A Lipid Primer - the Diversity of Natural Lipids


Definitions

Although most scientists with experience in this field tend to have a firm understanding of what is meant by the term "lipid", there is no widely accepted definition. General textbooks usually describe lipids in woolly terms as a group of naturally occurring compounds, which have in common a ready solubility in such organic solvents as hydrocarbons, chloroform and alcohols. They include a diverse range of compounds, like fatty acids, oxylipins and their ester or amide derivatives (e.g., triacylglycerols, phospholipids, sphingolipids), hydrocarbons, carotenoids, terpenes, sterols and bile acids. It should be apparent that many of these compounds have little by way of structure or function to relate them. However, it may be a useful guide for non-scientists in that it encompasses the common fats and oils encountered in everyday life.

cartoonIn fact, a definition of this kind is positively misleading as many of the substances that are now widely regarded as lipids may be almost as soluble in water as in organic solvents. Although the international bodies that usually decide such matters have shirked the task, a more specific definition of lipids than one based simply on solubility is necessary. A definition based on biochemical mechanisms has been put forward (see our page on Nomenclature), but it will only be meaningful to those with an advanced knowledge of biochemistry. Some scientists appear to consider that all organic compounds other than proteins, carbohydrates and nucleotides are lipids. While this may be valid viewpoint, it would make my task as a chronicler of the subject much more difficult. More seriously, there is a danger that the term 'lipid' becomes a catch-all (or even a dustbin!) for all classes of organic molecules that do not fit into other categories.

I would prefer to restrict the use of "lipid" to fatty acids or closely related compounds and their naturally occurring derivatives (esters or amides), what might be termed "main-stream lipids", with isoprenoids such as sterols, carotenoids, and most fat-soluble vitamins as a second category. Others will certainly disagree, but my own preferred definition avoids considerations of solubility, biosynthesis or function, and excludes such polar molecules as most polyketides. It is -

Lipids comprise a heterogeneous class of predominantly hydrophobic organic molecules of relatively low molecular weight (commonly <1000) that are defined by the presence either of linear alkyl chains, usually with even-numbers of carbon atoms and saturated or unsaturated with double bonds in characteristic positions, or of isoprene units in linear or cyclic structures. These can contain variable numbers of oxygenated substituents such as carboxylic acid, hydroxyl groups and/or other heteroatoms, such as nitrogen in amines/amides. Often, these are linked covalently to glycerol, carbohydrates, phosphate and other small polar entities, which can render the molecules more amphiphilic.

Scottish thistleThe key building blocks of main-stream lipids are fatty acids, which comprise a linear alkyl chain with a terminal carboxyl group and usually have even numbers of carbon atoms (commonly C14 to C24), which can be saturated or unsaturated. They can also contain other substituent groups, including oxygen atoms and ring structures. While fatty acids per se have important biological properties, they occur most often in esterified form as components of other lipids.

The most common lipid classes in nature consist of fatty acids linked by an ester bond to the trihydric alcohol - glycerol, or to other alcohols such as cholesterol, or by amide bonds to sphingoid bases, or on occasion to other amines. In addition, lipid classes may contain alkyl moieties other than fatty acids, phosphoric acid, organic bases, carbohydrates and many more components, which can be released by various hydrolytic procedures.

A further subdivision into two broad classes is convenient for analytical purposes especially. Simple lipids are defined as those that on hydrolysis yield at most two types of primary product per mole (e.g., triacylglycerols and cholesterol esters); complex lipids yield three or more primary hydrolysis products per mole. Alternatively, the terms "neutral" and "polar" lipids, respectively, are used to define these groups, but they are less exact. The complex lipids for many purposes are best considered in terms of the glycerophospholipids (or simply if less accurately as phospholipids), which contain a polar phosphorus moiety and a glycerol backbone, sphingolipids, containing a sphingoid base, or glycolipids (both glycoglycerolipids and glycosphingolipids), which contain a polar carbohydrate moiety. The picture is further complicated by the existence of phosphoglycolipids and sphingophospholipids (e.g., sphingomyelin).

The lipidome is the complete spectrum of lipids in a tissue, organelle or membrane, while the science of lipidomics has been defined as the analysis of lipids on the systems-level scale together with their interacting factors.


Fatty Acids

Fatty acids are often considered to be the defining components of lipids. The common fatty acids of plant tissues are C16 and C18 straight-chain compounds with zero to three double bonds of a cis (or Z) configuration. Such fatty acids are also abundant in animal tissues, together with other even numbered components with a somewhat wider range of chain-lengths and up to six cis double bonds separated by methylene groups (methylene-interrupted). Of course, the fatty acid components of animal tissue lipids are dependent on those received from the diet as well as those synthesised within tissues. Bacteria tend to produce saturated (including branched-chain) and monoenoic fatty acids. The systematic and trivial names of those fatty acids encountered most often, together with their shorthand designations, are listed in the table.

The common fatty acids of animal and plant origin
   Systematic name Trivial name Shorthand
 
Saturated fatty acids
   ethanoic acetic 2:0
   butanoic butyric 4:0
   hexanoic caproic 6:0
   octanoic caprylic 8:0
   decanoic capric 10:0
   dodecanoic lauric 12:0
   tetradecanoic myristic 14:0
   hexadecanoic palmitic 16:0
   octadecanoic stearic 18:0
   eicosanoic arachidic 20:0
   docosanoic behenic 22:0
 
Monoenoic fatty acids
   cis-9-hexadecenoic palmitoleic 16:1(n-7)
   cis-9-octadecenoic oleic 18:1(n-9)
   cis-11-octadecenoic cis-vaccenic 18:1(n-7)
   cis-13-docosenoic erucic 22:1(n-9)
   cis-15-tetracosenoic nervonic 24:1(n-9)
 
Polyunsaturated fatty acids*
   9,12-octadecadienoic linoleic 18:2(n-6)
   6,9,12-octadecatrienoic γ-linolenic 18:3(n-6)
   9,12,15-octadecatrienoic α-linolenic 18:3(n-3)
   5,8,11,14-eicosatetraenoic arachidonic 20:4(n-6)
   5,8,11,14,17-eicosapentaenoic EPA 20:5(n-3)
   4,7,10,13,16,19-docosahexaenoic DHA 22:6(n-3)
* all double bonds are of the cis configuration

The most abundant saturated fatty acid in nature is hexadecanoic or palmitic acid. It can also be designated a "16:0" fatty acid, the first numerals denoting the number of carbon atoms in the aliphatic chain and the second, after the colon, denoting the number of double bonds. All the even-numbered saturated fatty acids from C2 to C30 and beyond have been found in nature, but only the C14 to C18 homologues are likely to be encountered in appreciable concentrations in glycerolipids, other than in a restricted range of commercial fats and oils. Sphingolipids are a further exception (see below).

Formula of palmitic acid

Oleic or cis-9- or (9Z)-octadecenoic acid, the most abundant monoenoic fatty acid in nature, is designated as an "18:1" fatty acid, or more precisely as 9c‑18:1 or as 18:1(n-9), the latter to indicate that the last double bond is 9 carbon atoms from the terminal methyl group.

Formula of oleic acid

The second form of the nomenclature is of special value to biochemists and nutritionists, especially in relation to most polyunsaturated fatty acids (two or more cis-double bonds). Similarly, the more common cis-monoenoic acids fall into the same range of chain-lengths, i.e., 16:1(n-7) and 18:1(n-9), though 20:1 and 22:1 are abundant in fish.

Fatty acids with double bonds of the trans (or E) configuration are found occasionally in natural lipids, or they are formed during industrial processing (refining or hydrogenation) and so enter the food chain. They tend to be minor components only of animal tissue lipids, other than of ruminants, where they are formed naturally by biohydrogenation in the rumen. Their suitability for human nutrition is a controversial subject.

The C18 polyunsaturated fatty acids, linoleic or cis-9,cis-12-octadecadienoic acid (18:2(n-6)) and α-linolenic or cis-9,cis-12,cis-15-octadecatrienoic acid (18:3(n-3)), are major components of most plant lipids, including many of the commercially important vegetable oils. The cis-double bonds in these and related fatty acids are separated by one methylene group, i.e., they are 'methylene-interrupted'.

Formulae of linoleic and alpha-linolenic acids

They are essential fatty acids in that they cannot be synthesised in animal tissues but are required dietary constituents. As linoleic acid is almost always present in foods, it tends to be relatively abundant in animal tissues. In turn, these fatty acids are the biosynthetic precursors in animal systems of families of C20 and C22 polyunsaturated fatty acids with three to six cis-double bonds via sequential desaturation and chain-elongation steps (desaturases in animal tissues can only insert a double bond on the carboxyl side of an existing double bond). Those fatty acids derived from linoleic acid, especially arachidonic acid (20:4(n-6)), are important constituents of the membrane phospholipids in mammalian tissues, and they are also the precursors of biologically active molecules such as the prostaglandins and other oxygenated metabolites (oxylipins). α-Linolenic acid is of similar importance as the precursor of the family of polyunsaturated fatty acids of the (n-3) series, especially eicosapentaenoic acid (20:5(n-3) or EPA) and docosahexaenoic acid (22:6(n-3) or DHA), which tend to be major components of phospholipids in all tissues, but especially in the eye and brain, as well as being key components of fish oils. In turn, these are also utilized for synthesis of a separate range of biologically active oxylipins.

Formulae of arachidonic and eicosapentaenoic acids

Other fatty acids may not be 'essential' in the above sense, but they can have vital functions in tissues. For example, palmitic acid is the biosynthetic precursor of sphingoid bases and thence of all sphingolipids (see below); it is also a necessary component of one class of proteolipids, i.e., protein-lipid complexes. On the other hand. in a dietary excess, it may have harmful properties. Many other fatty acids of importance for nutrition and health do of course exist in nature, and at present there is a special interest in γ‑linolenic acid (6,9,12-octadecatrienoic acid, 18:3(n-6), GLA), available from evening primrose oil, while conjugated linoleic acid (mainly 9‑cis,11-trans-octadecadienoate) or 'CLA' is a natural constituent of dairy products that is claimed to have valuable health-giving properties.

Formula of gamma-linolenic acid + conjugated linoleic acid

Branched-chain fatty acids are synthesised by many microorganisms (most often with an iso- or an anteiso-methyl branch), and they are synthesised to a limited extent in higher organisms. They enter animal tissues from the intestinal microbiome and via the diet, especially from ruminant fats. Phytanic acid or 3,7,11,15-tetramethylhexadecanoic acid is a metabolite of phytol (from chlorophyll) and is found in animal tissues but usually at low levels only.

Formulae of iso and anteiso-methyl branched fatty acids

Fatty acids with many other substituent groups are found in some species of plants and microorganisms, and they may be encountered in animal tissues, which they can enter via the food chain. These substituents include acetylenic and allenic bonds, conjugated double bonds, cyclopropane, cyclopropene, cyclopentene and furan rings, and hydroxy-, epoxy- and keto-groups. For example, 2-hydroxy fatty acids are synthesised in animal and plant tissues, and they are often major constituents of the sphingolipids. 12‑Hydroxy-octadec-9-enoic or 'ricinoleic' acid is the main fatty acid constituent of castor oil.

Formula of ricinoleic acid


Eicosanoids and Related Oxylipins

Oxylipins can be defined as a family of oxygenated natural products that are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation catalysed by various enzymes (or by autoxidation). All can exert profound biological effects in tissues at minute concentrations. The term 'eicosanoid' is used to embrace those oxylipins derived from C20 fatty acids in animal tissues, including prostaglandins, thromboxanes, leukotrienes and other oxygenated derivatives, and the key precursor fatty acids are 8c,11c,14c-eicosatrienoic (dihomo-γ-linolenic or 20:3(n-6)), 5c,8c,11c,14c-eicosatetraenoic (arachidonic or 20:4(n-6)) and 5c,8c,11c,14c,17c-eicosapentaenoic (20:5(n-3) or EPA) acids. Docosanoids (resolvins, protectins and maresins or 'specialized pro-resolving mediators') derived from docosahexaenoic acid (C22) have biological properties that in the main tend to oppose or balance those of the eicosanoids. Other oxylipins are produced from the same precursors by non-enzymic means, e.g., the isoprostanes. Most of these are active in an unesterified form, but some are also present in tissues as components of complex lipids. Together they constitute the epilipidome, a subset of the natural lipidome required to regulate complex biological functions.

Formulae of prostaglandins and leukotrienes

Those eicosanoids derived from arachidonic acid illustrated above are of special importance, and they have been most studied to date. The prostaglandins and thromboxanes have cyclic structures generated by cyclooxygenase enzymes, and they are notably involved in the processes of inflammation. The hydroxy-eicosatetraenoic acids (HETE) are generated by lipoxygenases and cytochrome P450 oxidases, and of these the 5-lipoxygenase is especially notable in that it produces the first intermediate in the biosynthesis of leukotrienes. Many of these are pro-inflammatory, but the lipoxins derived from arachidonate and the specialized pro-resolving mediators derived from DHA have anti-inflammatory properties and indeed promote the resolution of inflammation.

Formula of 7-iso-jasmonic acidSimilarly, plant products such as the jasmonates and many other oxylipins are derived primarily from α‑linolenic (18:3(n-3)) acid, and they are also generated by the action of lipoxygenases and other oxidative enzymes. They are plant hormones, which are intimately involved in the growth and development of plants. In addition, they are involved in signalling in response to physical damage by animals, insects and pathogens, and to other environmental stresses. Despite their differing origins and functions, there are obvious structural similarities between the jasmonates and prostanoids.


Simple Lipids

Triacylglycerols: Most of the fatty acids in living tissues are present in an esterified form. Nearly all the commercially important fats and oils of animal and plant origin consist mainly of the simple lipid class triacylglycerols (termed "triglycerides" in the older literature). They contain a glycerol moiety with each hydroxyl group esterified to a fatty acid. Both butter and corn oil, for example, consist largely of triacylglycerols, but they differ substantially in their fatty acid compositions and thence their physical properties. In nature, they are synthesised by enzyme systems, which determine that a centre of asymmetry is created about carbon-2 of the glycerol backbone, so they exist in enantiomeric forms, i.e., with different fatty acids in each position.

Formulae of triacyl-sn-glycerols

A stereospecific numbering system has been recommended to describe these forms. In a Fischer projection of a natural L-glycerol derivative, the secondary hydroxyl group is shown to the left of C-2; the carbon atom above this then becomes C-1 and that below is C-3. The prefix "sn" is placed before the stem name of the compound when the stereochemistry is defined. As an example, the single molecular species 1,2-dihexadecanoyl-3-(9Z-octadecenoyl)-sn-glycerol is illustrated. From a practical standpoint, the composition of position sn-2 is often considered most relevant to biological and physical properties. The primary biological function of these lipids is to serve as a reservoir of energy and of structural components for membranes.

Formula of a 1,2-/2,3-diacylglycerolDiacylglycerols (formerly termed "diglycerides") and monoacylglycerols ("monoglycerides") contain two moles and one mole of fatty acids per mole of glycerol, respectively, and they exist in various isomeric forms; they are sometimes termed collectively "partial glycerides". Although they are rarely present at greater than trace levels in fresh animal and plant tissues, 1,2-diacyl-sn-glycerols are key intermediates in the biosynthesis of triacylglycerols and other lipids, and they are vital cellular messengers, generated on hydrolysis of phosphatidylinositol and related lipids by a specific phospholipase C. Synthetic materials have important commercial applications.

Formula of a monoacylglycerol2-Monoacyl-sn-glycerols are formed as intermediates or end-products of the enzymatic hydrolysis of triacylglycerols during digestion, for example; these and other positional isomers are powerful surfactants. 2‑Arachidonoylglycerol has important biological properties as an endocannabinoid (as is anandamide or N‑arachidonoylethanolamine).

Acyl migration occurs rapidly in partial glycerides at room temperature, but especially on heating, in alcoholic solvents or in the presence of acid or base, so special procedures are required for their isolation or analysis if the stereochemistry is to be retained. Synthetic 1/3‑monoacylglycerols are important in commerce as surfactants (more..).

Formula of cholesterolCholesterol is by far the most common member of the sterol lipid class in animal tissues; it has a tetracyclic ring system with a double bond in one of the rings and one free hydroxyl group. It is found both in the free state, where it has a vital role in maintaining the fluidity of cellular membranes, and in esterified form, i.e., as cholesterol esters. Other related sterols are present in free and esterified form in animal tissues, but at trace levels only. Cholesterol is of appreciable importance also as the biosynthetic precursor of the bile acids, vitamin D and steroidal hormones.

In plants, cholesterol is rarely detected in other than small amounts, but such phytosterols as sitosterol, stigmasterol, avenasterol, campesterol and brassicasterol, and their fatty acid esters are usually present, while ergosterol is characteristic of yeasts, and they have similar biological functions. Hopanoids are structurally similar lipids produced by some bacterial species.

Waxes: In their most common form, wax esters consist of fatty acids esterified to long-chain alcohols with similar chain-lengths; the latter tend to be saturated or have one double bond only. Such compounds are found in animal, plant and microbial tissues and they have a variety of functions, such as acting as energy stores, waterproofing and lubrication.

Formula of a wax ester

In some tissues, such as skin, avian preen glands or plant leaf surfaces, the wax components are much more complicated in their structures and compositions. For example, they can contain aliphatic diols, free alcohols, hydrocarbons (squalene, nonacosane, etc), aldehydes and ketones.

Formula of alpha-tocopherolTocopherols (collectively termed ‘vitamin E’) are substituted benzopyranols (methyl tocols) that occur in vegetable oils. Different forms (α-, β-, γ- and δ-) are recognized according to the number or position of methyl groups on the aromatic ring. α-Tocopherol (with the greatest vitamin E activity) illustrated is an important natural antioxidant, but it also is required for metabolic purposes. Tocotrienols have similar ring structures but with three double bonds in the aliphatic chain. Retinoids (vitamin A) are further important lipid-soluble isoprenoids derived from dietary carotenoids, and among many other vital functions they are essential for vision. In addition, vitamins D and K are usually classified as fat-soluble or lipidic molecules.

Free (unesterified) fatty acids are minor constituents of living tissues, but they are of biological importance as precursors of other lipids, as an energy source and as cellular messengers.


Glycerophospholipids

Phospholipids are the defining constituents of natural membranes with different individual phospholipid classes having distinct ionic states that govern their locations and functions within bilayers. In addition, they participate in innumerable biological processes sometimes as integral components of enzyme complexes. As amphiphilic molecules, phospholipids form micelles spontaneously in aqueous media.

Phosphatidic acid or 1,2-diacyl-sn-glycerol-3-phosphate is found in trace amounts only in tissues under normal circumstances, but it has great metabolic importance as a biosynthetic precursor of most other glycerolipids. In all organisms but in plants especially, it has key signalling functions. It is strongly acidic and is usually isolated as a mixed salt. One specific isomer is illustrated as an example.

Formulae for phosphatidic acid

Lysophosphatidic acid with one mole of fatty acid per mole of lipid (in position sn-1) is a marker for ovarian cancer, and it is a vital cellular messenger that is a ligand for several specific receptors. Similarly, biological functions have been revealed for other lysophospholipids.

Formula of phosphatidylglycerolPhosphatidylglycerol or 1,2-diacyl-sn-glycerol-3-phosphoryl-1'-sn-glycerol tends to be a trace constituent of most tissues, but it is often the main component of some bacterial membranes. It has important functions in lung surfactant, where its physical properties are significant, and in plant chloroplasts, where it has an essential role in photosynthesis. Also, it is the biosynthetic precursor of cardiolipin. In some bacterial species, the 3'-hydroxyl of the phosphatidylglycerol moiety is linked to an amino acid (lysine, ornithine or alanine) to form an O‑aminoacylphosphatidylglycerol or complex 'lipoamino acid'.

Cardiolipin (diphosphatidylglycerol or more precisely 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol) is a unique phospholipid with in essence a dimeric structure, having four acyl groups and potentially carrying two negative charges (and is thus an acidic lipid). It is an important constituent of mitochondrial lipids especially, so heart muscle is a rich source. Among other functions, as an integral component of the enzyme complexes concerned with oxidative phosphorylation and ATP production, it is essential for their activity.

Formula of cardiolipin

Formula of bis(monoacylglycero)phosphateBis(monoacylglycero)phosphate or lysobisphosphatidic acid is an interesting lipid in that its stereochemical configuration differs from that of all other animal glycero-phospholipids; the phosphodiester moiety is linked to positions sn-1 and sn-1' of glycerol, rather than to positions sn-3 and 3' to which the fatty acids are esterified (some experts think that position sn-2 and 2' are more likely for the latter, as illustrated). It is usually a rather minor component of animal tissues, but it is enriched in the lysosomal membranes and is considered to be a marker for this organelle. Because of the unusual stereochemistry, it is especially resistant to most lipases.

Formula of phosphatidylcholinePhosphatidylcholine or 1,2-diacyl-sn-glycerol-3-phosphorylcholine is zwitterionic and is usually the most abundant lipid in the membranes of animal tissues; it is often a major lipid component of plant membranes, but only rarely of bacteria. With the other choline-containing phospholipid, sphingomyelin, it is a key structural component and constitutes much of the lipid in the external monolayer of the plasma membrane of animal cells especially. The trivial name "lecithin" is sometimes applied, but this term is now used more often for the mixed phospholipid by‑products of seed oil refining.

Formula of lysophosphatidylcholineLysophosphatidylcholine, which contains only one fatty acid moiety in each molecule usually in position sn-1, is sometimes present as a minor component of tissues, although it is relatively abundant bound to albumin in plasma. Like all lysophospholipids, it is a powerful surfactant and is more soluble in water than most other glycerolipids; it could be disruptive to tissues in excess.

Formula of phosphatidylethanolaminePhosphatidylethanolamine (once given the trivial name "cephalin") is often the second most abundant phospholipid class in animal and plant tissues, and it can be the main lipid class in microorganisms. As part of an important cellular process, the amine group can be methylated enzymically to yield first phosphatidyl-N-monomethylethanolamine and then phosphatidyl-N,N-dimethylethanolamine, but these intermediates rarely accumulate in significant amounts; the eventual product is phosphatidylcholine.

N-Acylphosphatidylethanolamine is a minor component of some plant tissues, especially cereals, and it is occasionally found in animal tissues, where it is the precursor of some biologically active amides. Lysophosphatidylethanolamine contains only one mole of fatty acid per mole of lipid.

Formula of phosphatidylserinePhosphatidylserine is a weakly acidic lipid that is present in most tissues of animals and plants and is also found in microorganisms. Under normal conditions, it is located entirely in the inner monolayer leaflet of the plasma membrane and other cellular membranes. Phosphatidylserine is an essential cofactor for the activation of protein kinase C, and it is involved in many other biological processes, including blood coagulation and bone formation. As part of the mechanism of apoptosis (programmed cell death), it migrates to the outer leaflet of the plasma membrane where it acts as an "eat-me" signal to macrophages. N‑Acylphosphatidylserine has been detected in some animal tissues.

Formula of phosphatidylinositolPhosphatidylinositol, containing the optically inactive form of inositol, myo‑inositol, is a common constituent of animal, plant and microbial lipids. In animal tissues especially, it may be accompanied by small amounts of phosphatidylinositol 4‑phosphate and phosphatidylinositol 4,5-bisphosphate (and other 'poly-phosphoinositides'), each with specific biological functions. These compounds have a rapid rate of metabolism in animal cells, and they are converted to metabolites such as diacylglycerols and inositol phosphates, which are important in regulating vital metabolic processes. For example, diacylglycerols regulate the activity of a group of enzymes known as protein kinase C, which in turn control many key cellular functions, including differentiation, proliferation, metabolism and apoptosis. In addition, phosphatidylinositol is the primary source of the arachidonic acid used for eicosanoid synthesis in animals, and it is known to be the anchor that can link a variety of proteins to the external leaflet of the plasma membrane via a glycosyl bridge (glycosylphosphatidylinositol(GPI)-anchored proteins).

Formulae of plasmanyl- and plamenylethanolamineEther lipids: Many glycerolipids, but mainly phospholipids of animal and microbial origin but not those of plants, contain aliphatic residues linked either by an ether bond or a vinyl ether bond to position sn-1 of L-glycerol. When a lipid contains a vinyl ether bond, the generic term "plasmalogen" is often used. They can be abundant in the phospholipids of animals and microorganisms, and especially in the phosphatidylethanolamine fraction. In this instance, it has been recommended that the alkyl- and alk‑1‑enyl-forms should be termed "plasmanylethanolamine" and "plasmenylethanolamine", respectively. The mechanisms for biosynthesis of plasmalogens in animals and bacteria are so different that they are believed to have evolved separately.

1-Alkyl-2,3-diacyl-sn-glycerols, ether analogues of triacylglycerols, tend to be present in trace amounts only in animal tissues, but can be major constituents of certain fish oils and especially those of sharks. Related compounds containing a 1‑alk‑1'‑enyl moiety ('neutral plasmalogens') are occasionally present also.

On hydrolysis of glycerolipids containing an alkyl ether bond, 1-alkyl-sn-glycerols are released that can be isolated for analysis. Similarly, when plasmalogens are hydrolysed under basic conditions, 1-alkenyl-sn-glycerols are released, but aldehydes are formed from the latter on acidic hydrolysis. With both types of compound, the aliphatic residues generally have a chain-length of 16 or 18, and they are saturated or may contain one additional double bond, which is remote from the ether linkage.

Formula of platelet-activating factor'Platelet-activating factor' or 1-alkyl-2-acetyl-sn-glycerophosphorylcholine is a distinctive ether-containing phospholipid from animals that has been studied intensively because it can exert profound biological effects at minute concentrations. For example, it effects aggregation of blood platelets at concentrations as low as 10‑11M, and it induces a hypertensive response at very low levels; it is a mediator of inflammation and has signalling functions.


Glycoglycerolipids

In plants, especially the photosynthetic tissues, a substantial proportion of the lipids consists of 1,2-diacyl-sn-glycerols joined by a glycosidic linkage at position sn‑3 to a carbohydrate moiety. The main components are the mono- and digalactosyldiacylglycerols, but related compounds have been found with up to four galactose units, or in which one or more of these is replaced by glucose moieties. Monogalactosyldiacylglycerols especially have an essential role in photosynthesis as integral components of the photosystem complexes. They have a similar role in membranes to the glycerophospholipids for which they can sometimes substitute in part when phosphorus is limiting as a nutrient. In addition, a 6-O-acyl-monogalactosyldiacylglycerol is occasionally a component of plant tissues.

Formulae of mono- and digalactosyldiacylglycerols

Formula of sulfoquinovosyldiacylglycerolA related unique plant glycolipid is sulfoquinovosyldiacylglycerol or the 'plant sulfolipid'. Rather than a relatively common sulfate moiety, it contains a sulfonic acid residue linked by a carbon-sulfur bond to the 6‑deoxyglucose moiety of a monoglycosyldiacylglycerol and is found exclusively in the membranes of chloroplasts where it is also required for photosynthesis. It is an important reservoir of organic sulfur in the biosphere.

Monogalactosyldiacylglycerols are not solely plant lipids as they have been found in small amounts in brain and nervous tissue in some animal species. A range of complex glyceroglycolipids have also been characterized from intestinal tract and lung tissue that exist in both diacyl and alkyl,acyl forms. Such compounds are destroyed by some of the methods used in the isolation of glycosphingolipids, so they can be missed during analysis and may be more widespread than has been thought. A complex glyco-glycero-sulfolipid, termed seminolipid, of which the main component is 1-O-hexadecyl-2-O-hexadecanoyl-3-O-(3'-sulfo-β-D-galactopyranosyl)-sn-glycerol, is the principal glycolipid in testis and sperm. It differs from the comparable plant lipid in having a sulfate as opposed to a sulfonate linkage to the carbohydrate moiety in addition to having an ether-linked alkyl group in position sn-1.

A further range of highly complex glycolipids occur in bacteria and other micro-organisms, often with mannose as a carbohydrate moiety. These include acylated sugars that do not contain glycerol.


Sphingolipids

Sphingolipids consist of long-chain or sphingoid bases linked by an amide bond to a fatty acid and via the terminal hydroxyl group to complex carbohydrate or phosphorus-containing moieties. They have some similar functions in membranes to the glycerophospholipids, but they also have many unique metabolic properties.

Formula of sphingoid basesLong-chain bases (sphingoids or sphingoid bases) are the characteristic structural unit of sphingolipids. They are long-chain (12 to 22 carbon atoms) aliphatic amines, containing two or three hydroxyl groups, and often a distinctive trans-double bond in position 4. The commonest or most abundant of these in animal tissues is sphingosine ((2S,3R,4E)-2-amino-4-octadecen-1,3-diol) - illustrated. More than a hundred long-chain bases have been found in animals, plants and microorganisms, and many of these may occur in a single tissue but almost always as part of a complex lipid as opposed to in the free form. The aliphatic chains can be saturated, monounsaturated and diunsaturated, with double bonds in various positions and of either the cis or trans configuration; they may sometimes have methyl substituents. In plants, phytosphingosine ((2S,3S,4R)-2-amino-octadecanetriol) with three hydroxyl groups is the most common long-chain base.

For shorthand purposes, a nomenclature like that for fatty acids can be used, i.e., the chain-length and number of double bonds in the sphingoid base are denoted in the same manner with the prefix "d" or "t" to designate di- and trihydroxy bases, respectively. Thus, sphingosine is d18:1 and phytosphingosine is t18:0.

Formula of ceramideCeramides contain fatty acids linked by an amide bond to the amine group of a long-chain base. In general, they are present at low levels only in tissues, but they are intermediates in the biosynthesis of the complex sphingolipids. In addition, they have important functions in cellular signalling, and especially in the regulation of apoptosis and in cell differentiation, transformation and proliferation. Unusual ceramides are located in the epidermis of the pig and humans; the fatty acids with an amide link to the sphingoid base are C30 and C32 in chain length with an ω-hydroxyl groupto which the essential fatty acid, linoleic acid, specifically is esterified. These are ultimately modified to form a covalent link to proteins in the epidermis and are believed to have a special role in forming an impermeable barrier, which prevents the loss of moisture through the skin, for example.

Sphingomyelin is a sphingophospholipid and consists of a ceramide unit linked at position 1 to phosphorylcholine; it is found as a major component of the complex lipids of all animal tissues but not of plants or micro-organisms. It resembles phosphatidylcholine in some of its physical properties and can apparently substitute in part for this in membranes, although it also has its own unique role. For example, it is a major constituent of the plasma membrane of cells, where it is concentrated together with sphingoglycolipids and cholesterol in tightly organized sub-domains termed 'rafts'. Sphingosine tends to be the most abundant long-chain base constituent, and it is usually accompanied by sphinganine and C20 homologues. Sphingomyelin is a precursor for many sphingolipid metabolites that have important functions in cellular signalling, including sphingosine-1-phosphate (see below), as part of the 'sphingomyelin cycle'. A correct balance between the various metabolites is vital for good health. Niemann-Pick disease is a rare lipid storage disorder that results from of a deficiency in the enzyme responsible for the degradation of sphingomyelin.

Formulae for sphingomyelin

A similar lipid ceramide phosphorylethanolamine is found in the lipids of insects and some freshwater invertebrates, while the phosphonolipid analogue, ceramide 2-aminoethylphosphonic acid, has been detected in sea anemones and protozoa. Ceramide phosphorylinositol is also found in some organisms, and like phosphatidylinositol, it can be an anchor unit for oligosaccharide-linked proteins in membranes (more...).

The most widespread glycosphingolipids are the monoglycosylceramides, and they consist of a basic ceramide unit linked by a glycosidic bond at carbon 1 of the long-chain base to glucose or galactose. They were first found in brain lipids, where the principal form is galactosylceramide ('cerebroside'), but they are now known to be ubiquitous constituents of animal tissues. Glucosylceramide is also found in animal tissues, and especially in skin where it functions as part of the water permeability barrier, but it is of further importance as the biosynthetic precursor of lactosylceramide, and thence of the complex oligoglycolipids and gangliosides. In addition, glucosylceramide is present in plants, where the main long-chain base is phytosphingosine. O-Acyl-glycosylceramides have been detected in small amounts in some tissues, as have cerebrosides with other monosaccharides such as xylose, mannose and fucose.

Formula of glucosylceramide

Di-, tri- and tetraglycosylceramides (oligoglycosylceramides) are present in most animal tissues at lower levels. The most common diglycosyl form is lactosylceramide, and it can be accompanied by related compounds containing further galactose or galactosamine residues. Tri- and tetraglycosylceramides with a terminal galactosamine residue are sometimes termed "globosides", while glycolipids containing fucose are known as "fucolipids"; that illustrated is the main glycosphingolipid in erythrocytes.

Formula of a globoside

Lactosylceramide is the biosynthetic precursor of most of these glycosphingolipids with further monosaccharide residues being added to the end of the carbohydrate chain (up to as many as twenty in some tissues). They are an important element of the immune response system, and for example, some of these glycolipids are involved in the antigenicity of blood group determinants, while others bind to specific toxins or bacteria. As the complex glycosyl moiety is of primary importance in this respect, it has received most attention from investigators. However, certain of these lipids have been found to have distinctive long-chain base and fatty acid compositions, which enhance their biological activity. Some glycolipids accumulate in persons suffering from rare disease syndromes, characterized by deficiencies in specific enzyme systems related to glycolipid metabolism.

Sulfate esters of galactosylceramide and lactosylceramide (sulfoglycosphingolipids - often referred to as "sulfatides" or "lipid sulfates"), with the sulfate group linked to position 3 of the galactosyl moiety, are major components of brain lipids, but they are found in trace amounts only in other tissues apart from the kidney where they are involved in ion transport.

Structure of ganglioside GM1aGangliosides are highly complex oligoglycosylceramides, which contain one or more sialic acid groups (N‑acyl, especially acetyl, derivatives of neuraminic acid (Neu5Ac)) in addition to glucose, galactose and galactosamine. The polar and ionic nature of these lipids renders them soluble in water (contrary to some definitions of a lipid). They were first found in the ganglion cells of the central nervous system, hence the name, but are now known to be present in most animal tissues. Although the carbohydrate and sialic acid residues are of primary importance, the long-chain base and fatty acid components of gangliosides can vary markedly between tissues and species, and they are presumably related in some way to function. Gangliosides have been shown to control growth and differentiation of cells, and they have important roles in the immune defence system. They act as receptors for many tissue metabolites and in this way may regulate cell signalling. Also, they bind specifically to various bacterial toxins, such as those from botulinum, tetanus and cholera. Several unpleasant lipidoses have been identified involving storage of excessive amounts of gangliosides in tissues, the most important of which is Tay-Sachs disease.

Plants do not contain gangliosides, but complex sphingolipids, phytoglycosphingolipids containing glucosamine, glucuronic acid and mannose linked to the ceramide via phosphorylinositol, are now known to be major components of the membranes in plant tissues and in fungi.

Sphingosine-1-phosphate is one of the simplest sphingolipids structurally (akin to lysophospholipids). It is present at low levels only in animal tissues, but it is a pivotal lipid in many cellular signalling pathways (balancing the activities of ceramide and ceramide-1-phosphate). For example, within cells, sphingosine-1-phosphate promotes cellular division (mitosis), while in the blood it may play a critical role in platelet aggregation and thrombosis. It is also a key intermediate in the catabolism of sphingolipids.

Formula of sphingosine-1-phosphate

Fatty acids of sphingolipids: Although structures of fatty acids are discussed in greater depth above, it is worth noting that the fatty acyl groups of sphingolipids are very different from those in the glycerolipids. They tend to consist of long-chain (C16 up to C26 but occasionally longer) odd- and even-numbered saturated or monoenoic fatty acids and related 2-D-hydroxy fatty acids, both in plant and animal tissues. Linoleic acid may be present at low levels in sphingolipids from animal tissues, but polyunsaturated compounds are rarely found (although their presence is often reported in error).


Other Lipids

Of course, many more lipids occur in nature than can be described in this document. I have not touched here on arsenolipids, archaeal lipids, betaine lipids, rhamnolipids, some of the fat-soluble vitamins, lipoamino acids, anandamide (endocannabinoids) and other simple amides, proteolipids, lipoproteins, and lipopolysaccharides, to name but a few, but there is information on these and many other lipids elsewhere on this website. New lipids with novel structures and functions continue to be found, and no doubt many remain to be discovered.


Suggested Reading

Other than here, our host site LIPID MAPS® and Claude Leray's website www.cyberlipid.org are the best sources of information on lipid structures. In addition, I can recommend -



Lipid listings Updated: November 9th, 2022 © Author: William W. Christie LipidWeb icon
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