3497, Japan;
authors.forename: Urara
authors.initials: U
authors.lastname: Yokose
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Sugiura
authors.affiliation: Kao Corporation, Haga-gun, Tochigi 321-3497, Japan;
authors.forename: Junko
authors.initials: J
authors.lastname: Ishikawa
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan; kihara@pharm.hokudai.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
mesh_terms: D002518:Ceramides / Q000096:biosynthesis*; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D010539:Permeability; D012867:Skin / Q000201:enzymology / Q000378:metabolism*
chemical_list: D002518:Ceramides; D003577:Cytochrome P-450 Enzyme System; C559989:CYP4F22 protein, human
keywords: acylceramide; ceramide; lipid; skin; sphingolipid