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Phytosphingosine degradation pathway includes fatty acid alpha-oxidation reactions in the endoplasmic reticulum

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Title: Phytosphingosine degradation pathway includes fatty acid alpha-oxidation reactions in the endoplasmic reticulum
Authors: Kitamura, Takuya Browse this author
Seki, Naoya Browse this author
Kihara, Akio Browse this author →KAKEN DB
Keywords: alpha-oxidation
fatty acid
Issue Date: 28-Mar-2017
Publisher: National Academy of Sciences.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume: 114
Issue: 13
Start Page: E2616
End Page: E2623
Publisher DOI: 10.1073/pnas.1700138114
Abstract: Although normal fatty acids (FAs) are degraded via beta-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via alpha-oxidation. Phytosphingosine (PHS) is one of the long-chain bases (the sphingolipid components) and exists in specific tissues, including the epidermis and small intestine in mammals. In the degradation pathway, PHS is converted to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA alpha-oxidation. However, the detailed reactions and genes involved in the alpha-oxidation reactions of the PHS degradation pathway have yet to be determined. In the present study, we reveal the entire PHS degradation pathway: PHS is converted to C15: 0-COOH via six reactions [phosphorylation, cleavage, oxidation, CoA addition, cleavage (C1 removal), and oxidation], in which the last three reactions correspond to the alpha-oxidation. The aldehyde dehydrogenase ALDH3A2 catalyzes both the first and second oxidation reactions (fatty aldehydes to FAs). In Aldh3a2-deficient cells, the unmetabolized fatty aldehydes are reduced to fatty alcohols and are incorporated into ether-linked glycerolipids. We also identify HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like] as the major 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the FA alpha-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA alpha-oxidation in the peroxisomes, we have revealed the existence of FA alpha-oxidation in the endoplasmic reticulum in mammals.
Type: article (author version)
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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