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Sphingolipids are a class oflipids containing a backbone of sphingoid bases, which are a set ofaliphaticaminoalcohols that includessphingosine. They were discovered in brain extracts in the 1870s and were named after the mythologicalsphinx because of their enigmatic nature.[1][2] These compounds play important roles insignal transduction andcell recognition.[3]Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact onneural tissue. A sphingolipid with a terminal hydroxyl group is aceramide. Other common groups bonded to the terminal oxygen atom includephosphocholine, yielding asphingomyelin, and various sugarmonomers ordimers, yieldingcerebrosides andglobosides, respectively. Cerebrosides and globosides are collectively known asglycosphingolipids.
The long-chain bases, sometimes simply known as sphingoid bases, are the first non-transient products ofde novo sphingolipid synthesis in both yeast and mammals. These compounds, specifically known asphytosphingosine anddihydrosphingosine (also known as sphinganine,[4] although this term is less common), are mainly C18 compounds, with somewhat lower levels of C20 bases.[5] Ceramides and glycosphingolipids areN-acyl derivatives of these compounds.[6]
The sphingosine backbone is O-linked to a (usually) charged head group such asethanolamine,serine, orcholine.[citation needed]
The backbone is also amide-linked to anacyl group, such as afatty acid.[citation needed]
Simple sphingolipids, which include the sphingoid bases and ceramides, make up the early products of the sphingolipid synthetic pathways.
Complex sphingolipids may be formed by addition of head groups to ceramide or phytoceramide:
De novo sphingolipid synthesis begins with formation of 3-keto-dihydrosphingosine byserine palmitoyltransferase.[9] The preferred substrates for this reaction arepalmitoyl-CoA andserine. However, studies have demonstrated that serine palmitoyltransferase has some activity toward other species offatty acyl-CoA[10] and alternativeamino acids,[11] and the diversity of sphingoid bases has recently been reviewed.[12] Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine. Dihydrosphingosine is acylated by one of six (dihydro)-ceramide synthase,CerS - originally termed LASS - to form dihydroceramide.[13] The six CerS enzymes have different specificity foracyl-CoA substrates, resulting in the generation of dihydroceramides with differing chain lengths (ranging from C14-C26). Dihydroceramides are then desaturated to form ceramide.[14]
De novo generatedceramide is the central hub of the sphingolipid network and subsequently has several fates. It may be phosphorylated byceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated byglucosylceramide synthase orgalactosylceramide synthase. Additionally, it can be converted tosphingomyelin by the addition of aphosphorylcholine headgroup bysphingomyelin synthase.Diacylglycerol is generated by this process. Finally, ceramide may be broken down by aceramidase to formsphingosine.Sphingosine may be phosphorylated to form sphingosine-1-phosphate. This may be dephosphorylated to reform sphingosine.[15]
Breakdown pathways allow the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelin may be broken down by sphingomyelinase to form ceramide.[citation needed]
The only route by which sphingolipids are converted to non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.[16]
Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of theplasma membranelipid bilayer. Certain complexglycosphingolipids were found to be involved in specific functions, such ascell recognition and signaling. Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or withproteins.[citation needed]
Recently, simple sphingolipidmetabolites, such as ceramide andsphingosine-1-phosphate, have been shown to be important mediators in the signaling cascades involved inapoptosis,proliferation, stress responses,necrosis,inflammation,autophagy,senescence, anddifferentiation.[17][18][19][20][21] Ceramide-based lipids self-aggregate incell membranes and form separatephases less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or "lipid rafts" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport. At present, most research focuses on the organizing function during signal transduction.[22]
Sphingolipids are synthesized in a pathway that begins in theER and is completed in theGolgi apparatus, but these lipids are enriched in theplasma membrane and inendosomes, where they perform many of their functions.[23] Transport occurs via vesicles and monomeric transport in thecytosol. Sphingolipids are virtually absent frommitochondria and theER, but constitute a 20-35 molar fraction of plasma membrane lipids.[24]
In experimental animals, feeding sphingolipids inhibitscolon carcinogenesis, reducesLDL cholesterol and elevatesHDL cholesterol.[25]
Sphingolipids are universal ineukaryotes but are rare inbacteria andarchaea, meaning that they are evolutionally very old. Bacteria that do produce sphingolipids are found in some members of thesuperphylumFCB group (Sphingobacteria), particularly familySphingomonadaceae, some members of theBdellovibrionota, and some members of theMyxococcota.[26]
Because of the incredible complexity of mammalian systems, yeast are often used as amodel organism for working out new pathways. These single-celled organisms are often more genetically tractable than mammalian cells, and strain libraries are available to supply strains harboring almost any non-lethalopen reading frame single deletion. The two most commonly used yeasts areSaccharomyces cerevisiae andSchizosaccharomyces pombe, although research is also done in the pathogenic yeastCandida albicans.[citation needed]
In addition to the important structural functions of complex sphingolipids (inositol phosphorylceramide and its mannosylated derivatives), the sphingoid basesphytosphingosine and dihydrosphingosine (sphinganine) play vital signaling roles inS. cerevisiae. These effects include regulation ofendocytosis, ubiquitin-dependentproteolysis (and, thus, regulation of nutrient uptake[27]),cytoskeletal dynamics, thecell cycle,translation, posttranslational protein modification, and the heat stress response.[28] Additionally, modulation of sphingolipid metabolism byphosphatidylinositol (4,5)-bisphosphate signalingvia Slm1p and Slm2p andcalcineurin has recently been described.[29] Additionally, a substrate-level interaction has been shown between complex sphingolipid synthesis and cycling ofphosphatidylinositol 4-phosphate by the phosphatidylinositol kinase Stt4p and the lipid phosphatase Sac1p.[30]
Higher plants contain a wider variety of sphingolipids than animals and fungi.[citation needed]
There are several disorders of sphingolipid metabolism, known assphingolipidoses. The main members of this group areNiemann-Pick disease,Fabry disease,Krabbe disease,Gaucher disease,Tay–Sachs disease andMetachromatic leukodystrophy. They are generally inherited in anautosomal recessive fashion, but notablyFabry disease isX-linked. Taken together, sphingolipidoses have anincidence of approximately 1 in 10,000, but substantially more in certain populations such asAshkenazi Jews.Enzyme replacement therapy is available to treat mainlyFabry disease andGaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.[citation needed]
Sphingolipids have also been implicated with the frataxin protein (Fxn), the deficiency of which is associated withFriedreich's ataxia (FRDA). Loss of Fxn in the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.[31] Other research has demonstrated that iron accumulation in the nervous systems of flies enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors.[32]
Sphingolipids play a key role in neuronal survival in Parkinson's Disease (PD) and their catabolic pathway alteration in the brain is partly represented in cerebrospinal fluid and blood tissues (Table1) and have the diagnostic potential.[33]
