||Phytosphingosine degradation pathway includes fatty acid alpha-oxidation reactions in the endoplasmic reticulum
Kitamura, Takuya ,
Seki, NaoyaKihara, Akio
Proceedings of the National Academy of Sciences of the United States of America (PNAS)
E2623 , 2017-03-28 , National Academy of Sciences.
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.