J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M800158-JLR200 on June 9, 2008

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Journal of Lipid Research, Vol. 49, 2356-2364, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length

Yukiko Mizutani*, Akio Kihara{dagger},§, Hiroko Chiba*, Hiromasa Tojo** and Yasuyuki Igarashi1,*,{dagger}

* Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Sciences, Hokkaido University, Sapporo, Japan
{dagger} Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
§ Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
** Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka, Japan

Published, JLR Papers in Press, June 9, 2008.

This study was performed through special coordination funds for promoting science and technology from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government.

1 To whom correspondence should be addressed. e-mail: yigarash{at}pharm.hokudai.ac.jp

Ceramide is unusually abundant in epidermal stratum corneum and is important for permeability barrier function. Ceramides in epidermis also comprise an unusual variety, including 2-hydroxy ({alpha}-hydroxy)-ceramide. Six mammalian ceramide synthase/longevity assurance homologue (CerS/LASS) family members have been identified as synthases responsible for ceramide (CER) production. We reveal here that of the six, CerS3/LASS3 mRNA is the most predominantly expressed in keratinocytes. Moreover, its expression is increased upon differentiation. CerS family members have known substrate specificities for fatty acyl-CoA chain length and saturation, yet their abilities to produce 2-hydroxy-CER have not been examined. In the present study, we demonstrate that all CerS members can produce 2-hydroxy-CER when overproduced in HEK 293T cells. Each produced a 2-hydroxy-CER with a chain length similar to that of the respective nonhydroxy-CER produced. In HeLa cells overproducing the FA 2-hydroxylase FA2H, knock-down of CerS2 resulted in a reduction in total long-chain 2-hydroxy-CERs, confirming enzyme substrate specificity for chain length. In vitro CerS assays confirmed the ability of CerS1 to utilize 2-hydroxy-stearoyl-CoA as a substrate. These results suggest that all CerS members can synthesize 2-hydroxy-CER with specificity for 2-hydroxy-fatty acyl-CoA chain length and that CerS3 may be important in CER and 2-hydroxy-CER synthesis in epidermis.

Supplementary key words epidermis • fatty acid 2-hydroxylase • hydroxy fatty acids • keratinocytes

Abbreviations: CER, ceramide; CerS, ceramide synthase; FB1, fumonisin B1; LASS, longevity assurance homologue; LCB, long-chain base; MS/MS, tandem mass spectrometry; Sph, sphingosine


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