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In this article we will discuss about the classification of lipids.
Contrary to carbohydrates which constitute a family of relatively homogenous compounds, lipids form a very heterogenous class of compounds of widely differing structures and grouped according to their insolubility in water and solubility in organic solvents (ether, acetone, chloroform-alcohol mixtures, etc.).
These solubility criteria are not absolute. Lipids were therefore defined as compounds containing in their molecule an aliphatic chain (chain consisting of — CH2—) of at least 8 carbon atoms. Some short-chain fatty acids (like butyric acid, in C4) are the only exceptions to this rule.
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The term fats and oils denote mixtures of lipids respectively solid (lard) or liquid (olive oil) at ordinary temperature; one must avoid using these terms to designate esters of glycerol (only the industry still uses them).
In earlier manuals one finds the distinction between simple lipids (yielding an alcohol and one or several fatty acids on hydrolysis) and complex lipids (the hydrolysis of which liberates not only an alcohol and fatty acids but also phosphoric acid, carbohydrates, etc.). As structures of the so-called complex lipids were progressively elucidated a more precise and more rational classification appeared possible.
We are following a classification based on structural characteristics:
I. Fatty Acids:
They are found in small quantities in free state, but in large quantities involved in ester (or sometimes amide) linkages. As a general rule, these are monocarboxylic, straight unbranched chain acids containing an even number of carbon atoms (between 4 and 36). They may be saturated or unsaturated and sometimes hydroxylated or branched.
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1. Saturated Fatty Acids:
Their general formula is: CH3 — (CH2)n — COOH. The most frequent are palmitic acid (C10) and stearic acid (C18). In lower concentration are found the fatty acids with 14 or 20 carbon atoms. Longer fatty acids (up to 36 carbon atoms) are present in numerous cells (bacteria, unicellular eucaryotes, plants, vertebrates).
They are generally present in some types of lipids. Milk on the contrary, is rich in short-chain fatty acids. Besides the even-carbon fatty acids, are generally found small quantities of fatty acids having 15, 17 or 19 carbon atoms.
2. Unsaturated Fatty Acids:
Fatty acids are numbered from the terminal carboxyl (carbon 1) to the CH3 group (carbon n). The double bond is indicated by the sign ∆, accompanied by the number corresponding to the first carbon atom participating in the double bond. The sign: is being increasingly used; it is followed by the number of double bonds, the position of the latter being indicated within brackets.
There is also a biochemical nomenclature. In this case carbon 1 is the terminal methyl. The place of the last double bond is indicated by ω followed by the number of atoms of the carbon existing up to this double bond. In practically all biological unsaturated fatty acids, the double bond, has a cis isomerism.
The principal unsaturated fatty acids are:
A. Monounsaturated Fatty Acids (1 Double Bond):
Oleic acid (C18), double bond between carbon atoms C9 and C10 , abbreviated as: (C18, ∆9 or 18 :1(9) or 18 ω 9).
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CH3-(CH2)7-CH = CH-(CH2)7-COOH
B. Polyunsaturated Fatty Acids (Several Double Bonds):
In the most common of such acids, the non-conjugated double bonds are separated by a methylene group. Plants can however contain fatty acids with conjugated double bonds, for example, eleostearic acid.
Linoleic acid (C18, ∆9,12 or 18:2 (9,12) or 18 ω 6)
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CH3-(CH2)4-CH = CH-CH2-CH = CH-(CH2)7-COOH
Linolenic acid (C18, ∆9,12,15 or 18 : 3 (9,12,15) or 18 ω 3)
CH3—CH2—CH = CH—CH2—CH = CH—CH2—CH = CH—(CH2)7—COOH
Arachidonic acid (C20, ∆5,8,11,14).
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Docosahexaenoic acid (C22 ∆4,7,10,13,16,19).
Eleostearic acid (C18, ∆9,11,3).
In mammals, polyunsaturated fatty acids can have up to 22 carbon atoms and 6 double bonds, but in plants these acids do not exceed 18 carbon atoms and 4 double bonds.
An important physical property of fatty acids is their melting point; it decreases with increasing number of double bonds. For example, the melting point of stearic acid (18: 0) is 70°C, whereas that of oleic acid (18 :1) is 13°C, that of linoleic acid (18: 2), -5.8°C and that of arachidonic acid (20: 4), – 49.5°C.
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3. Hydroxylated Fatty Acids:
Plants can synthesize a series of hydroxylated fatty acids like ricinoleic acid for example:
Some of these hydroxylated fatty acids lead to the formation of cutin.
Other types of hydroxylated fatty acids are found in mammals. Some glycolipids contain large quantities of α-hydroxylated acids (OH on carbon 2) with 22, 23, 24 and 25 carbon atoms. Moreover, cells of the epiderm have lipids containing very long-chain ω hydroxylated acids which play a role in the structure of this particular tissue.
4. Branched Fatty Acids:
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Example: 15 methylhexadecaenoic acid
(CH3)2 – CH – (CH2)13 – COOH
The above type of fatty acid is particularly abundant in Gram+ bacteria.
5. Prostaglandins, Leukotriens and Peroxides:
Prostaglandins and leukotriens are derived from polyunsaturated fatty acids with 20 carbon atoms ω 6 and ω 3 (hence their general name, eicosanoids) and especially from arachidonic acid, under the action of cyclooxygenase (prostaglandines) and lipoxygenase (leukotriens).
In mammals, these are compounds having hormonal action with various biological effects. Prostaglandines E are powerful activators of adenylate cyclase. Prostaglandines F and leukotriens B, C, D, activate the contraction of various smooth muscles.
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These compounds have a short half-life because they are metabolized by the tissues into biologically inactive derivatives. In vertebrates, eicosanoids are synthesized by numerous tissues. Insects form prostaglandines from the polyunsaturated fatty acids present in food. Plants have lipoxygenases which metabolize linoleic acid into compounds analogous to leukotriens.
Besides these compounds, numerous organisms can “oxidize” fatty oxides to lipidic peroxides. The hydroxylated fatty acids of plants are formed by such a mechanism.
6. Other Close Compounds:
Besides the fatty acids, one finds aldehydes and fatty alcohols, such as for example, palmitaldehyde, stearaldehyde, olealdehyde and the corresponding primary alcohols. These compounds are rarely in free state, but are part of the structure of glycerophospholipids or cerides. Medium- chain linear aldehydes play a role of pheromone in insects.
II. Glycerolipids:
1. Glycerides:
These compounds are obtained by esterification of the alcohol groups of glycerol by fatty acids; there are mono-, di- and triglycerides. Moreover, glycerides may differ by the nature and position of esterified fatty acids. To indicate the position, the carbon atoms of glycerol are denoted 1, 2 and 3. Thus, the compound A of figure 5-2 is 1-palmitoyl 2-oleyl glycerol, compound B is 1-palmitoyl 2-oleyl-3-stearoyl glycerol.
When the fatty acids esterified in position 1 and 3 are different (as in the compound B), a centre of asymmetry appears in carbon 2 and one can therefore have the isomers I and II represented in figure 5-2. Most of the natural glycerolipids are of type II.
Glycerides are present in the quasi-totality of tissues of all living beings, but they are particularly abundant in the adipose tissue (where they may constitute more than 90% of lipids). In the following study of lipid metabolism, we will explain why they form a very convenient reserve of energy. Glycerides are generally present in cells in liquid state as cytoplasmic inclusions.
2. Glycerophospholipids:
Also called phosphatides they are the most numerous representatives of the large family of phospholipids.
They are found in high concentrations in the cellular and subcellular membranes of all living organisms. Only viruses called “non-enveloped” (viruses which do not incorporate in their structure, membrane elements of the host cell) are free from phosphatides. Some phosphatides are good emulsifying agents (lysophosphatides, lecithins).
A. Diacylphosphatides:
a) Phosphatide Acids:
They result from the esterification of glycerol by two fatty acids and phosphoric acid; the latter having only one of its acidic OH esterified, imparts an acid character to the molecule (see fig. 5-3). They exist in small quantities in free state and play an important role in the biosynthesis of glycerophospholipids, the structure of which derives from that of phosphatidic acids (see fig. 5-21).
As in the case of glycerides, the molecule is asymmetric. The 2 fatty acids of glycerol have the same orientation as observed in glycerides (fig. 5-2, II). This is generally true of all phosphatides.
b) Phosphatidyl Cholines (Lecithins):
As observed in figure 5-3, these compounds contain a molecule of choline (a quaternary ammonium compound having an alcohol group) esterified by phosphoric acid which is therefore involved in a phosphodiester linkage.
c) Other Phosphatides:
In these compounds, which are very similar to lccithins, choline is replaced by:
(i) Ethanolamine in phosphatidyl ethanolamines
(ii) Serine in phosphatidyl serines
These two types of lipids were earlier called “cephalins”.
Choline can also be replaced by some alcohols, like glycerol in phosphatidyl- glycerols (abundant in some micro-organisms and plants) or inositol, a cyclic polyalcohol, in phosphatidyl inositols. Important derivatives of the latter
phospholipids are phosphatidylinositol-4, 5-diphosphates. The structure of some of these lipids are represented in figure 5-3.
Mention may also be made of diphosphatidyl-glycerol or cardiolipid, a phosphatide which is specifically located in the mitochondria in mammals. It is formed by the union of 2 molecules of phosphatidic acid the phosphate atoms of which are linked through a molecule of glycerol.
B. Alkenylphosphatides (Plasmalogens):
They differ from diacyphosphatides in that the fatty acid bound in position 1 of the glycerophosphate is replaced by a fatty aldehyde, bound by an ethylcnic ether-oxide linkage (see fig. 5-3).
C. Alkylphosphatides (Etherphosphatides):
They are distinguished from diacylphosphatides by the fact that the fatly acid in 1 is replaced by a fatty alcohol bound by an ether-oxide linkage.
Like the diacylphosphatides, alkenyl- and alkyl phosphatides are found in a wide range of organisms from the unicellular to mammals. However, the percentage of these compounds varies considerably from one species to another and in the same species from one tissue to another.
An important derivative of alkylphos- phatides is PAF acether (Platelet Activating Factor). This compound, synthesized particularly by the platelets, has a very high aggregation activity and plays an important role in the formation of “platelet clots”.
3. Glycosyldiglycerides:
They result from the binding of one or several (up to 10) molecules of monosaccharides to the free alcohol group of a 1, 2-diglyceride. The most frequent monosaccharides are galactose and glucose. The mono- and di-galac- tosyldiglycerides are important compounds of chloroplasts. The glucosyl- and galactosyldiglycerides are major constituents of the plasmic membrane of numerous bacteria.
In the latter case, they can also exist in the form of more complex molecules intermediate between those of glycosyldiglycerides and phosphatides (e.g., phosphatidyldiglucosyldiglycerides). Glycosyldiglycerides were also found in some secretions (tears, saliva, gastric secretions) of mammals.
III. Sphingolipids:
In these compounds the alcohol is not glycerol but a long-chain amino- alcohol. The most frequent is sphingosine (fig. 5-4) which has 18 carbon atoms and a double bond. Dihydrosphingosine (saturated sphingosine) and phytos- phingosine (saturated sphingosine with an additional alcohol group) are also found but less frequently.
Sphingosine is linked to a fatty acid by its amine group forming a ceramide. The linkage is therefore an amide bond and not an ester bond as in glycerides, sterides or phosphatides. The fatty acid of sphingolipids can be a long-chain fatty acid with or without a hydroxyl group on carbon 2. The ceramides are found in small quantities, in free state, in numerous eucaryotic and procaryotic cells.
1. Sphingomyelins:
The ceramide is linked by its primary alcohol group (carbon 1) to a phos-phorylcholine (fig. 5-4). Sphingomyelins have been found in most organisms. They are present, like the phosphatides, in cellular membranes and particularly in the plasmatic membrane.
2. Sphingoglycolipids:
These are lipids characterized by the presence in their molecule, of one or more saccharides linked to the carbon 1 of a ceramide.
A. Galactolipids:
In the case of galactocerebrosides, the monosaccharide fixed on the ceramide is galactose. Galactose can be esterified by a molecule of sulphuric acid. The compounds are then called sulphatides. In mammals, galactocerebrosides and sulphatides are mainly located in the renal tissue and nervous tissue (myelin sheath). They are rarely found in organisms other than the vertebrates.
B. Neutral Glycolipids:
One or several (up to about ten) sugars are bound to the ceramide. In vertebrates, the first sugar is glucose. The compounds are then spoken of as glucocerebrosides. In addition to glucose, the most frequently found monosaccharides are galactose, mannose, fucose, glucosamine and galactosamine. Neutral glycolipids particularly the glucocerebrosides are present in a very large number of organisms ranging from the procaryotes to mammals where they can form up to 90% of lipids.
C. Gangliosides:
Their structure is that of a glucosylceramide to which are bound one or several molecules of galactose, N-acetyl galactosamine, N-acetylglucosamine or fucose (see fig. 5-4). The most characteristic sugar of gangliosides is however neuraminic acid (or sialic acid) in the N-acetylated or N-glycosylated form. They are found only in vertebrates. The brain is particularly rich in gangliosides.
D. Phytoglycolipids:
Besides the conventional neutral glycolipids, most plants, yeasts and fungi include more complex glycolipids which generally contain phosphorus and inositol, as for example, ceramide-phosphate-inositol-glucuronic acid- glucosamine-mannose. More than hundred different structures are known.
IV. Cerides:
These are constituents of waxes (plant waxes, insect waxes, sperm oil, etc.). They are esters formed by the union of long-chain fatty acids and long-chain alcohols (having up to 30 to 40 carbon atoms). Example; cetyl palmitate (fig. 5-5).
V. Hydrocarbons:
The general structure of these compounds is CH3 — (CH2)n— CH3. They are sometimes branched or unsaturated. They are found in small concentrations in most living organisms.
VI. Polyisoprenic Lipids:
1. Polyisoprenic Hydrocarbons:
A very large number of compounds present especially in plants, are formed by the polymerisation of isoprene units; this is the case (as maybe seen in figure 5-6) with squalene (an intermediate of the biosynthesis of sterols), carotenes and other terpenes like limonene.
In addition to these terpenes, there are other polyisoprenes in plants; the best known is rubber, formed by the condensation of thousands of isoprene units.
One may also cite a group of linear polyisoprenes, having in average 20 isoprenic units, like the dolichols whose general structure diagram is as follows:
These compounds exist either free, or in the form of phosphoric esters (dolichols monophosphates) or pyrophosphoric esters (dolichols diphosphates) combined with a mono- or polysaccharide. The latter are intermediates acting in the synthesis of N-glycosylated proteins.
A compound similar to dolichols is phytol:
This compound is part of the structure of chlorophyll. Phytanic acid, obtained by oxidation of the alcohol group of phytol, is one of the main fatty acids found in lipids of halophile and thermophile bacteria.
Some lipids can be considered as derivatives of isoprene (steroids, carotenoids, quinones with isoprenic side chain).
These compounds are studied in the following:
Sterols and Steroids:
These compounds derive from a polycyclic ring, called ring of cyclopen-tanophenanthrene. The stereochemistry and nomenclature problems of steroids are rather complex; we will not examine them in detail here.
As far as stereochemistry is concerned we will envisage the main possibilities of isomerism with the maximum possible simplification; and to denote the steroids we will use the terms adopted by usage instead of the nomenclature based on structure.
The study of the polycyclic ring shows that there are 6 asymmetric carbons (indicated by asterisks in figure 5-7). Additional asymmetric carbons are formed by the introduction of substituents in the cycle. The quasi-totality of sterols and their derivatives have a substituent in 10 or 13 (generally a methyl group).
Methyl groups 18 and/or 19 have the same orientation in space with respect to the plane in which the polycyclic ring is located. These 2 methyl groups serve as reference base.
Any substituent which is situated on the same side as the methyl groups in 18 or 19 with respect to the plane of the molecule is said to be in position cis, called “β” and represented by a solid valence line; substituents situated on the other side of the plane of the molecule with respect to the methyl groups in 18 or 19 are said to be in position trans, called “α” and represented by a dotted valence line, α and β isomers of sterols and their derivatives are known only on carbons 3, 5, 7 and 17.
Owing to the arrangement of cycles B, C, D in space and the existence of methyl groups 18 and 19, there is only one possibility of isomerism (β for 11 and α for 12) in carbons 11 and 12.
Steroids represent a very large and varied family of compounds. Their biological activities are very diverse and it is found that often, small variations of the structure or nature of the substituents result in major modifications of biological activity.
There are:
A. Sterols:
This is a very important group of lipids found in practically all eucaryotes. More than hundred sterols are known of which we may cite cholesterol (see fig. 5-7) which is the principal sterol of vertebrates, ergosterol which is a natural precursor of vitamin D, (see fig. 5-7), stigmasterol, sitosterol, important sterols in plants.
By esterification of the alcoholic group by fatty acids, sterols give sterides. In general, in normal physiological conditions, the quantity of sterides in a given tissue is very small compared to free sterols (blood is an exception to this rule). Sterides exist only as traces in biological membranes.
Their accumulation in the latter is pathological (atheroma). Plants contain an appreciable part of their sterols conjugated with a saccharide like glucose (sterylglucosides). The saccharide is linked by its reducing group to the alcohol group in position 3 of the sterol.
B. Derivatives of Sterols:
a) Bile Acids:
The two main bile acids are cholic acid and deoxycholic acid. Their solubility in aqueous medium is extremely low. They are found in the bile, conjugated with glycine or taurine (the latter derives from cysteine by oxidation of the SH group and decarboxylation), thus forming glycocholic, glycodeoxycholic, taurocholic and taurodeoxycholic acids (see fig. 5-7). Bile acids can be salified by monovalent ions (Na, K), thus forming bile salts.
b) Steroid Hormones:
TESTICULAR HORMONES, CALLED MALE SEX HORMONES.
Examples: testosterone (see fig. 5-7), androsterone.
OVARIAN AND PLACENTARY HORMONES, CALLED FEMALE SEX HORMONES. — Estrogen hormones.
They are phenolsteroids (cycle A is aromatic).
Examples: estradiol (see fig. 5-7), estrone, estriol.
— Luteal hormone.
Example: progesterone (see fig. 5-7).
HORMONES OF THE ADRENAL CORTEX.
Examples: Corticosterone (see fig. 5-7), Cortisol, aldosterone.
c) Hormones of Insects:
A large group of sterol derivatives is represented by the insects “pupation” hormones. These compounds are analogous to the steroid hormones of mammals. The most important is ecdysone (fig. 5-7). The other compounds differ by the number and position of hydroxyl groups.
d) Vitamin D:
There are several, very similar compounds having the same vitamin action; one of them is vitamin D2 or ergocalciferol (fig. 5-7). It must be noted that cycle B is open and therefore the cyclopentanophenantrene ring characteristic of steroids is no longer present; however, the study of vitamin D on sterols is justified by the fact that they derive from some sterols (especially ergosterol) by simple ultra-violet irradiation.
Vitamin D is necessary for the proper formation of bones and teeth because it controls the phospho-calcium metabolism. These vitamins D are actually the precursors of biologically active compounds which are derivatives hydroxylated in position 24 or 25.
e) Steroid Alkaloids and Heterosides:
They are represented by a large number of compounds (more than hundred) synthesized by plants. They derive from the molecule of steroids, generally by the introduction of new groups (acid, alcohol, amine…).
Some are combined with a sugar (glucose, galactose, arabinose, rhamnose…) linked to an alcohol or acid group of the cycle. The majority of these are pharmacologically active. Among the best known we may cite ouabain, digitoxygenin, saponins.
C. Hopanoids:
While some bacteria can incorporate cholesterol in their membranes, no procaryote is capable of synthesizing it. On the contrary, some procaryotes synthesize a group of polyisoprenic derivatives close to sterols: the hopanoids. The basic structure is the bacteriohopan.
More than about fifty compounds are known, deriving from the bacteriophan by the presence among other things, of double bonds, aldehyde, alcohol, acid groups. Hopanoids may play in procaryotes a role similar to that of sterols in eucaryotes.
Carotenoids:
A. Carotenes:
It has been stated in the foregoing (see fig. 5-6) that they are isoprene derivatives. They contain a large number of conjugated double bonds which give them a coloration ranging from yellow to red.
The α and β carotenes (pigment of the carrot) are cyclized at the two ends (and differ only by the position of one double bond of the ring), whereas γ-carotene has only one ring (see fig. 5-8) and lycopene (pigment of the tomato) is not cyclized at all.
B. Xanthophylls:
These pigments derive from carotenes by oxidation and have hydroxyl groups on the rings.
C. Vitamin A:
Compounds with vitamin A activity can be placed next to the carotenes because they derive directly from them, as shown in fig. 5-8. Actually, the animal organism splits carotene giving rise to retinal, aldehyde of vitamin A which can then be reduced to alcohol. It must be noted that vitamin A can result only from one of the halves of α-carotene or γ-carotene molecule (the left hand half in figure 5-8), because the other half, in the former case (α-carotene), has the double bond of the ring in a different position, and in the latter case, has no ring at all (γ-carotene); on the contrary, β-carotene could theoretically yield 2 molecules of vitamin A, but in reality the initial scission does not occur at the centre of the molecule, so that one molecule of β-carotene also gives only one molecule of vitamin A.
Vitamin A has several roles. It influences the growth of the animal and protects epithelial tissues. A derivative of vitamin A, retinoic acid (see fig. 5-8) is a modulator of cellular growth.
Its role in the protection of epitheliums seems to be correlated with the fact that retinol derivatives (retinol pyrophos-phoryl monosaccharide) are, like dolichols, important intermediates in the synthesis of some glycoproteins. Its best known role is that of a co-factor in the process of vision: vitamin A binds opsin, a protein of the retina, to give the visual pigment called rhodopsin.
Isoprenic Chain Quinones:
We are also listing under this heading, substances which can readily give quinones (tocopherols or vitamins E). All the substances examined in this paragraph can undergo the reversible transformation quinone <==> hydro- quinone. In two of them (ubiquinone and plastoquinon) this transformation appears to be the basis of their biological activity, but in others (vitamins E and K) it is not yet known whether this transformation has any relation with their physiological action.
A. Vitamin E:
These are compounds which can be transformed into hydroquinones by hydrolytic cleavage and oxidized – reversibly — to quinones; this enables them to act as antioxidants and to prevent, in particular, the oxidation of unsaturated fatty acids. Some tocopherols having very similar structures are known. Figure 5-9 shows α-tocopherol, its hydration product α-tocopherylhydroquinone, and the oxidation product of this hydroquinone α-tocopherylquinone (or in short, tocoquinone).
Besides its role as biological antioxidant, vitamin E has other functions. Vitamin E deficiency causes a series of disorders which are often specific for each type of animal: sterility in the rat, neurological disorders in the chicken, etc.
B. Ubiquinones and Plastoquinones:
As indicated by their name, ubiquinones are universally distributed; they are particularly found in animal and plant mitochondria where, as mentioned above, they play an important role in the electron transport chain. One of the most frequent is ubiquinone50 or coenzyme Q10 (50 carbon atoms, i.e. 10 isoprene units, in the side chain), the structure of which is shown in figure 5-9.
Plastoquinone has a very similar structure (fig. 5-9) and participates in electron transport in chloroplasts.
C. Vitamin K:
As may be observed in figure 5-9, the structure of vitamin K1 or phyllo-quinone is also very similar; it is a naphtoquinone with a chain of 4 isoprene units called phytyl residue, grafted on it. Phylloquinone is present in plants where it plays a role of electron acceptor in processes related to photosynthesis.
Menaquinones, or vitamins K2, differ from vitamin Ki by the number of isoprene units of the side chain (there may be up to 10 units), and the number of double bonds present in this chain. They are found in bacteria. Vitamin K2 is the active form of vitamin K in mammals (phylloquinone is converted into menaquinone in the liver).
Vitamin K is also the coenzyme of an enzyme catalyzing the carboxylation of glutamic residues of proteins. The carboxylation is for crumple, necessary for the activation of a serum factor permitting the synthesis of prothrombin, a substance indispensable for blood-clotting. This explains the anti-hemorragic action of vitamin K.
This last paragraph devoted to isoprenic chain quinones (and substances readily leading to such quinones), included vitamins E and K. On the contrary, ubiquinone is not a vitamin for mammals: the organism can synthesize the ring from tyrosine; as for the side chain, it results from the condensation of C5 units which are intermediate in the synthesis of cholesterol (see fig. 5-22).
In this study of isoprenic lipids we followed a classification based on the structural characteristics of various compounds and we thus found vitamins among the derivatives of steroids (D), carotenoids (A) and among isoprenic chain quinones (E and K), but we must bear in mind that these vitamins are often grouped under the name liposoluble vitamins.
