Platelet-activating factor and structurally related alkyl ether lipids
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Reliable biomarkers could also be useful in monitoring and controlling toxicity of antitumor treatment [ 31 ]. Based on the substitution present at the sn-1 position of the glycerol structure [ 32 ], GPL are divided into three subclasses: acyl, alkyl and alkenyl [ 33 ].
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The alkenyls formed are called plasmalogens or plasmenyls or 1Z-alkenyl acyl- glycerophospholipids [ 7 ]. Plasmalogens are characterized by the presence of a vinyl-ether bond at the sn-1 position and an ester bond at the sn-2 position of the glycerol backbone [ 34 , 35 ]. Other ether PL include plasmanyl PL containing a saturated ether moiety at the sn -1 position , platelet-activating factor PAF , seminolipid, and partly, the glycosylphosphatidylinositol anchor of membrane proteins.
In addition to being present in human biological fluids, plasmalogens are also widely found in anaerobic bacteria, invertebrates and vertebrate animal species [ 7 ]. The plasmalogens are located in the cell membrane, organelles and lipid rafts and may represent at least in selected cases major constituents of membrane lipids; their presence is responsible for characteristic biophysical properties. The perpendicular orientation of the sn-2 acyl chain and the lack of a carbonyl group at the sn-1 position affect the hydrophobicity of these lipids, causing stronger intermolecular hydrogen bonding between the individual phospholipid molecules [ 37 ].
Concerning the biophysical properties, experiments have demonstrated that plasmalogens have lower lamellar gel to liquid-crystalline and lamellar to inverse-hexagonal phase transition temperatures compared to their alky and diacyl counterparts [ 37 , 38 , 39 ]. In the GPL category, plasmalogens differ from the other components of the class because they have an ether vinyl at the sn-1 position of glycerol instead of a fatty acid [ 7 ]. To this ether vinyl R1 are attached the saturated C and saturated and monounsaturated carbon chains C and C, respectively [ 7 , 34 ].
As for the sn-3 X position, plasmalogens are classified mainly as PC plasmalogens also calledplasmenylcholines and PE plasmalogens also called plasmenylethalomines [ 23 ] Fig. Structure of plasmalogen. Plasmalogens are distributed both in the animal kingdom and in certain anaerobic microorganisms [ 41 ]. In most tissues, ethanolamine is the dominating head group.
Choline plasmalogens play an important role in cardiac tissue, but represent a minor species in most other organs. Other head groups, like serine or inositol, are extremely rare.
Demopoulos Constantinos A.
Zhan et al. The absence or dysfunction of peroxisomes may be the cause of some human diseases [ 40 ]. Synthesis of plasmalogens initiated in peroxisomes occurs in seven steps Fig. Subsequent steps occur in the endoplasmic reticulum and there is biosynthesis of diacylglycerophospholipids [ 9 ]. Then, in the fourth step, 1-alkyl-GP acylation occurs with acyl-CoA to produce alkylacylglycerophosphate [ 9 ].
The enzyme phosphatidate phosphohydrolase removes, in step five, the alkylacylglycerol phosphate diacylglycerol analogue , which will be used in step six as a substrate to produce choline or ethanolamine GPL [ 41 ]. In the final step of the biosynthesis, the desaturation of the ether present in these two GPL by the C1-alkyl desaturase leads to the production of choline or ethanolamine plasmalogens [ 9 , 41 ]. Schematic representation of the biosynthesis of plasmalogens. See text for nomenclature and abbreviations. Membrane plasmalogen composition is tightly controlled by synthesis, remodeling, signaling induced hydrolysis and degradation.
The fatty acyl-CoA reductase provides fatty alcohols used in the formation of alkyl bonds bound to ether [ 50 ]. Lysoplasmalogenase, a specific enzyme of the plasmalogens sn-2 position, catalyzes hydrolytic cleavage of the vinyl-ether bond of lisoplasmalogen, forming a fatty aldehyde and glycerophosphocholine or glycerophosphoethanolamine [ 51 ]. It modulates the properties by similarity of the cell membrane, controlling the levels of plasmalogens and lisoplasmalogen in the cells [ 52 ]. It catalyzes the hydrolysis of the sn-2 position of glycerol, releasing arachidonic acid, a precursor of eicosanoids prostaglandins and leukotrienes and it also produces lysophospholipids [ 53 ].
Although the role of plasmalogens has not yet been fully elucidated, studies suggest that they have unique functions within the cells and that these are directly related to the bonds of sn-1 vinyl ether and sn-2 positions of polyunsaturated fatty acids [ 7 ]. In addition, plasmalogens can act directly in reducing PL surface tension and viscosity, on the synaptic transmission process, on alveolar surfactants, improving membrane dynamics during respiratory cycles, on signal transduction [ 48 ], on membrane vesicle formation, on ion transport, on the platelet activation factor [ 54 ], the regulation of fusion, fission and fluidity of the cell membrane, control of membrane proteins activity [ 35 ], as a reservoir for second lipid messengers [ 41 ] and supporting polyunsaturated fatty acids [ 55 ].
Differences between the catabolism of ether GPL by specific phospholipase enzymes might be involved in the generation of lipid second messenger systems such as prostaglandins and arachidonic acid that are important in signal transduction [ 56 ]. Ether lipids can also act directly in cell signaling, as the PAF is an ether lipid signaling molecule that is involved in leukocyte function in the mammalian immune system [ 57 ].
Plasmalogens play a crucial role as endogenous antioxidants, protecting other PL, lipid and lipoprotein particles from oxidative stress [ 48 ].
This is due to the fact that the vinyl ether bond is preferably oxidized, while protecting the polyunsaturated fatty acids present in the sn-2 oxidation position [ 55 ]. As the hydrogen atoms adjacent to the vinyl ether bond have relatively low dissociation energy, they end up being oxidized when exposed to various oxidizing reagents peroxyl radicals, metal ions, UV light, singlet oxygen and halogenating species [ 58 ].
Consequently there is consumption of plasmalogens in the reaction and the polyunsaturated fatty acids and other membrane lipids are spared from oxidation, suggesting the role of sacrificial oxidant for plasmalogens [ 7 ]. They undergo oxidative decomposition more readily than their fatty acid ester analogues [ 59 ]. The oxidative products of plasmalogens are unable to further propagate lipid peroxidation; they may terminate the lipid oxidation process [ 60 ].
Thus, it is suggested that plasmalogens interfere in the propagation step rather than in the initiation of lipid peroxidation [ 61 ]. The product profile resulting from oxidation of plasmalogens will depend on the type of fatty acid esterified in the sn-1 and sn-2 positions of glycerol and on the nature of oxidative stress initiators [ 59 ].
These products have been used to assess the severity of pathological conditions involving oxidative stress [ 61 ]. Plasmalogens, in addition to being prone to the oxidative process, also play a role in the inhibition of iron-induced peroxidation of polyunsaturated fatty acid and in copper-induced oxidation of low density lipoproteins [ 48 ]. Thus plasmalogens could have a decisive role in the defense systems against lipid oxidation [ 62 ]. Several methods for identifying, characterizing and quantifying plasmalogen molecules have been developed with the aim of gaining broader knowledge about lipid ether activity in the pathogenesis of disease [ 35 , 63 ].
Plasmalogen analysis can be performed through various analytical techniques chromatography, mass spectrometry and other spectrometric techniques , each with its advantages and disadvantages [ 40 ]. Just as with any other lipid, prior to analysis by analytical methods, plasmalogens should normally be extracted using solvents such as chloroform and methanol to remove water-soluble metabolites [ 64 ].
The phase obtained with chloroform can be used without the need for purification [ 40 ].
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It is worth mentioning that any addition of acid should be avoided since plasmalogens are extremely sensitive and can affect the formation of lysophospholipids and aldehydes [ 65 ]. These techniques, based on relative or absolute quantification and the use of internal standards, help in the identification of different plasmalogen subspecies as well as new plasmalogens [ 7 ]. TLC allows several types of samples to be investigated in a single plate [ 43 ]. In this method the plasmalogens react with acid dinitrophenylhydrazine DNPH leading to their hydrolysis [ 66 ].
The aldehyde released in this process is converted to 2,4-dinitrophenylhydrazone, an orange compound, which can be measured densiometrically, determining the plasmalogens content in the sample [ 40 ]. Acid hydrolysis of the plasmalogens produces the lysophospholipid and a fatty acid, thus, the plasmalogen measurement is performed by quantifying one of the two products formed by HPLC [ 68 ].
Many applications of HPLC quantification for plasmalogen analysis exist and are well documented in the literature [ 68 , 69 , 70 ]. Strategies based on GC-MS and LC-MS for the analysis of chlorinated plasmalogen lipids which are generated in the presence of activated chlorine were summarized by Wacker et al.
Although a number of different ionization techniques are currently available in lipid research, only two of them play a major role: electrospray ionization ESI and matrix-assisted laser desorption and ionization MALDI. A very simple method to identify plasmalogens in crude lipid extracts has been suggested. The reaction of plasmalogens with acidic dinitrophenylhydrazine DNPH directly leads to the hydrolysis of the plasmalogens and the subsequent conversion of the released aldehyde into a 2,4-dinitrophenylhydrazone that is easily detectable in the negative ion MALDI spectrum [ 66 ].
Individual GPL classes and even the fatty acyl composition and the linkage type in sn-1 position of a given lipid can be differentiated by phosphorus nuclear magnetic resonance spectroscopy 31 P NMR [ 76 ]. Analysis of the tissue phospholipid extracts by 31 P NMR was found to be capable of discriminating between esophageal cancer and adjacent normal tissues, including the non-involved esophagus and normal stomach [ 77 ].
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Decades ago it was observed that cancer cells have remarkably higher levels of alkyl and alkenyl ethers lipids compared to normal cells [ 78 , 79 , 80 , 81 ]. Encouraged by these findings, there were efforts trying to establish ether lipids as tumor markers in medical cancer diagnostics. Some studies have also reported decreased amounts of ether lipids in cancer patients [ 75 , 77 ].
Original Research ARTICLE
Although many studies suggest altered plasmalogen production in cancer patients, the mechanism is not yet understood, suggesting a need for future research. It was observed that the plasmalogens can activate phosphatidylinositol 3-kinase, stimulate cell growth, participate in mitogenic responses [ 82 ] and have also been correlated with the levels of several oncogenic signaling lipids involved in the regulation of cell survival, cancer aggressiveness and tumor growth [ 83 ].
Benjamin et al. AGPS knockdown impaired experimental cancer pathogenesis, including cell survival, migration, and invasion. The pathogenic impairments conferred by AGPS knockdown in cancer cells are due to the specific depletion of the oncogenic signaling lipid lysophosphatidic acid ether and prostaglandins.
ether lipid (CHEBI)
The studies indicated that AGPS may serve as an attractive therapeutic target for combatting malignant human cancers, through altering the landscape of oncogenic signaling lipids that drive cancer aggressiveness [ 84 ]. Concerning the relationship of plasmalogens and tumors, Merchant et al. They also showed that the PE plasmalogens and PS are significantly diminished in esophageal tumors when compared to normal esophageal tissues obtained from the same patients. The data revealed a correlation between decreasing levels of four of the PL 5-dihydrosphingomyelin, lysoalkylacylphosphatidylcholine, LPC and phosphatidylglycerol and increasing tumor aggressiveness as indicated by T stage and tumor grade [ 77 ].
According to Dueck et al. For Christen et al. Quantitative chromatographic analysis of the phospholipid content of colorectal carcinoma showed a generally elevated concentration of PL, also including a PE plasmalogen species [ 87 ].
Ritchie et al. Although most of the individual metabolites showed a significant reduction in PC patient serum, the strongest discriminator based on multiple statistical criteria was PC In gastric carcinoma patients, the plasma plasmalogens content was significantly elevated and was positively correlated with elevated level of gangliosides and total cholesterols, but it was negatively correlated with level of total PL [ 88 ].