Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

Kondo, Natsuki; Ohno, Yusuke; Yamagata, Maki; Obara, Takashi; Seki, Naoya; Kitamura, Tatsuya; Naganuma, Tatsuro; Kihara, Akio

doi:10.1038/ncomms6338

Cited by 87 publications

(85 citation statements)

References 44 publications

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“…Although the anterior half of the PHS degradation pathway is similar to those of DHS and SPH (Figs. S1 and S2), the latter half is completely different and largely unknown but includes an FA α-oxidation step (27). We identified MPO1 as a gene involved in the PHS degradation pathway, likely in the FA α-oxidation step, in yeast (27), whereas an Mpo1 homolog does not exist in mammals.…”

Section: Significancementioning

confidence: 94%

“…Levels of PHS-containing CERs (PHS-CERs) are reduced in atopic dermatitis patients (26), implying the importance of PHS-CERs in epidermal permeability barrier formation. We recently revealed that PHS is metabolized to pentadecanoic acid (C15:0-COOH) via 2-OH C16:0-COOH in yeast and mammals (27). Thus, the PHS degradation pathway is another supply source of 2-OH FAs, in addition to FA2H.…”

Section: Significancementioning

confidence: 99%

“…PHS is a major LCB in yeast. We previously identified yeast MPO1 as the gene involved in the PHS degradation pathway, maybe at the α-oxidation step (27). Although Mpo1 is conserved in bacteria, fungi, plants, and protists, its homolog does not exist in mammals.…”

Section: Hacl2 Is a 2-oh Acyl-coa Lyase Involved In The Phs Degradationmentioning

confidence: 99%

“…S2C). The metabolism of PHS depended on SPH 1-phosphate lyase Sgpl1 as other LCBs (27), indicating that PHS is first converted to PHS 1-phosphate by SPH kinase and then cleaved to 2-OH hexadecanal (2-OH C16:0-CHO) by SPH 1-phosphate lyase upstream of the PHS degradation pathway. However, detailed downstream reactions linking 2-OH C16:0-CHO to C15:0-COOH and the responsible genes remained unclear (Fig.…”

Section: Aldh3a2 Ismentioning

confidence: 99%

“…We previously revealed that PHS was metabolized to C15:0-COOH and mainly incorporated into ester-linked glycerolipids in mammalian cells (HEK 293T cells and mouse embryonic carcinoma F9 cells) (27) (Fig. S2C).…”

Section: Aldh3a2 Ismentioning

confidence: 99%

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Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Kitamura

Seki

Kihara

2017

Proc. Natl. Acad. Sci. U.S.A.

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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.α-oxidation | fatty acid | metabolism | lipid | sphingolipid M ost cellular fatty acids (FAs) have a nonhydroxylated straight chain and are degraded via β-oxidation either in the mitochondria for long-chain FAs (C11-C20), or in the peroxisomes for very long-chain FAs (≥C21) (1, 2). However, unusual FAs, such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs (i.e., food-derived phytanic acid), are degraded via α-oxidation (2-4). During FA synthesis by FA synthase type I, acetyl-acyl carrier proteins (ACPs) receive two-carbon units from malonyl-ACP seven times to produce palmitoyl-ACP, followed by thioester bond cleavage to release palmitic acid (C16:0-COOH) (5). Some of the cellular FAs are further elongated via the FA elongation cycle in the endoplasmic reticulum (ER). In each cycle, the FA chain length is elongated by two (6, 7). In the FA degradation pathway (β-oxidation), the FA chain length is shortened by two as acetylCoA is released (1). Thus, all FA synthesis, elongation, and degradation steps proceed by two-carbon units. Accordingly, most cellular FAs are even-numbered. However, odd-numbered FAs also exist, albeit at much lower levels, because α-oxidation produces odd-numbered FAs from 2-OH FAs (8, 9).Sphingolipids are one of the major lipid classes in eukaryotes. The sphingolipid backbone ceramide (CER) is composed of a longchain base (LCB) and an FA (10, 11). Although the FA moiety of CERs is nonhydroxylated in most tissues, CERs...

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Section: Significancementioning

confidence: 94%

Section: Significancementioning

confidence: 99%

Section: Hacl2 Is a 2-oh Acyl-coa Lyase Involved In The Phs Degradationmentioning

confidence: 99%

Section: Aldh3a2 Ismentioning

confidence: 99%

Section: Aldh3a2 Ismentioning

confidence: 99%

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Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Kitamura

Seki

Kihara

2017

Proc. Natl. Acad. Sci. U.S.A.

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The membrane‐bound O‐acyltransferase Ale1 transfers an acyl moiety to newly synthesized 2‐alkyl‐sn‐glycero‐3‐phosphocholine in yeast

et al. 2018

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To elucidate the mechanism of acyl chain remodeling at the sn-1 position of phosphatidylcholine (PC), we investigated acyl chain introduction using a newly synthesized 1-hydroxy-2-hexadecyl-sn-glycero-3-phosphocholine (HHPC) in Saccharomyces cerevisiae. HHPC is incorporated into yeast cells and converted to a PC species containing acyl residues of 16 or 18 carbons. The efficiency of palmitoleic acid introduction to HHPCin vitro is lower in the reaction with the extract from the deletion mutant of ALE1, which encodes a membrane-bound O-acyltransferase, than in that with extracts from the wild-type strain. In addition, deletion of ALE1 causes reductions in the molecular species containing acyl residues in HHPC. These results reveal that ALE1 is involved in acyl chain transfer to the sn-1 position of HHPC in yeast.

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Microbial production of odd‐chain fatty acids

Qin

Wang

et al. 2022

Biotech & Bioengineering

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Odd-chain fatty acids (OcFAs) and their derivatives have attracted much attention due to their beneficial physiological effects and their potential to be alternatives to advanced fuels. However, cells naturally produce even-chain fatty acids (EcFAs) with negligible OcFAs. In the process of biosynthesis of fatty acids (FAs), the acetyl-CoA serves as the starter unit for EcFAs, and propionyl-CoA works as the starter unit for OcFAs. The lack of sufficient propionyl-CoA, the precursor, is usually regarded as the main restriction for large-scale bioproduction of OcFAs. In recent years, synthetic biology strategies have been used to modify several microorganisms to produce more propionyl-CoA that would enable an efficient biosynthesis of OcFAs. This review discusses several reported and potential metabolic pathways for propionyl-CoA biosynthesis, followed by advances in engineering several cell factories for OcFAs production. Finally, trends and challenges of synthetic biology driven OcFAs production are discussed.

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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

Cited by 87 publications

References 44 publications

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

The membrane‐bound O‐acyltransferase Ale1 transfers an acyl moiety to newly synthesized 2‐alkyl‐sn‐glycero‐3‐phosphocholine in yeast

Microbial production of odd‐chain fatty acids

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