Abstract Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes.
Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.
Biosynthesis of Ether Lipids The biosynthesis of glycerol ethers including plasmalogens has been studied in animal tissues mainly and resembles that of the corresponding diacyl-phospholipids see the appropriate web pages with a few key differences.
The first steps are carried out by enzymes associated with the membranes of peroxisomes, an organelle normally associated with the catabolism of lipids, with the process being completed in the endoplasmic reticulum.
The enzyme fatty acyl-CoA reductase 1, outside the peroxisome, appears to be the rate-limiting enzyme in plasmalogen biosynthesis and supplies most of the fatty alcohols used for the purpose; its activity is believed to be regulated by sensing the level of plasmalogens on the inner leaflet of the plasma membrane by an as yet unidentified mechanism.
Within the peroxisome, dihydroxyacetone phosphate DHAP is first esterified with a long-chain acyl-CoA ester, before the ether bond is introduced by replacing the acyl group with a long-chain alcohol, a reaction catalysed by an alkyl-DHAP synthase alkylglyceronephosphate synthase. A remarkable feature of this reaction is that the oxygen atom comes from the alcohol moiety not glycerol.
At this point, the intermediate is transferred from the peroxisome via a protein ACBD5 with an acyl-CoA binding domain to a protein VAP-B on the cytosolic face of the endoplasmic reticulum.
In the liver, a phosphatidylethanolamine N-methyltransferase can effect the same conversion. It should be noted that this pathway is very different and is separated spatially from that producing diacyl-phosphatidylethanolamines or phosphatidylcholine via the CDP-ethanolamine pathway.
A further route to glycerol ethers and plasmalogens involves phosphorylation of alkylglycerols with an alkylglycerol kinase. Similarly, the biosynthesis of alkyl and alkenyl lipids in anaerobic bacteria appears to be accomplished by a different route that does not require DHAP. While many of the details have still to be elucidated, it appears that the 1-O-alkyl glycerol ether is formed first but not in peroxisomes and this is then desaturated.
As with other phospholipids, the final fatty acid compositions of ether lipids are attained by remodelling processes. While this can occur by re-acylation after removal of the fatty acids of position sn-2 by the action of a phospholipase A2, with formation of lysophospholipids which may have messenger functions , much of the arachidonate and other polyunsaturated fatty acids are introduced by exchange reactions from diacyl phospholipids that are catalysed by CoA-independent transacylases.
Presumably, 1-alkyl,2-acyl-glycerols derived from phospholipids are the main source of the 1-alkyl,2,3-diacyl-sn-glycerols in animal cells, although 1-alkylglycerols can be acylated in position sn-2 by a variety of acyltransferases; acyl-CoA:diacylglycerol acyltransferase 1 DGAT1 is reported to be the main enzyme responsible for introducing the fatty acid into position sn Catabolism: The fatty acid in position sn-2 of an alkylacyl phospholipid, including platelet activating factor, is first released by the action of a phospholipase A2, before the O-alkyl linkage is cleaved oxidatively by a microsomal alkylglycerol monooxygenase present in liver and intestinal tissue.
The aliphatic product is a fatty aldehyde, which is then further oxidized to the corresponding acid by a fatty aldehyde dehydrogenase.
A report of the existence of a lysoplasmalogenase appears to have been discounted. Instead, the vinyl ether bond in plasmalogens is cleaved by a very different mechanism in which the key enzyme is cytochrome c, which is best known for its role in the respiratory chain of mitochondria.
This must first be activated to produce peroxidase activity by an interaction with cardiolipin. As the resulting lysophospholipid is likely enriched in arachidonic or docosahexaenoic acids, this process may have interesting implications for oxylipin production. Functions of Ether Lipids Within a membrane, the acyl chain in plasmalogens is oriented perpendicularly to the membrane surface as in diacyl phospholipids, but the head-group lacks a carbonyl oxygen in the sn-1 position and is much more lipophilic.
As a consequence, there is stronger intermolecular hydrogen bonding between head groups, leading to changes to the arrangement of lipids within membranes with a high propensity to form an inverse hexagonal phase non-bilayer forming , which is a requirement for membrane fusion. This occurs at lower temperatures than for the diacyl analogues and as they have a larger dipole moment, plasmalogen-containing cell membranes are less fluid than those deficient in plasmalogens, i.
This property is particularly important in the compact membrane structures present in myelin. In spite of the relatively high concentrations of polyunsaturated fatty acids, they have a tendency to accumulate in membrane raft domains, i. As well as being structural components of cell membranes, plasmalogens may have a number of other functions. The information is based partly on their distribution and properties in various types of cell and partly on their physical properties, but also on the effects of changes that occur in plasmalogen metabolism in certain mutant cells.
Plasmalogens serve as a store of polyunsaturated fatty acids that can be released by specific stimulant molecules, especially in membranes that are stimulated electrophysiologically, and they may act as intracellular signalling compounds. Thus, at least two plasmalogen-selective enzymes of the phospholipase A2 type are involved in the degradation of plasmalogens, releasing arachidonic and docosahexaenoic acids from position sn-2 for eicosanoid or docosanoid production as part of signalling mechanisms.
The other product is a lysoplasmalogen, which can be re-acylated or further degraded with formation of aldehyde and phosphoglycerol moieties. However, lysoplasmalogen may also have a signalling function as it is known to activate cAMP-dependent protein kinase. The plasmalogen form of phosphatidylethanolamine is a major precursor of the endocannabinoid anandamide in brain. Similarly, it has been established that plasmenylcholine, which is abundant in linoleoyl species in heart mitochondria, is a substrate for the transacylase tafazzin and may be important for the remodelling of cardiolipin.
Claims that plasmalogens protect membranes against oxidative stress by acting as sacrificial antioxidants in vivo have been more difficult to substantiate, although it has been demonstrated that singlet oxygen interacts more rapidly with ether lipids than with other lipids in vitro. Indeed, there are counter-suggestions that polyunsaturated fatty acids protect plasmalogens against oxidative damage.
However, there does appear to be good evidence from studies in rat brain and retina that plasmalogens do function as endogenous antioxidants in these tissues at least. It is believed that the oxidation by-products of plasmalogens are less toxic than the free aldehydes and hydroperoxides produced by oxidation at other unsaturated centres.
A study with genetic mutants of the nematode C. Ether lipids and disease: In contrast, it has long been known that greatly elevated levels of ether lipids are found in cancers, and there appears to be a strong correlation with the promotion of aggressive forms of the disease. It is known that the peroxisomal alkylglyceronephosphate synthase is up-regulated appreciably in cancer cells, leading to substantial changes in the content and composition of many types of lipid including signalling lipids such as lysophosphatidic acid and eicosanoids, which favour the development of cancers.
In the human peroxisomal disorder Rhizomelic Chondrodysplasia Punctata, which is characterized clinically by defects in eye, bone and nervous tissue, there are defects in the biosynthesis of plasmalogens.
Also, plasmalogens are involved in aspects of cholesterol metabolism, and it has been established that dysregulation of plasmalogen homeostasis inhibits cholesterol biosynthesis by reducing the stability of squalene monooxygenase, a key enzyme in cholesterol biosynthesis.
High concentrations in male reproductive tissues suggest that plasmalogens have a role in spermatogenesis and fertilization, while deficiencies in plasmalogens can lead to cataract formation in the eye. Studies of these phenomena are now being aided by the use of genetically modified mice lacking specific enzymes involved in the biosynthesis of ether lipids.
There is a tradition in Scandinavian folk medicine for the use of shark liver oils, which are rich in ether lipids, for the treatment of cancers and other ailments, including wound healing, gastric ulcers and arthritis, and there appears to be some substance to the claims that are under active investigation.
The alkylglycerol constituents, and the 2-methoxy constituents especially, are considered to be the key ingredients. The mechanism for the biological effects is uncertain, but they may bypass the peroxisome step, which is rate-limiting in plasmalogen biosynthesis. In addition, they are believed to increase the permeability of membranes and there is evidence for direct effects on the enzyme protein kinase C, which has vital functions in signal transduction.
Synthetic ether analogues of lysophospholipids are being tested as anticancer agents. Ether lipids and peroxidases: There are unwanted side effects upon plasmalogens with myeloperoxidase, an abundant protein in leukocytes such as neutrophils, monocytes, and macrophages.
On activation, the enzyme converts hydrogen peroxide to hypochlorous acid HOCl. This contributes to the antimicrobial and cytotoxic properties of leukocytes, but it can also react adventitiously with other cellular constituents, and in particular it reacts with the vinyl ether bond of choline and ethanolamine plasmalogens to generate lysophospholipids with the fatty acid component in position sn-2 and 2-chloro-fatty aldehydes.
In particular, they react rapidly with thiol groups including those of glutathione and proteins to form conjugates in the same manner as with other activated aldehydes. Chloro-fatty acids induce a process known as NETosis in which neutrophils produce extracellular traps NETs as a defense against bacterial pathogens, but these can also have harmful effects in relation to many different human diseases. The other products of the reaction, lysophospholipids, are cytotoxic and pro-atherogenic.
In addition, HOCl can react with the polar head group of ethanolamine-containing lipids to form chloramines. It seems likely that proposed protective action of plasmalogens as antioxidants is in competition with the damaging effects of the reaction with myeloperoxidase.
As HOCl is widely used as a disinfecting and antibacterial agent in commercial cleaning products, these may represent a source for concern if mishandled.Lodhi, Email: ude. Cytochrome c is an oxidative stress-activated plasmalogenase that cleavesthough these are believed to originate in symbiotic. Sponges can contain highly unusual glycosyldiacylglycerols with ether bonds plasmenylcholine and plasmenylethanolamine New graduate esthetician cover letter the sn-1 vinyl ether linkage. Another common approach to analysis consists in isolation and derivatization of the alkyl or alkenyl moieties for analysis. Upon dissolution, the partners have the right to get are most effective when they focus more on solutions.
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 ]. As well as being structural components of cell membranes, plasmalogens may have a number of other functions.
In anaerobic bacteria, the most common plasmalogens are forms of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine and cardiolipin, but many other phospholipids and even glycosyldiacylglycerols have been found with vinyl ether bonds. Biomarker prediction: predicts response to specific therapeutic interventions [ 25 ]. The aim of this review is to provide an overview of current knowledge of the biology and pathology of plasmalogens with an emphasis on their involvement in GI cancer. It seems likely that proposed protective action of plasmalogens as antioxidants is in competition with the damaging effects of the reaction with myeloperoxidase.
In addition, an unusual galactoglycerolipid with phytol ether-linked to position 1 of glycerol has been partially characterized from algae and cyanobacteria, and it may occur at trace levels in some higher plants. Lipidomic analysis can also provide information about the nature of cell dysfunction and help identify the underlying metabolic pathways and molecular mechanisms of disease [ 9 ]. Indeed, there are counter-suggestions that polyunsaturated fatty acids protect plasmalogens against oxidative damage. The other products of the reaction, lysophospholipids, are cytotoxic and pro-atherogenic. Corresponding author. Suggested Reading Benjamin, D.
Chloro-fatty acids induce a process known as NETosis in which neutrophils produce extracellular traps NETs as a defense against bacterial pathogens, but these can also have harmful effects in relation to many different human diseases. Several studies have shown that the interruption of lipid metabolism is related to the onset and severe progression of some types of human cancers [ 3 ]. 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. This article has been cited by other articles in PMC. However, lysoplasmalogen may also have a signalling function as it is known to activate cAMP-dependent protein kinase.