Eicosanoids and Related Oxylipins
The chemistry, biochemistry, pharmacology, and molecular biology of eicosanoids and related lipids, including the octadecanoids, docosanoids and plant oxylipins, are vast, complex and occasionally contradictory subjects that continue to develop at an extraordinarily rapid rate. The only generic term that adequately covers all of the relevant metabolites is oxylipin, defined as a family of oxygenated natural products that are formed from unsaturated fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. These can have hydroperoxyl, hydroxyl, epoxy, oxo, and/or endoperoxide groups. Simplistically, they are usually described as being synthesised in situ when needed in response to biological stimuli while having a short half-life and acting locally via interactions with specific receptors or intracellular effectors. Professors Bengt Samuelsson, Sune Bergström and John Vane were honoured by the award of the Nobel Prize for Medicine in 1982 for their discoveries in this field.
The term eicosanoid is used to embrace those biologically active lipid mediators derived primarily from C20 polyunsaturated fatty acids, including prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids, and related oxygenated derivatives. Note that the preferred IUPAC name is ‘icosanoid’, but this is largely ignored in the scientific literature. The key precursor fatty acid is 5c,8c,11c,14c-eicosatetraenoic (arachidonic or 20:4(n‑6)), although 8c,11c,14c-eicosatrienoic (dihomo-γ-linolenic or 20:3(n‑6)) and 5c,8c,11c,14c,17c-eicosapentaenoic (20:5(n‑3) or EPA) acids are also relevant (see our web page on 'polyunsaturated fatty acids'). While these have been of special importance from a historical perspective, it is now impossible to discuss such lipids and their biological activities properly without also considering the docosanoids, i.e. protectins, resolvins and maresins or 'specialized pro-resolving mediators', derived from 4c,7c,10c,13c,16c,19c-docosahexaenoic acid (22:6(n‑3) or DHA) and other polyunsaturated fatty acids of the n‑3 family (E‑series resolvins are eicosanoids). Nor can octadecanoids derived from linoleate be ignored. Related C20 and C22 products formed by non-enzymic means include the isoprostanes. Similarly, plant products such as the jasmonates and other oxylipins derived from 9c,12c,15c-octadecatrienoic (α-linolenic or 18:3(n‑3)) acid have some comparable structural features and functions. While unesterified oxylipins are of primary importance, it is becoming evident that they may have biological activity in esterified forms also, including as oxidized phospholipids, endocannabinoids and cholesterol esters (all with separate web pages on this site).
It is noteworthy that the precursors for all of these metabolites belong to either the omega-6 (n-6) or the omega-3 (n-3) families of polyunsaturated fatty acids. Oxylipins are so numerous and have such a range of biological activities that they must provide a substantial component of the reason for the essentiality of these polyunsaturated fatty acids for the survival and well-being of animals.
Other oxygenated fatty acids occur in nature that may not be lipid mediators, and these are discussed in a further web page here... However, the Fatty Acid esters of Hydroxy Fatty Acids (FAHFA), discovered relatively recently, should perhaps be classified as oxylipins now from a functional perspective. Similarly, radical nitrogen species can react with unsaturated fatty acids to produce nitro fatty acids, with important biological properties, especially as anti-inflammatory agents. Bioactive aldehydes produced by cleavage of fatty acid hydroperoxides must be discussed in this context also. While hypochlorous acid (HOCl) can add across double bonds in unsaturated fatty acyl chains to form chlorohydrins of significance to disease states, a more important reaction is with the vinyl ether bond in plasmalogens and is discussed in that context here.
A further collective term - the epilipidome - is increasingly being applied that encompasses these and other lipid mediators, i.e. a subset of the natural lipidome formed by lipid modifications via enzymatic and non-enzymatic reactions (e.g. oxidation, nitration, sulfation, halogenation) and required to regulate complex biological functions.
These pages are intended only as a broad overview of the topic that can be understood by scientists with some knowledge of lipids in general but not of oxylipins in particular. In this web page, I introduce some basic concepts and discuss the primary rate-limiting enzyme for eicosanoid production in animal tissues, i.e. phospholipase A2. Also, the mechanism for catabolism of oxylipins is common to most eicosanoid classes and for convenience is discussed below. Further web pages in this series explore the chemistry, biochemistry and function of the various types of oxylipin, although I am conscious that my approach may not adequately describe the true complexity of the interactions that occur in terms of metabolism and signalling or of physiological functions, especially in relation to the balance between different oxylipins and their pro- and anti-inflammatory effects. For example, as many as 500 distinct oxylipins have been detected in human plasma (if not fully characterized), and each of these may have its own specific role in metabolism. Those requiring a deeper insight should consult the publications cited below and at the end of the further documents in this website.
1. The Elements
Of the relevant fatty acids, arachidonic acid has been by far the most studied, and it is special in many ways. It is an essential fatty acid in that it cannot be synthesised de novo in animals, and linoleic acid from the diet is required as the primary precursor. As a major component of phospholipids, and especially of phosphatidylinositol, it is important for the integrity of cellular membranes. The four cis-double bonds mean that the molecule is highly flexible, and this helps to confer an appropriate degree of fluidity to membranes. When the arachidonic acid is esterified, the lipids often have distinctive biological activities. For example, diacylglycerols enriched in arachidonic acid and derived from phosphatidylinositol are important cellular messengers. Anandamide or N‑arachidonoylethanolamine is an endogenous cannabinoid or 'endocannabinoid', which produces neurobehavioral effects similar to those induced by cannabis and has important signalling roles in the central nervous system, especially in the perception of pain and in the control of appetite. 2‑Arachidonoyl-glycerol has similar properties. Indeed, there are suggestions that arachidonic acid per se may have some biological importance in animal tissues; for example, the cellular level of unesterified arachidonic acid may be a mechanism by which apoptosis is regulated. It is reported to be a safe protective agent against blood flukes of the genus Schistosoma by activating the tegument-associated neutral sphingomyelinase of the parasites to disrupt the membrane.
The oxygenated metabolites derived from arachidonic and related fatty acids are produced through a series of complex interrelated biosynthetic pathways sometimes termed the 'arachidonate or eicosanoid cascade'. The structures of some examples of the important eicosanoid classes are illustrated below. The prostanoids (prostaglandins, thromboxanes and prostacyclins) have distinctive ring structures in the centre of the molecule. While the hydroxyeicosatetraenes are apparently simpler in structure, they are precursors for families of more complex molecules, such as the leukotrienes and lipoxins.
The 'natural' eicosanoids are produced enzymatically with great stereochemical precision, and this is essential for their biological functions. They are highly potent in the nanomolar range in vitro in the innumerable activities that have been defined, especially in relation to inflammatory responses, pain and fever. Most organs and cell types produce them, but with a high degree of tissue specificity, and some are even synthesised cooperatively between cells.
Biosynthesis of eicosanoids involves the action of multiple enzymes, several of which can be rate limiting, not least the selective mechanisms for incorporation of arachidonate into phospholipids, including the formation of specific coA esters and remodelling by the Lands cycle. The figure below summarizes in simplistic terms the various pathways for the subsequent formation of eicosanoids from phospholipid precursors. The first step in their biosynthesis is the production of free arachidonic acid in tissues from membrane phospholipids upon stimulation of the enzyme phospholipase A2 by various physiological and pathological factors, including hormones and cytokines. There are then three main enzymatic pathways for eicosanoid formation, involving cyclooxygenases (COXs), lipoxygenases (LOXs) and epoxygenases of the cytochrome P-450 family (CYPs); the last are also important for sterol and bile acid oxidation. The COX pathway (two isoforms denoted COX-1 and COX-2) produces the prostaglandins PGG2 and PGH2, which are subsequently converted into further prostaglandins, prostacyclin and thromboxanes (TXs) by distinct synthases.
There are several lipoxygenases that act upon different positions of arachidonic acid, mainly 5, 12 and 15, although an 8-lipoxygenase is also relevant, to produce various hydroperoxyeicosatetraenoic acids (HPETEs) and thence into hydroxyeicosatetraenoic acids (HETEs) and further products. For example, leukotriene LTA4 is produced from 5-HETE and is in turn a precursor for leukotriene LTB4, cysteinyl-leukotrienes (CysLTs) and lipoxins (LXs). The cytochrome P-450 epoxygenase pathway produces hydroxyeicosatetraenoic acids (HETEs) and epoxides (EETs) as the primary products (with dihydroxy acids or DHET as secondary metabolites). While many of the requisite enzymes, precursors and products are specific to particular types of cells, the close proximity of some cell types can facilitate the transfer of eicosanoids between cells for further metabolism, and for example some of the leukotrienes are produced by trans-cellular mechanisms.
Most cell types can produce eicosanoids from phospholipid-derived precursors in this way, although much research has been concerned with those cells that are part of the innate immune system. In addition, triacylglycerols in cytoplasmic lipid droplets of human mast cells, which are potent mediators of immune reactions and influence many inflammatory diseases, have a high content of arachidonic acid, which can be released by adipose triacylglycerol lipase as a substrate for production of specific eicosanoids when the cells are stimulated appropriately. Indeed, there are now suggestions that lipid droplets in all cell types are essential for the response mechanisms to cellular stress, including inflammation and immunity, and act as hubs to integrate metabolic and inflammatory processes. Via their lipolytic machinery, they regulate the availability of fatty acids for the activation of signalling pathways and for the production of oxylipins from polyunsaturated fatty acids.
Eicosanoids are generated mainly from unesterified fatty acids, not the CoA esters, and they function in this form, but it is increasingly recognized that they may occur and some may indeed be synthesised while esterified to other lipids. These may simply be an inert storage form available for when a rapid response is required, but some also be active biologically as esters. This is especially true for oxygenated forms of endocannabinoids. Ultimately, many of the eicosanoids produced in this way are directed to the cellular membranes where they can interact with specific receptors.
While the eicosanoids were the first to be identified and studied intensively and I have used them as the main examples in this web page for illustrative purposes, it is now recognized that docosanoids (protectins, resolvins and maresins or 'specialized pro-resolving mediators' or SPMs) derived from the n-3 family of fatty acids such as EPA and DHA may be just as important in their biological functions, often opposing the actions of the eicosanoids. Octadecanoids derived from linoleate also have vital biological properties. All of these are oxylipins are produced by related means, often using the same enzymes as in eicosanoid production, so they are important elements of this story.
Many parallels can be drawn between the eicosanoids in animals and the structures and functions of plant oxylipins, which are derived primarily from C18 fatty acids and especially α-linolenic acid (18:3(n-3)), the most abundant polyunsaturated fatty acid in photosynthetic tissues. Jasmonic acid, for example, contains a cyclopentanone ring analogous to that in some prostaglandins, and the jasmonates have important signalling functions in relation to plant development and defense against pathogens and abiotic stresses of various kinds. Plants do not have the COX enzymes, but they do have lipoxygenases, which in fact were first characterized from plants, and a variety of other oxidases.
Arachidonic acid has only rarely been encountered in higher plants, but it is a constituent of some algae, fungi and moulds. During fungal infections of plants, it is known to elicit the production of plant defence compounds (phytoalexins), probably after conversion to oxygenated metabolites. Fungal species that are pathogenic to animals such as Aspergillus, Candida, and Cryptococcus spp. and parasitic protozoa such as Trypanosoma cruzi can produce the same oxylipins present in the host, including both eicosanoids and docosanoids, as well as some unique to the organisms by utilizing enzymes that are functionally comparable but evolutionarily distinct from those in animals.
Autoxidation: In contrast to the enzymatic reactions, lipids can be oxidized non-enzymatically in all animal and plant tissues in an uncontrolled manner by free radical mechanisms that involve an initial attack by free radicals, followed by chain propagation and ultimately termination steps. Such reactions occur on intact lipids and the result is usually a complex mixture of positional and stereo isomers of hydroperoxides that can rapidly rearrange or react to form other products that may also have biological activity both in the lipid-bound and free state. Among these are the oxidized phospholipids, isoprostanes and secondary oxygenated metabolites, often with reactive electrophilic carbonyl groups, such as short-chain aldehydes.
2. Phospholipase A2
Most of the arachidonic acid (and other polyunsaturated fatty acids) in animal tissues is in esterified form, mainly in phospholipids and in phosphatidylinositol and the polyphosphoinositides in particular. Before this arachidonate can be used for eicosanoid synthesis, it must be released by the action of the enzyme phospholipase A2 by the hydrolysis of the ester bond at the sn-2 position of membrane phospholipids, which are usually enriched in this acid; the other products are lysophospholipids. In addition to phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine can be substrates for arachidonic acid release, depending on the tissue and physiological conditions. This reaction sets in motion a cascade of cellular processes that involve cyclooxygenases, lipoxygenases and cytochrome P450 oxidases, which are key enzymes in the biosynthesis of oxylipins of all kinds.
A large number of enzymes with phospholipase A2 activity have been characterized in the PLA2 superfamily (more than 50 including isoforms), and three main types have been identified that are relevant here: cytosolic calcium-dependent PLA2 (cPLA2), cytosolic calcium-independent PLA2 (iPLA2, Group VIA) and secreted PLA2 (sPLA2, Group V). They are all water-soluble, membrane-associated enzymes with distinct structures and biological functions, and each has a characteristic active site, where the substrate binds, and an interfacial surface that facilitates association with cellular membranes. In general, different isoforms of these and other phospholipase As are present in specific tissues, cell types or organelles, where they each have particular substrate specificities and functions.
The cytosolic Ca2+-dependent phospholipase A2 (specifically the isoform 'cPLA2α' or 'Group IVA cPLA2') has a marked specificity for phospholipids containing arachidonic acid in the sn-2 position, and there is clear evidence that the enzyme plays a key role in the release of this fatty acid for generation of prostanoids and related metabolites. Indeed, it is believed to be rate limiting for eicosanoid production in many tissues. It makes use of a catalytic Ser-Asp dyad to hydrolyse fatty acids, and it contains a so-called ‘C2’ domain that facilitates a calcium-dependent translocation of the enzyme from the cytosol to the membrane surface, where the phospholipid substrate and the key enzymes of eicosanoid biosynthesis are located. In fact, there are six isoenzymes with molecular masses in the range of 60 to 100kDa, which are regulated by phosphorylation, although only the cPLA2α form is relevant here. It is believed that the specificity of cPLA2α is due to an interaction between certain of its aromatic residues of with the double bonds of arachidonic acid, together with a significant activity towards EPA but perhaps surprisingly not towards DHA (which does not have a Δ5-double bond).
To function in this way, cPLA2α must translocate from the cytosol to the perinuclear and endoplasmic reticulum membranes in response to an increase in cytosolic Ca2+, where it is phosphorylated and activated by mitogen-activated protein kinases. In addition to control via transcriptional regulation, the activity of the enzyme is responsive to various stimuli, such as hormones, cytokines and neurotransmitters. In particular, it has been demonstrated that ceramide-1-phosphate and phosphatidylinositol 4,5-bisphosphate bind to the enzyme. The latter is bound in a 1:1 stoichiometry and is required for activation and translocation of the enzyme to the site of action. Ceramide-1-phosphate stimulates release of arachidonic acid through direct activation of cPLA2α, and it also induces the translocation of cPLA2α to the Golgi apparatus. In so doing, it increases the inflammatory response and can inhibit wound healing, for example. Lactosylceramide has similar effects, but sphingomyelin is inhibitory.
cPLA2α is usually considered a pro-inflammatory enzyme in that it is the first step that leads to the production of the prostaglandins and leukotrienes, which tend to stimulate inflammatory processes. On the other hand, this enzyme is also responsible for the specific release of 15‑hydroxyeicosatetraenoic acid (15-HETE) from a storage form in phospholipids of macrophages when required for the synthesis of the pro-resolving lipid mediators, the lipoxins, i.e. it can switch the formation of eicosanoids of a pro-inflammatory type to those that inhibit inflammation. It is noteworthy that activation of cPLA2 is responsible for the massive production of pro-inflammatory eicosanoids that accompanies inflammation induced by systemic flagellin or the lethal anthrax toxin. Thus, prostaglandin synthesis via cyclooxygenase-1 can threaten life when produced systemically rather than acutely. The main phospholipase responsible for Ca2+-activated release of arachidonic acid in healthy mitochondria is phospholipase A2ζ (cPLA2ζ)
sPLA2 hydrolyses phospholipids at the plasma membrane to release lysophospholipids and free fatty acids with an increase in intracellular calcium concentration that activates cPLA2. sPLA2 is an inducible enzyme that enhances the effects of cPLA2 to control the magnitude and duration of elevated free fatty acid levels including that of arachidonic acid; it is not specific for the sn-2 position only. In contrast to cPLA2α, Ca2+ is required both for binding of the substrate phospholipids and for activation of the enzyme. A peroxisomal Ca2+‑independent phospholipase has only recently been identified, but may be of particular importance for eicosanoid production in that it generates arachidonoyl species, such as 2-arachidonoyl lysophosphatidylcholine, with high specificity. A further isoform of phospholipase A2 (sPLA2-IID), present in lymphoid tissue and skin, has a high specificity for the mobilization of omega-3 fatty acids and the subsequent formation of pro-resolving lipid mediators (SPMs) derived from eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. In effect, it is an immunosuppressive sPLA2 that tips the micro-environmental lipid balance toward an anti-inflammatory state.
iPLA2 shows no specificity for arachidonic acid in particular, and it appears to have a only minor role in eicosanoid production. Rather, it is involved mainly in phospholipid re-modelling or general catabolism, where it ensures the availability of the required substrates. However, there is increasing evidence that the Ca2+‑independent iPLA2β is important for the mobilization of DHA, especially in the brain, and thence for the synthesis of SPMs.
It should not be forgotten that the other products of the phospholipase A2 action, lysophospholipids, have distinct physiological activities, and the reverse reaction in which lysophosphatidylinositol is re-acylated occurs also to regenerate phosphatidylinositol for its signalling functions. For example, as in the Lands cycle for remodelling of phospholipids, a membrane-bound O-acyltransferase (MBOAT7) specific for lysophosphatidylinositol with a marked preference for arachidonoyl-CoA has been characterized from neutrophils, and this may be a means by which free arachidonic acid, eicosanoid, and phosphoinositide levels are regulated. All members of the phospholipase A2 family are of course required for many other purposes, for example as part of the normal turnover of membrane lipids, digestion of dietary phospholipids, host defence against bacterial infections, and the production of lysophospholipids for signalling purposes.
Enzyme coupling: As arachidonic acid is relatively mobile and can diffuse out of the cell or be re-incorporated into lipids, most eicosanoid production occurs in very close proximity to cPLA2 activity, so enzymes that can migrate to the perinuclear and endoplasmic reticulum membranes, where this phospholipase is located, can participate preferentially in arachidonic acid metabolism. For the synthesis of prostanoids, the newly mobilized arachidonic acid must cross the membrane bilayer from the cytosolic to the lumenal side where the cyclooxygenase enzymes are located. Some passive diffusion is possible but active transport by fatty acid-binding proteins (FABP) is also likely.
Other relevant enzymes: Adipose tissue lipase may hydrolyse triacylglycerols in cytoplasmic droplets of mast cells to provide unesterified arachidonic acid for eicosanoid biosynthesis, while catabolism (hydrolysis) of endocannabinoids can release arachidonic acid for eicosanoid production. In plants and fungi, release of fatty acids by the action of various acylhydrolases on membrane complex lipids is the first step towards the production of oxylipins for signalling purposes.
3. Catabolism of Eicosanoids
Efficient mechanisms for catabolism and deactivation of eicosanoids are essential for the regulation of their biological activities. While there are specific catabolic enzymes for thromboxanes and some leukotrienes, there is one major catabolic pathway that is common to most if not all other eicosanoids and is important for the control of their signalling activities. The first step occurs in the cytoplasm of cells and consists in the oxidation of the 15(S)‑hydroxyl group by a 15‑hydroxyprostaglandin dehydrogenase, which exists in two forms with an NAD+-dependent enzyme displaying the greater activity. This enzyme metabolizes E-series prostaglandins, lipoxins, 15‑HETE, 5,15‑diHETE, and 8,15‑diHETE, and probably many others to the corresponding 15-keto compounds. However, it is now recognized that α,β-unsaturated keto-eicosanoids generated in this way are electrophilic and may interact with nucleophilic centres in proteins and other molecules to modify their activities.
The second catabolic step consists of reduction of the Δ13 double bond by a Δ13-15-ketoprostaglandin reductase (NADPH/NADH dependent) to give an inactive product. This reductase was first identified as active against leukotriene B4, but is now known to metabolize many prostaglandins and lipoxins. Further catabolism of prostaglandins, HETEs (except for 5-HETE) and lipoxins occurs by the beta-oxidation pathway common to fatty acids in general, i.e. via the carboxyl end of the molecule (although some oxidation of the terminal methyl group can also occur), leading to the formation of short-chain metabolites, which are excreted in the urine. As an example, the process is illustrated for prostaglandin PGE2 with PGE-M as an end-product. 5-HETE and leukotrienes undergo beta-oxidation from the omega-terminus following an initial omega-hydroxylation. Some of these eicosanoids are also excreted following glucuronidation. Variations to this general mechanism are discussed in the web pages dealing with specific oxylipins.
As eicosanoids and other oxylipins tend to occur at low levels only in tissues and they have such a wide range of structures of varying stereochemistry, analysis has become a rather specialized task involving the use in the early years of gas chromatography linked to mass spectrometry but now increasingly of HPLC linked to tandem mass spectrometry with electrospray ionization. Chiral chromatography also has an important role.
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|Credits/disclaimer||Updated: July 20th, 2021||Author: William W. Christie|