Fatty acid 2-Hydroxylation in mammalian sphingolipid biology

Hama, Hiroko

doi:10.1016/j.bbalip.2009.12.004

Cited by 182 publications

(151 citation statements)

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“…24 The acetyl-CoA transporter SLC33A1 located in the ER membrane and required for the formation of O-acetylated gangliosides is mutated in SPG42. Defects in the metabolism of complex lipids cause at least four more HSP subtypes: in SPG39 the deacetylation of phosphatidylcholine, the major membrane phospholipid, is defective due to mutations in phospholipase B/neuropathy target esterase (PNPLA6), 7 mutations in fatty acid-2 hydroxylase (FA2H) affect synthesis of 2-hydroxysphingolipids in 25 and CYP2U1 mutations in SPG49 lead to disturbed o-and w-1 fatty acid hydroxylation. 3 In GBA2, mutated in autosomal recessive HSP SPG46, the conversion of glucosylceramide to free glucose and ceramide by the non-lysosomal glucosylceramidase is deficient.…”

Section: Ddhd2 (Spg54)mentioning

confidence: 99%

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

et al. 2013

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Hereditary spastic paraplegias (HSP) are a genetically heterogeneous group of disorders characterized by a distal axonopathy of the corticospinal tract motor neurons leading to progressive lower limb spasticity and weakness. Intracellular membrane trafficking, mitochondrial dysfunction and myelin formation are key functions involved in HSP pathogenesis. Only recently defects in metabolism of complex lipids have been implicated in a number of HSP subtypes. Mutations in the 23 known autosomal recessive HSP genes explain less than half of autosomal recessive HSP cases. To identify novel autosomal recessive HSP disease genes, exome sequencing was performed in 79 index cases with autosomal recessive forms of HSP. Resulting variants were filtered and intersected between families to allow identification of new disease genes. We identified two deleterious mutations in the phospholipase DDHD2 gene in two families with complicated HSP. The phenotype is characterized by early onset of spastic paraplegia, mental retardation, short stature and dysgenesis of the corpus callosum. Phospholipase DDHD2 is involved in intracellular membrane trafficking at the golgi/ endoplasmic reticulum interface and has been shown to possess phospholipase A1 activity in vitro. Discovery of DDHD2 mutations in HSP might therefore provide a link between two key pathogenic themes in HSP: membrane trafficking and lipid metabolism.

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Section: Ddhd2 (Spg54)mentioning

confidence: 99%

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

et al. 2013

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“…There are above 60 different sphingoid base backbones that vary in alkyl chain lenghts (Merrill, 2011), the degree of saturation and position of double bonds (Pruett et al, 2008) and the presence of a hydroxyl group (Hama, 2010). Mammalian organisms contain (Figure 3), mainly sphingosine (trans-4-sphingenine, d18:1D4), sphinganine (dihydrosphingosine, d18:0) and phytosphingosine (t18:0, 4-hydroxysphinganine) (Dickson, 2008).…”

Section: Structure and Classificationmentioning

confidence: 99%

Potential health benefits of sphingolipids in milk and dairy products

Potočki¹

2016

Mljekarstvo

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Sphingolipids are found in all eukaryotic and some prokaryotic cells. Milk and dairy products are one of the most important sources of sphingolipids. This compounds participate in a variety of indispensable metabolic, neurological, and intracellular signaling processes. Sphingolipids and their derivatives are highly bioactive compounds with anti-cancer, bacteriostatic and cholesterol-lowering properties. Therefore, this review focuses on the potential health benefits of the milk and dairy sphingolipids.

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“…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 with 2-OH FA exist in specific tissues such as the epidermis and brain (11,12). In accordance with the distribution pattern of 2-OH FA, the levels of odd-numbered CERs/sphingolipids are especially high in these tissues (13, 14).…”

mentioning

confidence: 75%

“…The FA 2-hydroxylase FA2H directly forms 2-OH FAs from FAs (12,17). Although the PHS degradation pathway generates 2-OH C16:0-COOH almost exclusively, FA2H can produces 2-OH FAs ranging from long chain to very long chain (17,41).…”

Section: Discussionmentioning

confidence: 99%

“…Their 2-OH groups are important for the formation and maintenance of the myelin sheath, which is composed of a multilayered lipid structure, probably by enhancing lipid-lipid interactions via hydrogen bonds. The FA 2-hydroxylase FA2H catalyzes conversion of FAs to 2-OH FAs (12,17). Reflecting the importance of the 2-OH groups of galactosylceramide and sulfatide in myelin, FA2H mutations cause hereditary spastic paraplegia in human (18, 19) and late-onset axon and myelin sheath degeneration in mice (16,20).…”

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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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Fatty acid 2-Hydroxylation in mammalian sphingolipid biology

Cited by 182 publications

References 108 publications

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

Potential health benefits of sphingolipids in milk and dairy products

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

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