Lipids

Simple Lipids: Triacylglycerols Di- &

monoacylglycerols Sterols & sterol esters Waxes Tocopherols Free (unesterified

) fatty acids Cyanolipids

Complex Glycerolipids: Ether lipids Phosphatidic

acid & related lipids Phosphatidylglycerol Diphosphatidylglycerol (

cardiolipin)   Phosphatidylinositol

& related lipids   Phosphatidylserine Phosphatidylethanolamine

Phosphatidylcholine •Mono- & digalactosyldiacylglycerols & related lipids from plants •Glycosyldiacylglycerols & related lipids from animals

Sphingolipids: oLong-chain or sphingoid bases oCeramides oSphingomyelin & related lipids oSphingosine -1-phosphate oMonoglycosylceramides (cerebrosides) oOligoglycosylceramides (neutral) oGangliosides oSulfoglycosphingolipids Fatty acids: oSaturated straight-chain oMonoenoic straight-chain   oMethylene-interrupted polyenoic oConjugated & multimethylene-interrupted polyenoic  oBranched-chain

Complex Glycerolipids:

Some Miscellaneous Lipids: oPhosphonolipids oCarnitine & acylcarnitines oCoenzyme A esters oProteolipids oAnandamide, oleamide & other fatty amides

S-1Triacylglycerols(Triglyceride):This includes all the vegetable oils, such as those from corn (maize), olive, palm, sunflower, and animal fats, such as tallow, lard and butter, as well as commercial products such as margarines. Most of these are depots fats where their main function may be a store of energy, but some triacylglycerols (e.g. those of plasma or liver) may have a more dynamic function.

                                                                    

         

Simple Lipids

Diacylglycerols (or "diglycerides") are esters of the trihydric alcohol glycerol in which two of the hydroxyl groups are esterified with long-chain fatty acids.

S-2 Diacylglycerols

It is believed that sitosterol and 24-methylcholesterol are able to regulate membrane fluidity and permeability in plant membranes in a similar manner to cholesterol in mammalian cells. Also, plant sterols can modulate the activity of membrane-bound enzymes. Stigmasterol may be required specifically for cell proliferation. Certain sterols in minute amounts, such as campesterol in Arabidopsis thaliana, are precursors of oxidized steroids acting as growth hormones collectively named brassinosteroids, which have crucial importance for growth and development .

S-3 Plant sterols and sterol derivatives

S-4 WAXES

a substance similar in composition and physical properties to beeswax. All of these tend to contain wax esters as major components, i.e. esters of long-chain fatty alcohols with long-chain fatty acids.

Plant leaf surfaces are coated with a thin layer of waxy material that serves a myriad of functions. This layer is microcrystalline in structure and forms the outer boundaryof the cuticular membrane; it is the interface between the plant and the atmosphere.

The major constituents of plant leaf waxesCompound Structure

n-Alkanes CH3(CH2)xCH3 21 to 35C - odd numbered

Alkyl esters CH3(CH2)xCOO(CH2)yCH3 34 to 62C - even numbered

Fatty acids CH3(CH2)xCOOH 16 to 32C – even numbered

Fatty alcohols (primary) CH3(CH2)yCH2OH 22 to 32C - even numbered

Fatty aldehydes CH3(CH2)yCHO 22 to 32C - even numbered

Ketones CH3(CH2)xCO(CH2)yCH3 23 to 33C - odd numbered

Fatty alcohols (secondary) CH3(CH2)xCHOH (CH2)yCH3 23 to 33C - odd numbered

ß-Diketones CH3(CH2)xCOCH2CO(CH2)yCH3 27 to 33C - odd numbere

S-5 TOCOPHEROLS

S-6 TOCOPHEROLS

Tocopherols constitute a series of related benzopyranols (or methyl tocols) that occur in vegetable oils.

In the tocopherols, the C16 side chain is saturated, and in the tocotrienols it contains three double bonds.

The four main constituents are termed - alpha (5,7,8-trimethyl), beta (5,8-dimethyl), gamma (7,8-dimethyl) and delta (8-methyl).

Of these, alpha-tocopherol is most readily absorbed from the intestines.

They are all important natural antioxidants with some Vitamin E activity, but only alpha-tocopherol (including synthetic material) or natural mixtures containing this can be sold as 'Vitamin E'.

However, the tocotrienols are more potent antioxidants, while gamma-tocopherol has some specific biological properties that are distinct from those of alpha-tocophe

Cyanolipids are components of the lipids of seeds in the family Sapindaceae mainly, although some are known from the Hippocastaneaceae and Boraginaceae.

Thus, type I and II cyanolipids are diesters of 1-cyano-2-hydroxymethylprop-2-en-1-ol and 1-cyano-2-hydroxymethylprop-1-en-3-ol, respectively, while type III and IV cyanolipids are monoesters of 1-cyano-2-hydroxymethylprop-1-ene and 1-cyano-2-methylprop-2-en-1-ol, respectively.

S-7 CYANOLIPIDS

C-1-1 Alkyldiacylglycerols

C-1-2 Ether Phospholipids

C-1ETHER LIPIDS

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, especially.

Complex Lipid

•Phosphatidic acid •Lysophosphatidic acid •Cyclic phosphatidic acid •Pyrophosphatidic acid •Lysobisphosphatidic acid

C-2 PHOSPHATIDIC ACID AND RELATED LIPIDS

C-2-1 Phosphatidic AcidPhosphatidic acid is not an abundant lipid constituent of any living organism to common knowledge, but it is extremely important as an intermediate in the biosynthesis of triacylglycerols and of most phospholipids.

C-2-2 Lysophosphatidic Acid

Lysophosphatidic acid or 1-acyl-sn-glycerol-3-phosphate (LPA) differs from phosphatidic acid in having only one mole of fatty acid per mole of lipid. Although it is present at very low levels only in animal tissues, it is extremely important biologically, influencing many biochemical processes. These activities seem to be shared by the 1-alkyl- and alkenyl-ether forms. In particular, lysophosphatidic acid is an intercellular lipid mediator with growth factor-like activities, and is rapidly produced and released from activated platelets to influence target cells.

C-2-3 Cyclic phosphatidic Acid

Cyclic phosphatidic acid (sometimes termed ‘cyclic lysophosphatidic acid’) was isolated originally from a slime mould, but has now been detected in a wide range of organisms including humans. It has a cyclic phosphate at the sn-2 and sn-3 positions of the glycerol carbons, and this structure is absolutely necessary for its activities.In particular, it is found in tissues subject to injury, and while it may have some similar functions to lysophosphatidic acid per se, it also has some quite distinct biological activities. For example, cyclic phosphatidic acid is known to be a specific inhibitor of DNA polymerase alpha.

C-2-4 Pyrophosphatidic Acid

Pyrophosphatidic acid or diacylglycerol pyrophosphate is an unusual and little known phospholipid that was first identified in yeasts, and is also know to be a product of a phosphatidic acid kinase reaction in higher plants.It is rapidly metabolized back to phosphatidic acid and thence to diacylglycerols, and may have a function in the phospholipase C and D signalling cascades in plants.

C-2-5 Lysobisphosphatidic acid

Lysobisphosphatidic acid or bis(monoacylglycerol)phosphate is an interesting lipid from several standpoints (although it is only superficially related to phosphatidic acid per se). For example, its stereochemical configuration differs from that of other animal glycero-phospholipids in that the phosphodiester moiety is linked to positions sn-1 and sn-1' of glycerol, rather than to position sn-3, to which the fatty acids are esterified. The most abundant fatty acids can be 16:1, 18:1, 20:4 and especially 22:6(n-3), but this is very dependent on the specific tissue or cell type. For example, the testis lipid contains more than 70% 22:5(n-6).

C-3 PHOSPHATIDYLGLYCEROLPhosphatidylglycerol is a ubiquitous lipid that can be the main component of some bacterial membranes, and it is found also in membranes of plants and animals where it appears to perform specific functions.In plants, phosphatidylglycerol is found in all cellular membranes, but it appears to be especially important in the thylakoid membrane where it can comprise 10% of the total lipids with a high proportion (up to 70%) in the outer monolayer. In cereals such as oats, a form with an additional fatty acid linked to the 3'-hydroxyl of the glycerol moiety has been found.

C-4 DIPHOSPHATIDYLGLYCEROL (CARDIOLIPIN)

Diphosphatidylglycerol or 'cardiolipin' is a unique phospholipid with in essence a dimeric structure, having four acyl groups and potentially carrying two negative charges.

C- 5 PHOSPHATIDYLINOSITOL AND RELATED LIPIDS

C-5-1 Phosphatidylinositol

Phosphatidylinositol is an important lipid, both as a key membrane constituent and as a participant in essential metabolic processes in plants and animals (and in some bacteria). It is an acidic (anionic) phospholipid that in essence consists of a phosphatidic acid backbone, linked via the phosphate group to inositol (hexahydroxycyclohexane).

C-5-2 Phosphatidylinositol phosphates

These are usually present at low levels only in tissues, typically at about 1 to 3% of the concentration of phosphatidylinositol.

They are maintained at a steady state level in the inner leaflet of the plasma membrane by a continuous and sequential series of phosphorylation and dephosphorylation reactions by specific kinases and phosphatases, respectively, which are regulated and/or relocated through cell surface receptors for extracellular ligands.

C-5-3 Phosphatidylinositol anchors for proteins

Phosphatidylinositol is known to be the anchor that links a variety of proteins to the external leaflet of the plasma membrane via a glycosyl bridge (glycosylphosphatidyl-inositol(GPI)-anchored proteins).

C-5-4 Lyso-phosphoinositides and the glycerolphosphoinositidesIt has long been known that the water-soluble glycerolphosphoinositides, the fully deacylated forms of phosphatidylinositol and the phosphatidylinositol phosphates have key roles in cellular signalling pathways.

C-6 PHOSPHATIDYLSERINE

Phosphatidylserine or 1,2-diacyl-sn-glycero-3-phospho-L-serine is the only amino acid-containing glycerophospholipid in animal cells.

Although it is distributed widely among animals, plants and microorganisms, it is usually less than 10% of the total phospholipids, the greatest concentration being in myelin from brain tissue. However, it may comprise 10 to 20 mol% of the total phospholipid in the plasma membrane and endoplasmic reticulum of the cell. 

C-7 PHOSPHATIDYLETHANOLAMINE AND RELATED LIPIDSC-7-1 Phosphatidylethanolamine

Phosphatidylethanolamine (once given the trivial name 'cephalin') is usually the second most abundant phospholipid in animal and plant lipids and it is frequently the main lipid component of microbial membranes.

As such, it is obviously a key building block of membrane bilayers.

The major pathway for biosynthesis of phosphatidylethanolamine de novo in animals and plants is -

C-7-2 Lysophosphatidylethanolamine

Lysophosphatidylethanolamine, with one mole of fatty acid per mole of lipid, is found in small amounts in tissues.

It is formed by hydrolysis of phosphatidylethanolamine by the enzyme phospholipase A2, as part of a de-acylation/re-acylation cy

cle that controls its overall molecular species composition.

C-7-3 N-Acyl phosphatidylethanolamineN-acyl phosphatidylethanolamine in which the free amino group of phosphatidylethanolamine is acylated by a further fatty acid is a common constituent of cereal grains (e.g. wheat, barley and oats) and of some other seeds, but it may occur in other plant tissues, especially under conditions of physiological stress. 

C-7-4 Mono- and dimethyl-phosphatidylethanolamine

Mono- and dimethyl-phosphatidylethanolamines are formed by sequential methylation of phosphatidylethanolamine as part of a minor mechanism for biosynthesis of phosphatidylcholine.

They are never found at greater than trace levels in animal or plant tissues, and it is not known whether they have any more specific functions.

On the other hand, they are more abundant in some bacteria, especially those that interact with plants.

C-7-5 PhosphatidylethanolPhosphatidylethanol has little in common with phosphatidylethanolamine other than the obvious structural similarity.

It is formed slowly in cell membranes, especially erythrocytes, by a transphosphatidylation reaction from phosphatidylcholine in the presence of ethanol, and catalysed by the enzyme phospholipase D.

As such, it has been proposed as a biochemical marker for alcohol abuse, since chronic alcoholics have very much higher levels in the blood than healthy subjects who consume alcohol in moderation.

Phosphatidylcholine (once given the trivial name 'lecithin') is usually the most abundant phospholipid in animal and plants, often amounting to almost 50% of the total, and as such it is obviously the key building block of membrane bilayers.

C-8 PHOSPHATIDYLCHOLINE AND RELATED LIPIDS

C-8-1 PHOSPHATIDYLCHOLINE

C-8-2 Lysophosphatidylcholine

Lysophosphatidylcholine, with one mole of fatty acid per mole of lipid in position sn-1, is found in small amounts in most tissues.

It is formed by hydrolysis of phosphatidylcholine by the enzyme phospholipase A2, as part of the de-acylation/re-acylation cycle t

hat controls its overall molecular species composition.

C-8-3 Platelet-activating factor Platelet-activating factor (PAF) or 1-alkyl-2-acetyl-sn-glycero-3-pho

sphocholine is an ether analogue of phosphatidylcholine that are bi

ologically active.

C-8 MONO- AND DIGALACTOSYLDIACYLGLYCEROLS AND RELATED LIPIDS FROM PLANTS

C-8-1 1. Mono- and digalactosyldiacylglycerolsMonogalactosyldiacylglycerols and digalactosyldiacylglycerols are the main glycolipid components of the various membranes of chloroplasts and related organelles, and indeed these are the most abundant lipids in all photosynthetic tissues, including those of higher plants, algae and certain bacteria. In non-photosynthetic tissues of plants, the proportion of glycosyldiacylglycerols is greatly reduced. The predominant structures are 1,2-di-O-acyl-3-O-beta-D-galactopyranosyl-sn-glycerol and 1,2-di-O-acyl-3-O-(6'-O-alpha-D-galactopyranosyl-beta-D-galactopyranosyl)-sn-glycerol.In higher plants, the galactolipids contain a high proportion of polyunsaturated fatty acids, up to 95% of which can be linolenic acid (18:3(n-3)). It is clear that the galactosyldiacylglycerols have important functions in photosynthesis, and the nature of these functions is the topic of active research although much of the detail remains obscure.

C-8-2 Other neutral glycosyldiacylglycerols1,2-Di-O-acyl-3-O-beta-D-glucopyranosyl-sn-glycerol has been fo

und in rice bran, where it occurs with the corresponding galactoli

pids in an approximate ratio of 1:2. Interestingly, the two forms di

ffer appreciably in their fatty acid compositions.

C-8-3 Sulfoquinovosyldiacylglycerol

Sulfoquinovosyldiacylglycerol or 1,2-di-O-acyl-3-O-(6'-deoxy-6'-sulfo-alpha-D-glucopyranosyl)-sn-glycerol (quinovose = 6-deoxyglucose) is the single glycolipid most characteristic of photosynthetic organisms.

It appears that this is the only lipid known to have a sulfonic acid linkage.

Sphingolipids

Sph-1 LONG-CHAIN OR SPHINGOID BASES

Long-chain bases (sphingoids or sphingoid bases) are the characteristic or defining structural unit of the sphingolipids (the root term “sphingo-” was first coined by J.L.W. Thudichum in 1884 because the enigmatic nature of the molecules reminded him of the riddle of the sphinx). The bases are long-chain aliphatic amines, containing two or three hydroxyl groups, and often a distinctive trans-double bond in position 4. To be more precise, they are 2-amino-1,3-dihydroxy-alkanes or alkenes with (2S,3R)-erythro stereochemistry, with various further structural modifications.phytosphingosine or 4D-hydroxy-sphinganine ((2S,3R,4R)-2-amino-octadecanetriol), although unsaturated analogues, for example with a trans double bond in position 8, i.e. dehydrophytosphingosine or 4D-hydroxy-8-sphingenine, tend to be much more abundant.

Sphingoid bases are unusual amongst lipids in that they bear a small positive charge at neutral pH, a consequence of intra-molecular hydrogen bonding. This enables them to cross membranes or move between membranes with relative ease.

They inhibit protein kinase C indirectly, for example, by a mechanism involving inhibition of diacylglycerol synthesis. In addition, sphingoid bases are known to be potent inhibitors of cell growth, although they stimulate cell proliferation and DNA synthesis. They may have a protective role against cancer of the colon in humans.

Sph-2 CERAMIDES

Ceramides consist of a long-chain or

sphingoid base linked to a fatty acid via an amide bond.

They are rarely found at greater than trace levels in tissues, although they can exert important biological effects.

Ceramides are formed as the key intermediates in the biosynthesis of all the complex sphingolipids, in which the terminal primary hydroxyl group is linked to carbohydrate, phosphate, etc.

Each organism and indeed each tissue may synthesise ceramides in which there are a variety of di- and trihydroxy long-chain bases and fatty acids, the latter consisting mainly of longer-chain saturated and monoenoic (mainly (n-9)) chains (to C24 or greater), sometimes with

a hydroxyl group in position 2.

In plants, 2-hydroxy acids predominate sometimes accompanied by small amounts 2,3-dihydroxy acids. However, ceramides are usually converted rapidly to more complex sphingolipids, and the precursors never accumulate.

Sph-3 SPHINGOMYELIN AND RELATED LIPIDS

Sphingomyelin (or ceramide phosphorylcholine) consists of a ceramide unit with a phosphorylcholine moiety attached to position 1. It is thus the sphingolipid analogue of phosphatidylcholine.It is a ubiquitous component of animal cell membranes, where it is by far the most abundant sphingolipid. Indeed, it can comprise as much as 50% of the lipids in certain tissues, though it is usually less abundant than phosphatidylcholine. For example, it makes up about 10% of the lipids of brain. It is the single most abundant lipid in erythrocytes of most ruminant animals, where it replaces phosphatidylcholine entirely. In this instance, there is known to be a highly active phospholipase A that breaks down the glycerophospholipids, but not sphingomyelin. Like phosphatidylcholine, sphingomyelin tends to be most abundant in the plasma membrane, and especially in the outer leaflet, of cells.Sphingomyelin does not appear to occur in plants or microorganisms, and its evolutionary significance is a matter for speculation.

Sph-4 SPHINGOSINE-1-PHOSPHATE

Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomyelin cycle (in animal cells). It has also been found in insects, yeasts and plants.Like its precursors, sphingosine-1-phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine. The balance between these various sphingolipid metabolites may be important for health. For example, within the cell, sphingosine-1-phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits in fact. Intracellularly, it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. Current opinion appears to suggest that the balance between sphingosine-1-phosphate and ceramide and/or sphingosine levels in cells is critical for their viability.

Sph-5 MONOGLYCOSYLCERAMIDES (CEREBROSIDES)

Galactosylceramide (Galß1-1'Cer) is the principal glycosphingolipid in brain tissue, hence the trivial name "cerebroside", which was first conferred on it in 1874, although it was much later before it was properly characterized. In fact, galactosylceramides are found in all nervous tissues, but they can amount to 2% of the dry weight of gray matter and 12% of white matter.Presumably, it functions as part of the water permeability barrier. In addition, higher than normal concentrations of glycosphingolipids have been reported for the apical plasma membrane domain of epithelial cells from intestine and urinary bladder. However, of greater importance than the natural occurrence of glucosylceramide per se is its role as the biosynthetic precursor of lactosylceramide, and thence of the complex neutral oligoglycolipids and gangliosides.Glucosylceramide is usually the principal glycosphingolipid in plants, especially in photosynthetic tissues, where the main long-chain bases are C18 4,8-diunsaturated (Z/Z and E/Z) (not sphingosine as illustrated).

Sph-6 LACTOSYLCERAMIDE AND NEUTRAL OLIGOGLYCOSYLCERAMIDES

The most important and abundant of the diosylceramides is ß-D-galactosyl-(1-4)-ß-D-glucosyl-(1-1')-ceramide, more conveniently termed lactosylceramide (LacCer), using the trivial name of the disaccharide.Lactosylceramide may assist in stabilizing the plasma membrane and activating receptor molecules in the special micro-domains or rafts, as with the cerebrosides. Neutral oligoglycosylceramides with from three to more than twenty monosaccharide units in the chain have been detected in animal tissues ('megaloglycolipids' with up to 50 carbohydrate groups occur in erythrocytes). Fucolipids are oligoglycolipids in any of the above series in which a fucose (Fuc) residue substitutes for one of the usual carbohydrate residues. In addition, certain of the oligoglycolipids exist as lipid sulphates, and others are linked to sialic acid residues, i.e. gangliosides.

Sph-7 GANGLIOSIDES

The name gangliosides was first applied by the German scientist Ernst Klenk in 1942 to lipids newly isolated from ganglion cells of brain. They were shown to be oligoglycosylceramides containing N-acetylneuraminic acid (sialic acid or 'NANA' or 'SA' or Neu5Ac) residues (or less commonly N-glycoloyl-neuraminic acid, Neu5Gc), joined via glycosidic linkages to one or more of the monosaccharide units, i.e. via the hydroxyl group on position 2, or to another sialic acid residue.In experimental systems, gangliosides have been shown to control growth and differentiation of cells, and they have an important role in the interactions between cells. In particular, they have key functions in the immune defense systems, and they are involved in pathological states such as cancer. They act as receptors of interferon, epidermal growth factor, nerve growth factor and insulin and in this way may regulate cell signaling. Also, they bind specifically to various bacterial toxins, such as those from botulinum, tetanus and cholera.

Sph-8 SULFOGLYCOSPHINGOLIPIDS

Sulfoglycosphingolipids (sometimes termed "sulfatides" or "sulfatoglycosphingolipids") are glycosphingolipids carrying a sulfate ester group attached to the carbohydrate moiety.

They were first identified in brain tissue by the pioneering lipid chemist Thudichum in 1884, although it was much later before they were properly characterized.

Although sulfoglycosphingolipids tend to be minor components of tissues, 3'-sulfo-galactosylceramide or galactosylceramide-I3-sulfate (illustrated) is one of the more abundant glycolipid constituents of brain myelin, and it is also present in many other organs, especially the kidney.

There are suggestions that they may have a similar role in kidney. A high content of sulfatides in the gastric and duodenal mucosa, where mucosa can be attacked by acid, pepsin and bile salts, may be closely related to a function in mucosal protection.

Fatty acids

F-1 STRAIGHT-CHAIN SATURATED FATTY ACIDSStraight- or normal-chain, saturated components (even-numbered) make up 10-40% of the total fatty acids in most natural lipids.

The most abundant saturated fatty acids in animal and plant tissues are straight-chain compounds with 14, 16 and 18 carbon atoms, but all the possible odd- and even-numbered homologues with 2 to 36 carbon atoms have been found in nature in esterified form.

They are named systematically from the saturated hydrocarbon with the same number of carbon atoms, the final 'e' being changed to 'oic'

Acetic or ethanoic acid is of great importance in living tissues, as the biosynthetic precursor of fatty acids and a range of other metabolites. However, it is not often found in association with fatty acids of highe

r molecular weight in esterified form in lipid molecules, although it does occur esterified to glycerol in ruminant milk fats (presumably in position sn-3).

It is also the most common fatty acid linked to platelet-activating factor.

In seed oils, acetic acid occurs in position sn-3 of triacylglycerols of Euonymus verrucosus, and in other vegetable oils, it has been detected in linkage to the hydroxyl group of a hydroxy fatty acid, which is in turn esterified to glycerol, i.e. as an estolide.

Acetates of long-chain alcohols are found in plant and insect waxes and as insect pheromones.

Propanoic acid is important as the biosynthetic precursor of some amino acids. It is rarely found in esterified form in natural lipids, and to my knowl

edge the only exception is for molecules related to platelet-activating factor.

Butanoic acid comprises 3-4% by weight (much more in molar terms) of the total fatty acids in cow's milk, where it is found exclusively in position 3 of the triacyl-sn-glycerols. It is found in milk fats of other ruminants, but not in the lipids of other tiss

ues of these species.

Hexanoic acid comprises 1-2% of the totals fatty acids in ruminant milk triacylglycerols, where most of it is esterified to position 3 of the triacyl-sn-glycerols. It is also found as a minor component of certain seed oils rich in medium-

chain saturated fatty acids (see below).

Medium-chain fatty acids, such as octanoic, decanoic and dodecanoic, are found in esterified form in most milk fats, including those of non-ruminants, though usually as minor components, but not elsewhere in animal tissues in significant amounts. They are never detected in membrane lipids, for example. They are abse

nt from most vegetable fats, but with important exceptions. Thus, they are major components of such seed oils and coconut oil, palm

kernel oil and Cuphea species.

Myristic acid is a ubiquitous component of lipids in most living organisms, but usually at levels of 1-2% only. However, it is more abundant in cow's milk fat, some fish oils and in those

seed oils enriched in medium-chain fatty acids (e.g. coconut and palm kernel). This fatty acid is found very specifically in certain proteolipids, where it is linked via an amide bond to an N-terminal glycine residue.

Palmitic acid is usually considered the most abundant saturated fatty acid in nature, and it is found in appreciable amounts in the lipids of animals, plants and lower organisms. It comprises 20-30% of the lipids in most animal tissues, and it is present in

amounts that vary from 10 to 40% in seed oils. Among commercial sources, it is most abundant in palm oil (40% or more).

Stearic acid is the second most abundant saturated fatty acid in nature, and again it is found in the lipids of most living organisms. In lipids of some commercial importance, it occurs in the highest concentrat

ions in ruminant fats (milk fat and tallow) or in vegetable oils such as cocoa butter, and of course in industrially hydrogenated fats.

It can comprise 80% of the total fatty acids in gangliosides.

Eicosanoic acid can be detected at low levels in most lipids of animals, and not infrequently in plants and microorganisms. They do occur in many plant waxes, which by some estimations are t

he most abundant lipids on earth, and in some animal waxes such as wool wax. Saturated fatty acids up to 26:0 are normal constituents of animal sphingolipids

Biosynthesis of saturated fatty acids

The biosynthesis of saturated fatty acids requires a primer molecule, usually acetic acid in the form of its Coenzyme A ester, and a chain extender, malonyl-CoA.

The latter is formed from acetyl CoA by the activity of the enzyme acetyl-CoA carboxylase in which biotin is the prosthetic group (and thus can be inhibited by avidin).

In the first step of the reaction, carbon dioxide is linked to the biotin moiety, and this is subsequently transferred to acetyl-CoA to form malonyl-CoA.

As a first step, both the primer and extender substrates are attached to acyl carrier protein (ACP), which has the same prosthetic group as Coenzyme A. A sequence of reactions follows in which the chain is extended and butanoate is formed, as illustrated. First, 3-oxobutanoate is formed by a reaction catalysed by ß-ketoacyl-ACP synthetase, this is reduced to 3-hydroxy-butanoate by ß-ketoacyl-ACP reductase, which is in turn dehydrated to trans-2-butenoate by ß-hydroxyacyl-ACP hydratase before it is reduced to butanoate by enoyl-ACP reductase. The process then continues with the addition of a further six units of malonyl-ACP by successive cycles of these reactions until palmityl-ACP is formed. At this point, a thioesterase removes the fatty acyl product and converts it to the CoA-ester, which can then enter into the various biosynthetic pathways for the production of specific lipids.

Or, the palmityl-CoA can be further elongated by C2 units to form longer-chain fatty acids by a Type III fatty acid synthetase. Medium-chain fatty acids are produced by enzymes in which the specificity of the thioesterase component differs from normal, i.e. the chain-elongation cycle is terminated prematurely.

F-2 STRAIGHT-CHAIN MONOENOIC FATTY ACIDS

Straight- or normal-chain (even-numbered), monoenoic components, i.e. with one double bond, make up a high proportion of the total fatty acids in most natural lipids. Normally the double bond is of the cis- or Z-configuration, although some fatty acids with trans- or E-double bonds are known.The most abundant monoenoic fatty acids in animal and plant tissues are straight-chain compounds with 16 or 18 carbon atoms, but analogous fatty acids with 10 to 36 carbon atoms have been found in nature in esterified form. They are named systematically from the saturated hydrocarbon with the same number of carbon atoms, the final 'ane' being changed to 'enoic'. Thus, the fatty acid with 18 carbon atoms and the structural formula is systematically named cis-9-octadecenoic acid, although it is more usual to see the trivial name oleic acid in the literature.

F-3 METHYLENE-INTERRUPTED DOUBLE BONDS

The lipids of all higher organisms contain appreciable quantities of polyunsaturated fatty acids ('PUFA') with

methylene-interrupted double bonds, i.e.

with two or more double bonds of the

cis-configuration separated by a single methylene group.

In higher plants, the number of double bonds in fatty acids only rarely exceeds three, but in algae and animals there can be up to six.

Two principal families of polyunsaturated fatty acids occur in nature that are derived biosynthetically from linoleic (9-cis,12-cis-octadecadienoic) and alpha-linolenic (9-cis,12-cis,15-cis-octadecatrienoic) acids.

Linoleic acid is a ubiquitous component of plant lipids, and of all the seed oils of commercial importance. For example, corn, sunflower and soybean oils usually contain over

50% of linoleate, and safflower oil contains up to 75%. Although all the linoleate in animal tissues must be acquired from th

e diet, it is usually the most abundant di- or polyenoic fatty acid in mammals (and in most lipid classes) typically at levels of 15 to 25%, although it can amount to as much as 75% of the total fatty acids of heart cardiolipin.

gamma-Linolenic acid ('GLA' or 6-cis,9-cis,12-cis-octadecatrienoic acid or 18:3(n-6)) is usually a minor component of animal tissues in quantitative terms (< 1%), as it is rapidly converted to higher metabolites. It is found in a few seed oils, and those of evening primrose, borage

and blackcurrant have some commercial importance. Evening primrose oil ( 달맞이꽃 )contains about 10% GLA, and is wi

dely used both as a nutraceutical and a medical product.

8-cis,11-cis,14-cis-Eicosatrienoic acid (dihomo-gamma-linolenic acid or 20:3(n-6)) is the immediate precursor of arachidonic acid, and of a family of eicosanoids (PG1 prostaglandins). However, it does not accumulate to a significant extent in animal tissue lipid

s, and is typically about 1-2% of the phospholipid fatty acids.

Arachidonic acid (5-cis,8-cis,11-cis,14-cis-eicosatetraenoic acid or 20:4(n-6) is the most important metabolite of linoleic acid in animal tissues, both in quantitative and biological terms. It is often the most abundant polyunsaturated component of the phospholipi

ds, and can comprise as much as 40% of the fatty acids of phosphatidylinositol.

Several families of eicosanoids are derived from arachidonate, including prostaglandins (PG2 series), thromboxanes, leukotrienes, and lipoxins, with phosphatidylinositol being the primary source.

In addition, 2-arachidonoylglycerol and anandamide (N-arachidonoylethanolamine) have important biological properties, although they are minor lipids in quantitative terms.

While arachidonate is found in all fish oils, polyunsaturated fatty acids of the (n-3) families tend to be present in much larger amounts.

Arachidonic acid is frequently found as a constituent of mosses, liverworts and ferns, but there appears to be only one definitive report of its occurrence in a higher plant (Agathis robusta).

The fungus Mortierella alpina is a commercial source or arachidonate.

alpha-Linolenic acid (9-cis,12-cis,15-cis-octadecatrienoic acid or 18:3(n-3)) is a major component of the leaves and especially of the photosynthetic apparatus of algae and higher plants, where most of it is synthesised. It can amount to 65% of the total fatty acids of linseed oil, where its relativ

ely susceptibility to oxidation has practical commercial value in paints and related products.

In contrast, soybean and rapeseed oils have up to 7% of linolenate, and this reduces the value of these oils for cooking purposes. alpha-Linolenic acid is the biosynthetic precursor of jasmonates in plants, which appear to have functions that parallel those of the eicosanoids in animals.

In animal tissue lipids, alpha-linolenic acid tends to be a minor component (<1%), the exception being grazing non-ruminants such as the horse or goose, where it can amount to 10% of the adipose tissue lipids.

11,14,17-Eicosatrienoic acid (20:3(n-3)) can usually be detected in the phospholipids of animal tissue but rarely at above 1% of the total. Somewhat higher concentrations may be found in fish oils.Stearidonic acid (6,9,12,15-octadecatetraenoic or 18:4(n-3)) is occasionally found in plants as a minor component, and it occurs in algae and fish oils.

3,6,9,12,15-Octadecapentaenoic acid or 18:5(n-3) is a significant component of the lipids of dinoflagellates, and it can enter the marine food chain from this source.8,11,14,17-Eicosatetraenoic acid (20:4(n-3)) is found in most fish oils and as a minor component of animal phospholipids. It is frequently encountered in algae and mosses, but rarely in higher pla

nts.

5,8,11,14,17-Eicosapentaenoic acid ('EPA' or 20:5(n-3)) is one of the most important fatty acids of the (n-3) family. It occurs widely in algae and in fish oils, which are major commercial so

urces, but there are few definitive reports of its occurrence in higher plants.

It is an important constituent of the phospholipids in animal tissues, especially in brain, and it is the precursor of the PG3 series of prostaglandins.

There is currently great interest in the role of this acid in neurological disorders such as schizophrenia.

7,10,13,16,19-Docosapentaenoic acid (22:5(n-3)) is an important constituent of fish oils, and it is usually present in animal phospholipids at a level of 2-5%.

4,7,10,13,16,19-Docosahexaenoic acid ('DHA' or 22:6(n-3)) is usually the end point of alpha-linolenic acid metabolism in animal tissues. It is a major component of fish oils, especially from tuna eyeballs, a

nd of animal phospholipids, those of brain synapses and retina containing particularly high proportions.

While it is found in high concentrations in many species of algae, especially those of marine origin, it is not present in higher plants.

DHA has recently been shown to be the precursor of docosanoids, termed 'resolvins', which are analogous to the eicosanoids and may have related biological activities.

The concentration of DHA in tissues has been correlated with a number of human disease states, and it is essential to many neurological functions.

As a phospholipid constituent, it has profound effects on membrane properties, and together with cholesterol may act by modulating the structure and function of membranes.

The linoleic acid, which is the primary precursor molecule for the (n-6) family of fatty acids, must come from the diet. Biosynthesis of polyunsaturated fatty acids requires a sequence of chain elongation and desaturation steps, as illustrated below, and the various enzymes require the acyl-Coenzyme A esters as substrates not intact lipids (unlike plants). The liver is the main organ involved in the process.

Again, the alpha-linoleic acid, which is the primary precursor molecule for the (n-3) family of fatty acids in animal tissues, must come from the diet. The main pathway to the formation of docosahexaenoic acid (22:6(n-3)) requires a sequence of chain elongation and desaturation steps (Delta-5 and Delta-6 desaturases), as illustrated below, with acyl-Coenzyme A esters as substrates.

F-4 POLYUNSATURATED WITH OTHER THAN METHYLENE-INTERRUPTED DOUBLE BONDS

Conjugated fatty acids from animal tissuesFatty acids with conjugated diene systems are found in tissues of ruminant animals, and thence in meat and dairy products, where it is formed as an intermediate or by-product in the biohydrogenation of linoleic acid by microorganisms in the rumen. The main isomer, 9-cis,11-trans-octadecadienoic acid, amounts to about 1% of milk fat, and it may be accompanied by a small proportion of positional and geometrical isomers (6,8- to 12,14-18:2).There is considerable interest in conjugated linoleic acid ('CLA') at present because of reports that it has a number of beneficial medical properties, especially anti-cancer effects. It is also claimed to have anti-atherosclerosis effects, to help the immune system and to affect energy metabolism, promoting protein deposition as opposed to fat (see our web-pages on CLA).

Conjugated fatty acids from plants

trans-10,trans-12-Octadecadienoic acid comprises about 10% of the seed oil of Chilopsis linearis and appears to be the only long-chain conjugated dienoic fatty acid from plant sources, although trans-2,cis-4-decadienoic acid is present in estolide linkage to an allenic hydroxy acid in Stillingia oil. Conjugated dienoic fatty acids in refined oils are mainly artefacts o

f processing.

In contrast, fatty acids with conjugated triene systems have been found in a large number of different plant species. Of these, 9-cis,11-trans,13-trans-octadecatrienoic (alpha-eleostearic) acid is the most widespread and best known. Tung oil is the main commercial source.

Bis- and polymethylene-interrupted unsaturated fatty acids from animal tissues

The primitive animals, the sponges (family - Spongillidae) and some other marine invertebrates are known to contains a wide range of distinctive fatty acids, the demospongic acids, with bis-methylene-interrupted cis-double bonds, and ranging in chain-length from C16 to C34.

These have a cis,cis-dienoic system, either with the double bonds in positions 5 and 9, or derived from 5,9-16:2 by chain-elongation.

The last is usually a relatively minor component of sponges, and was first reported from the cellular slime mould Dictyostelium discoideum.

Bis- and polymethylene-interrupted unsaturated fatty acids from plantsDelta-5-unsaturated polymethylene-interrupted fatty acids, with cis-double bonds only, are found in appreciable amounts in seeds, leaves and other tissues of the relatively primitive plants, the gynosperms (conifers). Of these, the best known is probably 5-cis,9-cis,12-cis-octadecatrienoic ('pinolenic') acid, which is widespread in species of pines.

5-cis,13-cis-Docosadienoic acid (16% of the total fatty acids) occurs in the seed oil of a plant from a quite different family Limnanthes alba (meadowfoam). Trace levels of dienoic fatty acids with cis-double bonds in positions 5 and 9 have been found in a few other plant species, while 9,15-octadecadienoate occurs in mango pulp. In addition, an analogue of pinolenic acid with a trans double bond in position 5 (5t,9c,12c-18:3) is the main fatty acid constituent of the seed oil of Aquilegia vulgaris (columbine). A positional isomer of this, i.e. 3-trans,9-cis,12-cis-octadecatrienoate, is a common constituent of seed oils from the Compositae, and the all-cis isomer has also been described. 

F-5 BRANCHED-CHAIN FATTY ACIDS

Branched-chain fatty acids are common constituents of the lipids of bacteria and animals, although they are rarely found in the integral lipids of higher plants.

Normally, the fatty acyl chain is saturated and the branch is a methyl-group.

However, unsaturated branched-chain fatty acids are found in marine animals, and branches other than methyl may be present in microbial lipids.

The most common branched chain fatty acids are mono-methyl-branched, but di- and poly-methyl-branched fatty acids are also known.

Their main function may be to increase the fluidity of lipids as an alternative to double bonds, which are more liable to oxidation.

Saturated iso- and anteiso-methyl-branched fatty acids

iso-Methyl branched fatty acids have the branch point on the penultimate carbon (one from the end), while anteiso-methyl-branched fatty acids have the branch point on the ante-penultimate carbon atom (two from the end) as illustrated.

Fatty acids with structures of this type and with 10 to more than 30 carbons in the acyl chain are found in nature, but those most often encountered have 14 to 18 carbons.

They are common constituents of bacteria but are rarely found in other microorganisms.

In higher plants, 14-methylhexadecanoic occurs at a level of 0.5 to 1% in seed oils from the family Pinaceae, where it appears to be a useful taxonomic marker.

iso-/anteiso-Methyl-branched fatty acids are major components of plant surface waxes.

Saturated mid-chain methyl-branched fatty acids

10-R-Methyloctadecanoic acid or tuberculostearic acid is a major component of the lipids of the tubercle bacillus and related bacterial species.

Indeed its presence in bacterial cultures and sputum from patients is used in the diagnosis of tuberculosis.

It is also found in Corynebacterium and many other species.

Biosynthesis of branched chain fatty acids of this type involves methylation of oleic acid esterified as a component of a phospholipid, with S-adenosylmethionine as the methyl donor.

The resulting 10-methyleneoctadecanoyl residue is reduced to the 10-methyl compound with NADPH as the cofactor.

A related mechanism is in used for biosynthesis of cyclopropane fatty acids in bacteria.

Di- and poly-methyl-branched fatty acidsA number of isoprenoid fatty acids occur naturally in animal tissues that are derived from the metabolism of phytol (3,7,11,15-tetramethylhexadec-trans-2-en-1-ol), the aliphatic alcohol moiety of chlorophyll. These range from 2,6-dimethylheptanoic to 5,9,13,17-tetramethyloctadecanoic acids, but those encountered most often are 3,7,11,15-tetramethylhexadecanoic (phytanic) and 2,6,10,14-tetramethylpentadecanoic (pristanic) acids. 4,8,12-Trimethyltridecanoic acid is especially common in fish and other marine organisms. Phytanic acid is formed in animal tissues by oxidation of phytol to phytenic acid (only encountered in tissues under artificial feeding conditions), followed by reduction. The shorter chain isoprenoid fatty acids are formed from this by sequential alpha- and/or beta-oxidation reactions. In natural phytanic acid, each of the methyl groups would be expected to have the D-configuration, but in that prepared via chemical hydrogenation of phytol, the 3-methyl group is racemic (D,L).

Unsaturated methyl-branched fatty acids

Monounsaturated methyl branched-chain fatty acids have been detected in bacteria and marine animals.

Often, usually the branch is in the iso/anteiso-positions, but it can also be more central in the aliphatic chain.

For example, one of the first acids of this type to be described was 7-methyl-7-hexadecenoic acid from lipids of the ocean sunfish (Mola mola), while 7-methyl-6- and 7-methyl-8-hexadecenoic acids were later found in a sponges.

Similar fatty acids with iso-/anteiso-methyl groups found in related marine organisms include 13-methyltetradec-4-enoic, 14-methylhexadec-6-enoic, 14-methylpentadec-6-enoic and 17-methyloctadec-8-enoic acids, and many others.

It is possible that the primary origin of these fatty acids is in bacteria, since many comparable fatty acids have been found in bacteria, for example in Bacillus cereus and Desulfovibrio desulfuricans.

Unsaturated methyl-branched fatty acids

Monounsaturated methyl branched-chain fatty acids have been detected in bacteria and marine animals.

Often, usually the branch is in the iso/anteiso-positions, but it can also be more central in the aliphatic chain.

For example, one of the first acids of this type to be described was 7-methyl-7-hexadecenoic acid from lipids of the ocean sunfish (Mola mola), while 7-methyl-6- and 7-methyl-8-hexadecenoic acids were later found in a sponges.

Similar fatty acids with iso-/anteiso-methyl groups found in related marine organisms include 13-methyltetradec-4-enoic, 14-methylhexadec-6-enoic, 14-methylpentadec-6-enoic and 17-methyloctadec-8-enoic acids, and many others.

It is possible that the primary origin of these fatty acids is in bacteria, since many comparable fatty acids have been found in bacteria, for example in Bacillus cereus and Desulfovibrio desulfuricans.

Mycolic acidsThe mycolic acids, major components of the Mycobacteria and related species, are beta-hydroxy-alpha-alkyl branched structures of high molecular weight (88 carbons or more). Depending on species, these can contain a variety of functional groups, including double bonds of both the cis- and trans-configuration (but when the latter they also possess an adjacent methyl branch) and cyclopropane rings, which can also be of the cis- and trans-configuration. In addition, they can contain, methoxy-, epoxy- and keto groups, which are also adjacent to a methyl branch normally. The mycolic acids are key structural components of the membranes of mycobacteria, where they appear to confer distinctive properties, including a low permeability to hydrophobic compounds, resistance to dehydration, and the capacity to survive the hostile environment of the macrophage. The beta-hydroxy group is especially important in that it is believed to modulate both the phase transition temperature and the molecular packing within the membrane. While there is evidence that mycolic acid-containing glycolipids have some influence on the host immune system, they do not appear to be important for the virulence of the pathogenic Mycobacteria.

Some Miscellaneous LipidsPHOSPHONOLIPIDS

Phosphonolipids consist of aminoethylphosphonic acid residues, i.e. with a phosphorus-carbon bond, attached to a lipid backbone, which can be either a ceramide or diacylglycerol.

The first of the sphingolipids to be discovered was ceramide 2-aminoethylphosphonate, which was found in sea anemones.

Subsequently, it was detected in a variety of molluscs, protozoa, bacteria, and even

bovine brain tissue,

sometimes

accompanied by

an N-methyl-

ethanolamine

analogue.

CARNITINE AND ACYLCARNITINESCarnitine (L-3-hydroxy-4-aminobutyrobetaine or L-3-hydroxy-4-N-trimethylaminobutanoic acid), and its acyl esters (acylcarnitines) are essential compounds for the metabolism of fatty acids.Carnitine can be synthesised de novo in animal cells, but it is believed that most comes from the diet. Its main function is to assist the transport and metabolism of fatty acids into  mitochondria, where they are oxidized for energy production. In so doing, carnitine maintains a balance between free and esterified coenzyme A, since an excess of acyl- CoA intermediates is potentially toxic to cells. In addition, carnitine is required to remove any surplus of acyl groups from mitochondria. 

Coenzyme A estersBefore a fatty acid can be metabolized in tissues, for example by being esterified, oxidized or subjected to synthetic modification, it must usually be activated by conversion to a Coenzyme A ester or acyl-CoA, with the fatty acid group linked to the terminal thiol moiety. The thiol ester is a highly energetic bond that permits a facile transfer of the acyl group to receptor molecules. This is true for the simplest fatty acid of all, acetic acid (i.e. as acetyl-CoA), as well as for long-chain fatty acids.Coenzyme A (CoASH) itself is a highly polar molecule, consisting of adenosine 3',5'-diphosphate linked to 4-phosphopantethenic acid (Vitamin B5) and thence to ß-mercaptoethylamine. Not only is it intimately associated with most reactions of fatty acids, but it is also a key molecule in the catabolism of carbohydrates via the citric acid cycle in which acetyl-CoA is a major end-product.It is interesting that the 4-phosphopantetheine moiety, linked via its phosphate group to the hydroxyl group of serine, is the active component in another important molecule in lipid metabolism, acyl carrier protein. This is a small protein (8.8 kDa), which is part of the mechanism of fatty acid synthesis.

PROTEOLIPIDSIn 1951, proteins that were soluble in organic solvents such as chloroform-methanol were found in rat brain myelin, although it was another twenty years before it was shown that they contained covalently bound fatty acids and so differed from the lipoproteins. Such proteins are now known to be widespread in nature with a variety of important functions. The term proteolipid is used to define all proteins containing covalently bound lipid moieties, including fatty acids, isoprenoids, cholesterol and glycosylphosphatidyl-inositol.

In the N-myristoylated proteins, myristic acid (14:0) specifically, which is a ubiquitous but usually minor component of cellular lipids, is bound to the amino-terminal glycine residue (of a relatively conserved sequence of the protein) via an amide linkage that is relatively stable to hydrolysis.

In the palmitoylated proteins, palmitic acid (16:0) is linked to one or more (up to four) internal cysteine (or occasionally threonine or serine) residues via labile thioester bonds.

Prenylated proteins are formed by attachment of isoprenoid lipid units, farnesyl (C15) or geranylgeranyl (C20), via cysteine thio-ether bo

nds at or near the carboxyl terminus. Such proteins are ubiquitous in mammalian cells, where they can amount to up to 2% of the total proteins, and they are increasingly being found in plants.

Relatively recently, proteins linked covalently to cholesterol was discovered that cholesterol can be found in covalent linkage to specific proteins, known as the "hedgehog" signalling family. These are formed post-translationally by attachment of cholesterol via an ester bond to glycine in a highly conserved region of the protein.

ANANDAMIDE, OLEAMIDE AND OTHER FATTY AMIDESFatty amides are produced synthetically in industry in large amounts (> 300,000 tons per annum) for use as ingredients of detergents, lubricants, inks and many other products. In nature, fatty acids are linked to the complex sphingolipids via amide bonds. However, here we are concerned only with those simple fatty amides that occur naturally and have profound biological functions.

Long-chain N-acylethanolamines are ubiquitous trace constituents of animal and human cells, tissues and body fluids, with important pharmacological properties.

Anandamide or N-arachidonoylethanolamine has attracted special interest, because of its marked biological activities. Like the pharmacologically active compounds in marijuana or cannabis (from

Cannabis sativa), it exerts its effects through binding to and activating specific cannabinoid receptors, designated 'CB1' and 'CB2', both of which are membrane-bound G-proteins.

CB1 is found in the central nervous system and in some other organs, including the heart, uterus, testis and small intestine, while the CB2 receptor is found in the periphery of the spleen and other cells associated with immunochemical functions, but not in brain.

cis-9,10-Octadecenamide or 'oleamide' is a primary fatty acid amide. It was first isolated from the cerebrospinal fluid of sleep-deprived cats, and has been characterized and identified as the signalling molecule responsible for causing sleep.

Very recently, N-arachidonoyldopamine has been detected as an endogenous component of mammalian nervous tissue with distinctive biological effects.

N-Acylglycine derivatives of short-chain fatty acids (C2 to C12) have long been recognized as minor constituents of urine and blood, and their compositions may have some relation to metabolic disease.

However, more recently, it has become apparent hat N-arachidonylglycine is present in bovine and rat brain as well as other tissues at low levels, and that it suppresses inflammatory pain.