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 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.
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.
Kanae
K
Nakahara
Aya
A
Ohkuni
Takuya
T
Kitamura
Kensuke
K
Abe
Tatsuro
T
Naganuma
Yusuke
Y
Ohno
Raphael A
RA
Zoeller
Akio
A
Kihara
D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005800:Genes, Fungal; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D009154:Mutation; D010169:Palmitic Acids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D016111:Sjogren-Larsson Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000214:Acyl Coenzyme A; D008246:Lysophospholipids; D010169:Palmitic Acids; D029701:Saccharomyces cerevisiae Proteins; C060506:sphingosine 1-phosphate; C093821:hexadecenoic acid; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase; D003066:Coenzyme A Ligases; C511244:Faa1 protein, S cerevisiae; C090206:FAA4 protein, S cerevisiae; D013110:Sphingosine