The Sjögren-Larsson Syndrome Gene Encodes a Hexadecenal Dehydrogenase of the Sphingosine 1-Phosphate Degradation Pathway

Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1...

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Bibliographic Details
Published in:Molecular cell 2012-05, Vol.46 (4), p.461-471
Main Authors: Nakahara, Kanae, Ohkuni, Aya, Kitamura, Takuya, Abe, Kensuke, Naganuma, Tatsuro, Ohno, Yusuke, Zoeller, Raphael A., Kihara, Akio
Format: Article
Language:English
Subjects:
acyl coenzyme A
Acyl Coenzyme A - genetics
Acyl Coenzyme A - metabolism
Aldehyde Oxidoreductases - genetics
Aldehyde Oxidoreductases - metabolism
Animals
biochemical pathways
CHO Cells
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Cricetinae
Cricetulus
genes
Genes, Fungal
Humans
ligases
Lysophospholipids - metabolism
mammals
Metabolic Networks and Pathways
metabolism
metabolites
mutants
Mutation
Palmitic Acids - metabolism
pathogenesis
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Sjogren-Larsson Syndrome - etiology
Sjogren-Larsson Syndrome - genetics
Sjogren-Larsson Syndrome - metabolism
sphingosine
Sphingosine - analogs & derivatives
Sphingosine - metabolism
yeasts
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Summary:Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1 and the Sjögren-Larsson syndrome (SLS)-causative mammalian gene ALDH3A2 are responsible for conversion of the S1P degradation product hexadecenal to hexadecenoic acid. The absence of ALDH3A2 in CHO-K1 mutant cells caused abnormal metabolism of S1P/hexadecenal to ether-linked glycerolipids. Moreover, we demonstrate that yeast Faa1 and Faa4 and mammalian ACSL family members are acyl-CoA synthetases involved in the sphingolipid-to-glycerolipid metabolic pathway and that hexadecenoic acid accumulates in Δfaa1 Δfaa4 mutant cells. These results unveil the entire S1P metabolic pathway: S1P is metabolized to glycerolipids via hexadecenal, hexadecenoic acid, hexadecenoyl-CoA, and palmitoyl-CoA. From our results we propose a possibility that accumulation of the S1P metabolite hexadecenal contributes to the pathogenesis of SLS. ► Hfd1 and ALDH3A2 are aldehyde dehydrogenases involved in sphingolipid metabolism ► The S1P-to-glycerolipid metabolic pathway is conserved between yeast and mammals ► Long-chain bases are metabolized to ether-linked glycerolipids in ALDH3A2 null cells ► Hexadecenal, hexadecenoic acid, and hexadecenoyl-CoA are metabolic products of S1P
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.04.033