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Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

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Title: Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation
Authors: Ohno, Yusuke Browse this author →KAKEN DB
Nakamichi, Shota Browse this author
Ohkuni, Aya Browse this author
Kamiyama, Nozomi Browse this author
Naoe, Ayano Browse this author
Tsujimura, Hisashi Browse this author
Yokose, Urara Browse this author
Sugiura, Kazumitsu Browse this author →KAKEN DB
Ishikawa, Junko Browse this author
Akiyama, Masashi Browse this author →KAKEN DB
Kihara, Akio Browse this author →KAKEN DB
Keywords: acylceramide
ceramide
lipid
skin
sphingolipid
Issue Date: 23-Jun-2015
Publisher: National Academy of Sciences
Journal Title: Proceedings of the National Academy of Sciences
Volume: 112
Issue: 25
Start Page: 7707
End Page: 7712
Publisher DOI: 10.1073/pnas.1503491112
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 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 an ichthyosis patient 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 ?C28 fatty acids. In conclusion, our findings demonstrated that CYP4F22 is an ultra long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provides important new 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.
Type: article (author version)
URI: http://hdl.handle.net/2115/60363
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 木原 章雄

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