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Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum
- Source :
- Proceedings of the National Academy of Sciences. 114
- Publication Year :
- 2017
- Publisher :
- Proceedings of the National Academy of Sciences, 2017.
-
Abstract
- Although normal fatty acids (FAs) are degraded via β-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via α-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 α-oxidation. However, the detailed reactions and genes involved in the α-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 α-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 α-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA α-oxidation in the peroxisomes, we have revealed the existence of FA α-oxidation in the endoplasmic reticulum in mammals.
- Subjects :
- 0301 basic medicine
Stereochemistry
Aldehyde dehydrogenase
CHO Cells
Endoplasmic Reticulum
Palmitic acid
03 medical and health sciences
chemistry.chemical_compound
Cricetulus
Sphingosine
Alpha oxidation
Animals
Humans
chemistry.chemical_classification
Multidisciplinary
biology
Endoplasmic reticulum
Fatty acid
Metabolism
Peroxisome
Lyase
Aldehyde Oxidoreductases
HEK293 Cells
030104 developmental biology
PNAS Plus
chemistry
Biochemistry
Proteolysis
biology.protein
Oxidation-Reduction
Metabolic Networks and Pathways
HeLa Cells
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 114
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....b23b78f44e44ff974a62d49448fe58b7