Lipids with ether bonds to long-chain alkyl or alkenyl moieties, in addition to having ester bonds to fatty acids, are not important constituents of many lipids of commercial value, but they are very common in nature as membrane constituents especially. Usually the ether bond is in position sn-1 of a glycerol moiety, which may be part of a non-polar lipid or more often a phospholipid in animal tissues, protozoa and anaerobic bacteria. They are also found in the Archaea, albeit with differing stereochemistry, but not in plants and fungi or in in facultative and aerobic bacteria (except for Myxobacteria). At one time, ether lipids were considered to be little more than a biological novelty, differing little in function from the fully acylated equivalents, although they comprise nearly 20% of the human phospholipidome. However, findings of elevated levels of ether lipids in cancer tissues, followed by the discovery of distinctive ether lipids, such as platelet-activating factor and glycosylphosphatidylinositol anchors for proteins (with their own web pages here), with important biological activities have greatly stimulated the interest in these compounds.
1. Basic Chemistry
Two main types of glycerol ether bonds exist in natural lipids - ether (alkyl) and vinyl (alk-1-enyl) ether as illustrated. The double bond adjacent to the oxygen atom in the latter has the Z or cis configuration. The terms "plasmanyl-" and "plasmenyl-" lipids for alkyl and alk-1-enyl ethers, respectively, are recommended by IUPAC-IUB, but they do not appear to have been widely taken up in the literature.
In animal tissues, the alkyl and alkenyl moieties in both non-polar and phospholipids tend to be rather simple in composition with 16:0, 18:0 and 18:1 (double bond in position 9) predominating. Other alkyl groups may be present, but other than in fish lipids they are found at low levels only. The trivial names - chimyl, batyl and selachyl alcohols are given to the glycerol ethers with 16:0, 18:0 and 18:1 alkyl groups, respectively, in the sn-1 position.
Alkyl ether bonds are stable to both alkaline and acidic hydrolysis under most practical conditions, but alk-1-enyl-ether bonds open readily under acidic conditions to form aldehydes (or depending on conditions, acetal derivatives - see the Analysis section below). On hydrolysis with alkali, the ether bonds of 1-alkyldiacyl-sn-glycerols and its 1-alk-1'-enyl equivalent are stable, and 1-alkyl- and 1-alk-1'-enylglycerols, respectively, and free (unesterified) acids are the products.
2. Alkyldiacylglycerols and Neutral Plasmalogens
Ether analogues of triacylglycerols, i.e. 1-alkyldiacyl-sn-glycerols, are present at trace levels only if at all in most animal tissues, but they can be major components of some marine lipids. For example, they can make up 50% of the total lipids in dogfish (Squalus acanthias) and in ratfish (Hydrolagus colliei), and they can comprise 30% of the liver lipids of other sharks. In such species, alkyldiacylglycerols must be a form of storage lipid, and they appear to be stored intracellularly in liver in lipid vacuoles. It has been suggested that they have a function in density control affecting buoyancy. Similarly, 1-alkyldiacyl-sn-glycerols can be a major component of lipids of marine invertebrates (80% of squid liver lipids), and they are present in the lipids of all corals, where it is proposed that they confer resistance to lipases. The alkyl moieties are the conventional saturated and monoenoic components, though usually with a wider range of chain lengths than in other animal tissues (ruminants may be a further exception). For example in dog fish, the composition of alkyl groups is reported to be 10:0 (6%), 14:0 (2%), 16:0/16:1 (24%), 18:0 (18%), 18:1 (44%) and 22:0/22:1 (2%). In terrestrial mammals, 1-alkyldiacyl-sn-glycerols have been found in liver and adipose tissue, and in tumours, though usually in low proportions relative to triacylglycerols. Chromatographic separation of these two lipid classes is a technical challenge, and is only rarely attempted.
Neutral plasmalogens, i.e. related compounds with vinyl ether bonds in position 1, have rarely been found at greater than trace levels in animal tissues, though again they can be more abundant in some marine species (up to 5% of ratfish lipids, for example). In terrestrial mammals, they have been found in liver, adipose tissue and tumours. 1-Alkenyldiacylglycerols, together with the corresponding 1-alkyl lipids and ether-containing phospholipids, are reported to be major components of lipid droplets or ‘adiposomes’ in cultured CHO K2 cells. As an example, in bovine heart muscle, 1-alkyldiacyl-sn-glycerols and 1-alkenyldiacylglycerols comprised 1.6% and 0.25-0.8% of the simple lipids (mainly triacylglycerols), respectively. The compositions of the fatty acids and alkyl substituents of each of these lipids are listed in Table 1.
Table 1. Composition (wt %) of aliphatic moieties of 1-alkyldiacyl-sn-glycerols, 1-alkenyl-sn-diacylglycerols and triacylglycerols of bovine heart muscle.
|Fatty acids||Fatty acids|
|Data from Schmid, H.H.O. and Takahashi, T. Biochim. Biophys. Acta, 164, 141-147 (1968); DOI.|
The fatty acid components of the ether lipids are more similar to those of the phospholipids in composition than to those of the triacylglycerols (see below). In marine invertebrates, polyunsaturated fatty acids tend to be concentrated in position sn-2.
Small amounts of methoxy-substituted glyceryl ethers have been found in alkyldiacylglycerols and alkylacyl phospholipids in liver oils from sharks and other cartilaginous fish species, as deduced by analysis of the hydrolysis products. In addition to the methoxyl group in position 2, the main components have C16 saturated and C16/18 monounsaturated alkyl chains with a cis double bond in position 4, although one isomer with an alkyl group analogous to that of docosahexaenoic acid is known. It is claimed that they have potent antibacterial and anti-cancer activities and that they boost the immune system.
Non-acylated 1-O-alkyl-sn-glycerols are present in animal tissues, including human breast milk. While it is possible that they have some biological activity in their own right, it is more likely that they act as an inert reservoir for biosynthesis of platelet-activating factor. Fecapentaenes are mono-alkyl-glycerols produced in animals by colonic bacteria and have five conjugated double bonds in the alkyl moiety (12 or 14 carbons in total); they have genotoxic and mutagenic potential.
3. Phospholipids with Ether-Linked Substituents
While neutral ether lipids tend to be encountered only rarely, the membrane phospholipids of many animal and microbial species usually contain appreciable proportions of molecular species with ether and vinyl ether bonds in position sn-1, in addition to diacyl forms, and often the vinyl ether or plasmalogen form predominates. Diplasmalogens (1,2-di-(O-1'-alkenyl) forms) have been reported to constitute a high proportion of the phosphatidylethanolamine in epididymal spermatozoa from rabbits.
In adult humans, approximately 20% of the total phospholipids have an ether linked moiety, but the proportions in different tissues vary greatly. For example, liver phospholipids contain less than 5% of ether lipids, while spermatozoa can contain up to 40%. Other than in the heart, plasmenylethanolamine tends to be the main ether lipid (illustrated above), with as much as 80% of the total ethanolamine-phospholipids in some brain tissues in this form, while in kidney, skeletal muscle and retina it can amount to 20-40%. Much less of the phosphatidylcholine and commonly little or none of the other phospholipids, such as phosphatidylinositol (but see below) or phosphatidylserine, are in this form. In phosphatidylcholine of most tissues, a higher proportion is often of the O-alkyl rather than the O-alkenyl form (neutrophils contain over 40% as the O-alkyl form), but the reverse tends to be true in heart lipids. It has been suggested that much more needs to be done to determine the compositions of ether lipids in specific membranes/organelles within cells in different tissues, but they have been detected in the plasma membrane and lipid droplets.
As an example, in bovine heart muscle, alkylacyl-, alkenylacyl and diacyl forms of phosphatidylcholine comprised 1%, 16% and 24% of the phospholipids, respectively, and the corresponding proportions in phosphatidylethanolamine were 0.5%, 11% and 16%, respectively. The compositions of the fatty acids and alkyl substituents of the phosphatidylcholine forms are listed in Table 2.
Table 2. Composition (wt %) of aliphatic moieties of alkylacyl-, alkenylacyl- and diacyl-forms of phosphatidylcholine of bovine heart muscle.
|Data again from Schmid, H.H.O. and Takahashi, T. Biochim. Biophys. Acta, 164, 141-147 (1968); DOI, and this paper has data on the three phosphatidylethanolamine forms also.|
The corresponding forms of phosphatidylethanolamine differ in having much higher proportions of 18:0 components in position sn-1 and much more arachidonate (20:4(n‑6)) in position sn-2. In brain and retina, a high proportion of the fatty acid constituents are 20:4, 22:4 and 22:6 species. The nematode Caenorhabditis elegans, now considered a useful model for studies of ether lipid function, contains high proportions of alkylacyl and alkenylacyl forms of phosphatidylethanolamine but not of other phospholipids; it has mainly C18 constituents in both positions of the glycerol moiety. In addition to phospholipids, small amounts of alkyl,acyl- and alkenyl,acyl-monoglycosyldiacylglycerols are present in the central nervous system of animals.
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. Plasmalogens do not occur in aerobic or facultative anaerobic bacteria (except Myxobacteria), fungi or plants, and it has been suggested that during evolution there has been an appearance, disappearance and reappearance of plasmalogens. This theory is supported by differences in the biosynthetic mechanisms between bacteria and animals. The annamox bacteria, which contain ladderane fatty acids, are unusual in that the alkyl moieties are in position sn-2 of their phospholipids.
4. Biosynthesis of Ether Lipids
The biosynthesis of glycerol ethers including plasmalogens has been studied in animal tissues mainly, and there are key differences from that of the corresponding diacyl-phospholipids (see the appropriate web pages). The first steps are carried out by enzymes associated with the membranes of peroxisomes, an organelle in constant interaction with various other organelles via contact sites and normally associated with the catabolism of lipids, with later steps being completed in the endoplasmic reticulum. The enzyme fatty acyl-CoA reductase 1 (FAR1), anchored to the external surface of the peroxisome (or to lipid droplets), utilizes a specific pool of fatty acids produced at the cytoplasmic side of the peroxisomal membrane to generate most of the fatty alcohols that are the precursors for the alkyl moieties of ether lipids. FAR1 is reported to be the rate-limiting enzyme in plasmalogen biosynthesis, and its activity may be regulated by sensing the level of plasmalogens on the inner leaflet of the plasma membrane by an as yet unidentified mechanism.
Glycerol 3-phosphate is imported into the lumen of the peroxisome and converted into dihydroxyacetone phosphate (DHAP), which is first esterified with a long-chain acyl-CoA ester by means of a glyceronephosphate O-acyltransferase, before the ether bond is introduced by exchanging the acyl group for 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 effect, the VAP-ACBD5 complex acts as a tether to link the two organelles. Subsequent reactions occur at the endoplasmic reticulum, and following reduction of the ketone group at the sn-2 position to form 1-alkyl-sn-glycero-3-phosphate, a fatty acyl moiety is introduced by a distinctive alkyl/acyl-glycero-3-phosphate acyltransferase to form 1-alkyl-2-acyl-sn-glycero-3-phosphate. A phosphohydrolase removes the phosphate group, and the resulting 1-alkyl-2-acyl-sn-glycerol is converted to the ethanolamine/choline phospholipids by the enzyme systems used to produce the diacyl forms (see the appropriate web pages).
1-Alkyl-2-acyl-sn-glycero-3-phosphoethanolamine is the main substrate for an oxygen-dependent Δ1’-desaturase to yield the plasmalogen 1-alk-1’-enyl-2-acyl-GPE. This last enzyme activity has only recently been shown to reside in a protein designated TMEM189 in humans, or CarF in the aerobic bacterial species Myxococcus xanthus.
1-Alk-1’-enyl-2-acyl-GPE is the precursor for the corresponding choline lipid, first by the removal of phosphoethanolamine by an ethanolamine plasmalogen-specific phospholipase C to produce 1-alkenyl-2-acyl-sn-glycerol, which is then converted to 1-alk-1’-enyl-2-acyl-sn-glycero-3-phosphocholine by a choline-phosphotransferase. 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 phosphatidylcholines) via the CDP-ethanolamine pathway. A further route to glycerol ethers and plasmalogens involves phosphorylation of alkylglycerols with an alkylglycerol kinase. The mechanism for biosynthesis of the 2‑methoxy ethers in sharks has yet to be established.
As with other phospholipids, the final fatty acid compositions of ether lipids are attained by remodelling processes as in the Lands' cycle. 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). For example, in macrophages, cytosolic-group IVC phospholipase A2γ (cPLA2γ) is the enzyme responsible for this activity. Much of the arachidonate and other polyunsaturated fatty acids are obtained from diacyl phospholipids by exchange reactions 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-3. 1‑O‑Alkyl- and 1-O-alkenyl-glycerols in the diet are rapidly absorbed from the gastrointestinal tract from which they are transported to other tissues and utilized for synthesis of a full range of ether-containing lipids (3-O-alkylglycerols are absorbed equally rapidly but are then oxidized to fatty acids). Dietary 1‑O‑alkyl-glycerols can also be converted to the alkenyl forms, as this step in biosynthesis occurs after those in peroxisomes.
Bacteria: Aerobic bacteria such as the gram-negative myxobacterium Myxococcus xanthus produce appreciably amounts of ether lipids with C14 iso-methyl-branched acyl and alkyl/alkenyl chains, both as phospholipids and alkyldiacylglycerols, and especially in fruiting bodies where they assist in spore formation. Many of the relevant enzymes have yet to be characterized, although the oxygen-dependent Δ1’-desaturase responsible for plasmalogen synthesis was first described from this species, but in general the mechanism is similar to that for animals.
A quite different pathway for the biosynthesis of ether lipids must exist in anaerobic bacteria, and details are now emerging. It is known that sn-glycerol-3-phosphate, rather than dihydroxyacetone phosphate, is the initial precursor for biosynthesis of the common range of diacylphospholipids before the ether forms are produced from these. In Clostridium perfringens, a two-gene operon, believed to encode a multi-domain complex containing reductase and dehydratase enzymes, has been identified that is responsible for plasmalogen biosynthesis by reduction of the ester bond in position sn-1 of the diacylphospholipid intermediate to a vinyl ether. The relevant genes have been detected in many different obligate and facultative anaerobic bacteria, including a number from the human gut.
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. After a complex series of reactions, the products are a lysophospholipid and an α-hydroxyaldehyde. Elegant mass spectrometric studies with stable isotopes demonstrated that the carbonyl oxygen is derived from water while that of the α-hydroxyl group comes from molecular oxygen (or possibly from oxidized cardiolipin). As the resulting lysophospholipid is likely enriched in arachidonic or docosahexaenoic acids, this process may have interesting implications for oxylipin production. The findings are also relevant to Alzheimer's disease (see below), as it has long been known that α-hydroxyaldehydes accumulate in the brains of affected patients.
5. Functions of Ether Lipids
Ether lipids in membranes: 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. While this is especially true for the predominant phosphatidylethanolamine forms, the phosphatidylcholine forms tend to produce lamellar phases. Hexagonal phase formation 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.e. they form more compressed, thicker and rigid lipid bilayers in comparison with the diacyl equivalents. 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.e. regions of membranes enriched in cholesterol and sphingolipids where many cellular signaling proteins are concentrated.
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. For example, some of the biological effects of ether lipids are connected to their distribution in ion channels embedded in membranes. They are able to regulate the function and activities of ion channels either directly via their physical location and properties in membranes or indirectly as second messengers that control innumerable aspects of cell physiology.
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. elegans demonstrated that ether lipids were important for optimal fertility, lifespan, survival at cold temperatures, and resistance to oxidative stress. There is also an intriguing report that human centenarians have elevated concentrations of specific ether and vinyl ether species in their plasma.
Ether lipids and signalling: 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, respectively, 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, lysoplasmalogens may also have a signalling function as they are known to activate cAMP-dependent protein kinase, while they assist the maturation and stimulation of semi-invariant natural killer T (iNKT) cells in the thymus.
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. Peroxisomal synthesis of plasmenyl-phospholipids in brown adipose tissue is believed to regulate thermogenesis by mediating mitochondrial fission.
Ether lipids and disease: Changes in the ether content of lipids has been noted in many disease states, although it is not always clear whether these are causal or side effects. 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. 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. Ethanolamine plasmalogens enriched in arachidonic acid in position sn-2 make up a high proportion of the lipids in cardiomyocytes, and may act as a reservoir of the eicosanoid precursor to influence heart pathologies. 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, 'glaucoma-like' optic nerve abnormalities, and developmental defects in the eye.
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. This is also true of Zellweger’s syndrome and Niemann–Pick type C disease, where there are known to be peroxisomal dysfunctions. In Alzheimer’s disease (and other neurodegenerative diseases), there is a significant loss of ethanolamine plasmalogens in brain tissue that appears to be correlated with the progression of the illness, but it is not yet known whether this is a cause or consequence. Neutral ether lipids but not the analogous phospholipids accumulate in the tissues of those who suffer from Wolman’s disease, another rare genetic disorder caused by a deficiency in lysosomal acid lipase, while elevated plasmalogen levels have been detected in visceral fat of obese patients. Impaired ether metabolism has also been implicated in Sjögren-Larsson syndrome, a rare inherited metabolic disease characterized by ichthyosis and intellectual impairment, where a very substantial increase in alkylglycerols and the alcohol precursors has been observed in the lipids of the stratum corneum of the skin relative to normal controls. These were mainly non-polar alkyl-diacylglycerols and free non-esterified alkylglycerols, but with very little of the plasmalogen form.
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. In addition, the recent identification of the 1-O-alkyl desaturase responsible for the last step in plasmalogen biosynthesis makes possible the engineering of host cells such as yeasts for functional studies. Production of larger quantities of plasmalogens for oral consumption by this means may have therapeutic potential.
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 ferroptosis: It has become evident that the biosynthesis of ether-linked phospholipids influences ferroptosis, an iron-dependent form of non-apoptotic cell death induced by excess accumulation of peroxidized phospholipids. This seems to explain why saturated fatty acids have been implicated in promoting ferroptosis, as they are reduced by FAR1 to the alcohol precursor of ether lipids, i.e., the plasmanyl forms, with subsequent addition of polyunsaturated fatty acids into position sn-2 of phospholipids, although these are not the important factor in this instance. Plasmanyl forms exacerbate ferroptosis. However, another key factor is the action of the desaturase TMEM189 to generate the vinyl ether bond in plasmenyl phospholipids, which have different effects upon ferroptosis. The nature of the effects varies in different cell types, and this may be dependent upon the concentrations of plasmalogens, especially plasmenylethanolamine, in the inner leaflet of the plasma membrane. One suggestion is that at high levels of plasmenylethanolamine, TMEM189 is down-regulated with protective effects against ferroptosis, while at lower levels, down-regulation of TMEM189 may not change the sensitivity to ferroptosis significantly. To further complicate matters, plasmalogens are reported to act as antioxidants in some circumstances.
Ether lipids and heme 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 and chloride to hypochlorous acid (HOCl), the primary function of which is to aid the innate immune response to kill invading pathogens (e.g. bacteria, yeasts, fungi and parasites). If this is poorly controlled, an unfortunate side effect is an adventitious reaction with other cellular constituents, and in particular hypochlorous acid 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. The latter can be reduced in tissues to 2-chloro-fatty alcohols or oxidized to 2-chloro-fatty acids, which may react further to produce many other metabolites. 2-Bromo-aldehydes can be formed similarly by an eosinophil peroxidase in activated eosinophils.
Activated neutrophils and monocytes together with infarcted myocardium and human atherosclerotic lesions have been shown to produce significant amounts of 2‑chlorohexadecanal and related lipids for which a number of deleterious pro-inflammatory effects have been demonstrated. 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. 2-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. Increased levels in tissues have been correlated with mortality in animal models of sepsis, possibly as a result of disruption to epithelial barrier function. 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.
6. Other Ether Lipids
Platelet-activating factor - this biologically active lipid, related to phosphatidylcholine, has its own web page. Di- and tetra-alkyl ether lipids of the Archaea are unique lipids based on 2,3-dialkyl-sn-glycerol backbones and also have their own web page, as does seminolipid or 1‑O‑hexadecyl-2-O-hexadecanoyl-3-O-β-D-(3'-sulfo)-galactopyranosyl-sn-glycerol, which is an important constituent of the lipids of testis and spermatozoa.
In recent years an unusual group of branched dialkyl glycerol tetraether lipids has been discovered in peat bogs and soils. In general, they consist of octacosane (C28) alkyl units with either 13,16-dimethyl- or 5,13,16-trimethyl substituents, and forms with 4 to 6 methyl groups attached to the n-alkyl chains and/or with 0 to 2 cyclopentyl moieties in the alkyl chain. Related membrane-spanning diabolic acids are also present. In addition to being non-isoprenoid in nature, these lipids differ from those of the Archaea in that they have a 1,2-di-O-alkyl-sn-glycerol rather than the 2,3‑di‑O-alkyl-sn-glycerol configuration typical of the latter.
It is believed that these branched membrane lipids are produced by anaerobic soil bacteria, probably of the genus Acidobacteria. The nature of the intact lipids from which they are derived has also to be fully elucidated, although some components have been identified with glucuronosyl or glucosyl units attached to the glycerol ether backbone.
Many other types of natural lipids with ether bonds have been reported, some very different in structure from those discussed above. These include cholesterol ethers and vinyl ethers, glycerol thio-ethers, and dialkylglycerophosphocholines, which have been found in bovine heart. Small amounts of ether analogues of galactosyldiacylglycerols, including seminolipid, have been found in brain and nervous tissue. Also in mammalian tissues, the glycosylphosphatidylinositol (GPI) component of GPI-anchored proteins generally contain a 1-O-alkyl-2-O-acyl-sn-2-glycerol residue. Sponges can contain highly unusual glycosyldiacylglycerols with ether bonds, though these are believed to originate in symbiotic bacteria. A biologically active ether lipid, noladin ether an analogue of 2-arachidonylglycerol, has been detected in porcine brain; it is an endogenous agonist of a cannabinoid receptor. 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. Several species of the bacterial genus Clostridium contain glycerolacetals that appear to be derived biosynthetically from plasmenylethanolamine.
Cyclic ether lipids, e.g. epoxy and furanoid fatty acids, and betaine lipids in which the polar moiety is linked to glycerol via an ether bond are also discussed in separate pages of this website. Similarly, bacterial proteolipids contain a diacylglycerol unit linked from position sn-3 via a thio ether bond to a protein.
7. Analysis of Ether Lipids
Pure ether lipids are rarely easy to separate from the fully acylated forms, and often their presence in tissues is inferred from isolation of their hydrolysis products or from spectroscopic methods. However, 1‑alkyldiacylglycerols and neutral plasmalogens can be separated from triacylglycerols by exacting thin-layer chromatography techniques. It is usually necessary to convert phospholipids to non-polar forms, either by modifying or removing the polar head group, before alkylacyl-, alkenylacyl- and diacyl-forms can be isolated by TLC or HPLC. Another common approach to analysis consists in isolation and derivatization of the alkyl or alkenyl moieties for analysis by gas chromatography-mass spectrometry. When acidic transesterification methods are used to prepare fatty acid methyl esters from lipid extracts that contain a proportion of vinyl ether bonds, free aldehydes are generated (see Figure 2 above) that are rapidly converted to dimethyl acetals and can be analysed in this form along with the methyl ester derivatives of the fatty acid components. In the native form, ether-containing phospholipids of all types can be quantified readily by 31P NMR spectroscopy, although mass spectrometry is often the preferred methodology nowadays.
- Almsherqi, Z.A. Potential role of plasmalogens in the modulation of biomembrane morphology. Front. Cell Developm. Biol., 9, 673917 (2021); DOI.
- Christie, W.W. and Han, X. Lipid Analysis - Isolation, Separation, Identification and Lipidomic Analysis (4th edition), 446 pages (Oily Press, Woodhead Publishing and now Elsevier) (2010) - see Science Direct.
- Dean, J.M. and Lodhi, I.J. Structural and functional roles of ether lipids. Protein Cell, 9, 196-206 (2018); DOI.
- Dorninger, F., Forss-Petter, S., Wimmer, I. and Berger, J. Plasmalogens, platelet-activating factor and beyond - Ether lipids in signaling and neurodegeneration. Neurobiol. Disease, 145, 105061 (2020); DOI.
- Fontaine, D., Figiel, S., Félix, R., Kouba, S., Fromont, G., Mahéo, K., Potier-Cartereau, M., Chantôme, A. and Vandier, C. Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease. J. Lipid Res., 61, 840-858 (2020); DOI.
- Gallego-García, A., Monera-Girona, A.J., Pajares-Martínez, E., Bastida-Martínez, E., Pérez-Castano, R., Iniesta, A.A., Fontes, M., Padmanabhan, S. and Elías-Arnanz, M. A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis. Science, 366, 128-132 (2019); DOI.
- Honsho, M. and Fujiki, Y. Plasmalogen homeostasis - regulation of plasmalogen biosynthesis and its physiological consequence in mammals. FEBS Letts, 591, 2720-2729 (2017); DOI.
- Iannitti, T. and Palmieri, B. An update on the therapeutic role of alkylglycerols. Marine Drugs, 8, 2267-2300 (2010); DOI.
- Jackson, D.R., Cassilly, C.D., Plichta, D.R., Vlamakis, H., Liu, H., Melville, S.B., Xavier, R.J., and Clardy, J. Plasmalogen biosynthesis by anaerobic bacteria: identification of a two-gene operon responsible for plasmalogen production in Clostridium perfringens. ACS Chem. Biol., 16, 6-13 (2021); DOI.
- Jenkins, C.M., Yang, K., Liu, G., Moon, S.H., Dilthey, B.G. and Gross, R.W. Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage J. Biol. Chem., 293, 8693-8709 (2018); DOI.
- Jimenez-Rojo, N. and Riezman, H. On the road to unraveling the molecular functions of ether lipids. FEBS Letts, 593, 2378-2389 (2019); DOI.
- Magnusson, C.D. and Haraldsson, G.G. Ether lipids. Chem. Phys. Lipids, 164, 315-340 (2011); DOI.
- Paul, S., Lancaster, G.I. and Meikle, P.J. Plasmalogens: A potential therapeutic target for neurodegenerative and cardiometabolic disease. Prog. Lipid Res., 74, 186-195 (2019); DOI.
- Rangholia, N., Leisner, T.M. and Holly, S.P. Bioactive ether lipids: primordial modulators of cellular signaling. Metabolites, 11, 41 (2021); DOI.
- Schröter, J. and Schiller, J. Chlorinated phospholipids and fatty acids: (patho) physiological relevance, potential toxicity, and analysis of lipid chlorohydrins. Oxidative Med. Cell. Longevity, 8386362 (2016); DOI.
- Vítová, M., Palyzová, A. and Rezanka, T. Plasmalogens - Ubiquitous molecules occurring widely, from anaerobic bacteria to humans. Prog. Lipid Res., 83, 101111 (2021); DOI.
|Credits/disclaimer||Updated: September 20th, 2021||Author: William W. Christie|