Chapter 10: Lipids

Sphingolipids at Cell Surfaces Are Sites of Biological Recognition

.In humans, at least 60 different sphingolipids have been identified in cellular membranes. Many of these are especially prominent in the plasma membranes of neurons, and some are clearly recognition sites on the cell surface, but a specific function for only a few sphingolipids has been discovered thus far. The carbohydrate moieties of certain sphingolipids define the human blood groups and therefore determine the type of blood that individuals can safely receive in blood transfusions

Five general types of membrane lipids:

1. Glycerophospholipids, in which the hydrophobic regions are composed of two fatty acids joined to glycerol 2. Galactolipids and 3. sulfolipids, which also contain two fatty acids esterified to glycerol, but lack the characteristic phosphate of phospholipids 4. archaeal tetraether lipids, in which two very long alkyl chains are ether-linked to glycerol at both ends; 5. sphingolipids, in which a single fatty acid is joined to a fatty amine, sphingosine; and sterols, compounds characterized by a rigid system of four fused hydrocarbon rings.

polyunsaturated fatty acids (PUFAs)

A fatty acid with more than one double bond, generally nonconjugated. With a double bond between the third and fourth carbon from the methyl end of the chain are of special importance in human nutrition. Because the physiological role of PUFAs is related more to the position of the first double bond near the methyl end of the chain than to that near the carboxyl end, an alternative nomenclature is sometimes used for these fatty acids. The carbon of the methyl group—that is, the carbon most distant from the carboxyl group—is called the ω (omega; the last letter in the Greek alphabet) carbon and is given the number 1 (C-1); the carboxyl carbon in this convention has the highest number. The positions of the double bonds are indicated relative to the ωcarbon.

Glycolipids

A lipid containing a carbohydrate group. Other sphingolipids lack phosphate but have a simple sugar or complex oligosaccharide at their polar ends; these are the glycolipids.

Phospholipids

A lipid containing one or more phosphate groups. The hydrophilic moieties in these amphipathic compounds may be as simple as a single —OH group at one end of the sterol ring system, or they may be much more complex. In glycerophospholipids and some sphingolipids, a polar head group is joined to the hydrophobic moiety by a phosphodiester linkage; these are the phospholipids.

Sterols Have Four Fused Carbon Rings

A lipid containing the steroid nucleus.Sterols are structural lipids present in the membranes of most eukaryotic cells. The characteristic structure of this fifth group of membrane lipids is the steroid nucleus,consisting of four fused rings, three with six carbons and one with five. The steroid nucleus is almost planar and is relatively rigid; the fused rings do not allow rotation about C—C bonds.

Fatty acids in fats and oils (not nec. lipids)

A long-chain aliphatic carboxylic acid in natural fats and oils

Fatty acids

A long-chain aliphatic carboxylic acid in natural fats and oils; also a component of membrane phospholipids and glycolipids.

Plasmalogens

A phospholipid with an alkenyl ether substituent on C-1 of glycerol. Plasmalogens have an ether-linked alkenyl chain where most glycerophospholipids have an ester-linked fatty acid At least one ether lipid, platelet-activating factor, is a potent molecular signal. It is released from leukocytes called basophils and stimulates platelet aggregation and the release of serotonin (a vasoconstrictor) from platelets.

Gangliosides

A sphingolipid containing a complex oligosaccharide as a head group; especially common in nervous tissue.

Some common types of storage and membrane lipids

All the lipid types shown here have either glycerol or sphingosine as the backbone, to which are attached one or more long-chain alkyl groups and a polar head group. In triacylglycerols, glycerophospholipids, galactolipids, and sulfolipids, the alkyl groups are fatty acids in ester linkage. Sphingolipids contain a single fatty acid, in amide linkage to the sphingosine backbone. The membrane lipids of archaea are variable; that shown here has two very long, branched alkyl chains, each end in ether linkage with a glycerol moiety. In phospholipids, the polar head group is joined through a phosphodiester, whereas glycolipids have a direct glycosidic linkage between the head-group sugar and the backbone glycerol.

Glycosphingolipids,

An amphipathic lipid with a sphingosine backbone to which are attached a long-chain fatty acid and a polar alcohol.

Sphingolipids

An amphipathic lipid with a sphingosine backbone to which are attached a long-chain fatty acid and a polar alcohol.

Vitamins

An organic substance required in small quantities in the diet of some species; generally functions as a component of a coenzyme.

2. Thromboxanes (TX

Any of a class of eicosanoid lipids with a six-membered ether-containing ring; involved in platelet aggregation during blood clotting.

3. Leukotrienes (LT)

Any of a class of noncyclic eicosanoid signaling lipids with three conjugated double bonds; they mediate inflammatory responses, including smooth muscle activity.

Waxes Serve as Energy Stores and Water Repellents

Biological waxes are esters of long-chain (C14 to C36) saturated and unsaturated fatty acids with long-chain (C16 to C30) alcohols (Fig. 10-5). Their melting points (60 to 100 °C) are generally higher than those of triacylglycerols.

Cholesterol

Cholesterol, the major sterol in animal tissues, is amphipathic, with a polar head group (the hydroxyl group at C-3) and a nonpolar hydrocarbon body (the steroid nucleus and the hydrocarbon side chain at C-17), about as long as a 16-carbon fatty acid in its extended form.

Many Natural Pigments Are Lipidic Conjugated Dienes

Conjugated dienes have carbon chains with alternating single and double bonds. Because this structural arrangement allows the delocalization of electrons, the compounds can be excited by low-energy electromagnetic radiation (visible light), giving them colors visible to humans and other animals.

Dolichols Activate Sugar Precursors for Biosynthesis

During assembly of the complex carbohydrates of bacterial cell walls, and during the addition of polysaccharide units to certain proteins (glycoproteins) and lipids (glycolipids) in eukaryotes, the sugar units to be added are chemically activated by attachment to isoprenoid alcohols called dolichols

Eicosanoids Carry Messages to Nearby Cells

Eicosanoids are paracrine hormones, substances that act only on cells near the point of hormone synthesis instead of being transported in the blood to act on cells in other tissues or organs. These fatty acid derivatives have a variety of dramatic effects on vertebrate tissues.

Storage Lipids

Fats and oils are common storage lipids. The fats and oils used almost universally as stored forms of energy in living organisms are derivatives of fatty acids.

Fatty Acids Are Hydrocarbon Derivatives

Fatty acids are carboxylic acids with hydrocarbon chains ranging from 4 to 36 carbons long (C4 to C36). In some fatty acids, this chain is unbranched and fully saturated (contains no double bonds); in others, the chain contains one or more double bonds. A few contain three-carbon rings, hydroxyl groups, or methyl-group branches.

Melting points are also strongly influenced by the length and degree of unsaturation of the hydrocarbon chain.

In the fully saturated compounds, free rotation around each carbon-carbon bond gives the hydrocarbon chain great flexibility; the most stable conformation is the fully extended form, in which the steric hindrance of neighboring atoms is minimized. These molecules can pack together tightly in nearly crystalline arrays, with atoms all along their lengths in van der Waals contact with the atoms of neighboring molecules. In unsaturated fatty acids, a cis double bond forces a kink in the hydrocarbon chain. Fatty acids with one or several such kinks cannot pack together as tightly as fully saturated fatty acids, and their interactions with each other are therefore weaker. Because less thermal energy is needed to disorder these poorly ordered arrays of unsaturated fatty acids, they have markedly lower melting points than saturated fatty acids of the same chain length

Triacylglycerols Provide Stored Energy and Insulation

In vertebrates, specialized cells called adipocytes, or fat cells, store large amounts of triacylglycerols as fat droplets that nearly fill the cell (Fig. 10-3a). Triacylglycerols are also stored as oils in the seeds of many types of plants, providing energy and biosynthetic precursors during seed germination. Adipocytes and germinating seeds contain lipases, enzymes that catalyze the hydrolysis of stored triacylglycerols, releasing fatty acids for export to sites where they are required as fuel.

Lipids

Lipids are water-insoluble cellular components, of diverse structure, that can be extracted from tissues by nonpolar solvents.

Structural Lipids in Membranes

Membrane lipids are amphipathic: one end of the molecule is hydrophobic, the other hydrophilic. Their hydrophobic interactions with each other and their hydrophilic interactions with water direct their packing into sheets called membrane bilayers.

Phospholipids and Sphingolipids Are Degraded in Lysosomes

Most cells continually degrade and replace their membrane lipids. For each hydrolyzable bond in a glycerophospholipid, there is a specific hydrolytic enzyme in the lysosome (Fig. 10-15). Phospholipases of the A type remove one of the two fatty acids, producing a lysophospholipid. (These esterases do not attack the ether link of plasmalogens.) Lysophospholipases remove the remaining fatty acid. Gangliosides are degraded by a set of lysosomal enzymes that catalyze the stepwise removal of sugar units, finally yielding a ceramide. A genetic defect in any of these hydrolytic enzymes leads to the accumulation of gangliosides in the cell, with severe medical consequences

Partial Hydrogenation of Cooking Oils Improves Their Stability but Creates Fatty Acids with Harmful Health Effects

Most natural fats, such as those in vegetable oils, dairy products, and animal fat, are complex mixtures of simple and mixed triacylglycerols. These contain a variety of fatty acids differing in chain length and degree of saturation (Fig. 10-4). Vegetable oils such as corn (maize) oil and olive oil are composed largely of triacylglycerols with unsaturated fatty acids and thus are liquids at room temperature. Triacylglycerols containing only saturated fatty acids, such as tristearin, the major component of beef fat, are white, greasy solids at room temperature. When lipid-rich foods are exposed too long to the oxygen in air, they may spoil and become rancid.Partial hydrogenation, however, has another, undesirable, effect: some cis double bonds are converted to trans double bonds. There is now strong evidence that dietary intake of trans fatty acids (often referred to simply as "trans fats") leads to a higher incidence of cardiovascular disease, and that avoiding these fats in the diet substantially reduces the risk of coronary heart disease.

4. Lipoxins (LX)

One of a class of hydroxylated linear derivatives of arachidonate that act as potent antiinflammatory agents.

1. Prostaglandins

One of a class of polyunsaturated, cyclic eicosanoid lipids that act as paracrine hormones.

Phosphatidylinositols and Sphingosine Derivatives Act as Intracellular Signals

Phosphatidylinositol and its phosphorylated derivatives act at several levels to regulate cell structure and metabolism. Inositol phospholipids also serve as points of nucleation for supramolecular complexes involved in signaling or in exocytosis Membrane sphingolipids also can serve as sources of intracellular messengers. Both ceramide and sphingomyelin are potent regulators of protein kinases, and ceramide or its derivatives are involved in the regulation of cell division, differentiation, migration, and programmed cell death

Vascular Plants Produce Thousands of Volatile Signals

Plants produce thousands of different lipophilic compounds, volatile substances that are used to attract pollinators, to repel herbivores, to attract organisms that defend the plant against herbivores, and to communicate with other plants.

Polyketides Are Natural Products with Potent Biological Activities

Polyketides are a diverse group of lipids with biosynthetic pathways (Claisen condensations) similar to those for fatty acids. They are secondarymetabolites, compounds that are not central to an organism's metabolism but serve some subsidiary function that gives the organism an advantage in some ecological niche. Many polyketides find use in medicine as antibiotics (erythromycin), antifungals (amphotericin B), or inhibitors of cholesterol synthesis (lovastatin)

10.4 Working with Lipids

SUMMARY 10.4 Working with Lipids ■ In the determination of lipid composition, the lipids are first extracted from tissues with organic solvents and separated by thin-layer, gas, or high-performance liquid chromatography. ■ Phospholipases specific for one of the bonds in a phospholipid can be used to generate simpler compounds for subsequent analysis. ■ Individual lipids are identified by their chromatographic behavior, their susceptibility to hydrolysis by specific enzymes, or mass spectrometry. ■ High-resolution mass spectrometry allows the analysis of crude mixtures of lipids without prefractionation—the "shotgun" approach. ■ Lipidomics combines powerful analytical techniques to determine the full complement of lipids in a cell or tissue (the lipidome) and to assemble annotated databases that allow comparisons between lipids of different cell types and under different conditions.

Some Glycerophospholipids Have Ether-Linked Fatty Acids

Some animal tissues and some unicellular organisms are rich in ether lipids, in which one of the two acyl chains is attached to glycerol in ether, rather than ester, linkage.The ether-linked chain may be saturated, as in the alkyl ether lipids, or may contain a double bond between C-1 and C-2, as in plasmalogens.

Archaea Contain Unique Membrane Lipids

Some archaea that live in ecological niches with extreme conditions—high temperatures (boiling water), low pH, high ionic strength, for example—have membrane lipids containing long-chain (32 carbons) branched hydrocarbons linked at each end to glycerol (Fig. 10-11). These linkages are through ether bonds, which are much more stable to hydrolysis at low pH and high temperature than are the ester bonds found in the lipids of bacteria and eukaryotes. In their fully extended form, these archaeal lipids are twice the length of phospholipids and sphingolipids, and can span the full width of the plasma membrane. At each end of the extended molecule is a polar head consisting of glycerol linked to either phosphate or sugar residues. The general name for these compounds, glycerol dialkyl glycerol tetraethers (GDGTs), reflects their unique structure.

Lipids as Signals, Cofactors, and Pigments

Some types of lipids, although present in relatively small quantities, play critical roles as cofactors or signals 1. Signals 2. Enzyme cofactors 3. Pigment molecules that absorb light 4. In plants (signaling mol.)

Sphingolipids Are Derivatives of Sphingosine

Sphingolipids, the fourth large class of membrane lipids, also have a polar head group and two nonpolar tails, but unlike glycerophospholipids and galactolipids they contain no glycerol. Sphingolipids are composed of one molecule of the long-chain amino alcohol sphingosine (also called 4-sphingenine) or one of its derivatives, one molecule of a long-chain fatty acid, and a polar head group that is joined by a glycosidic linkage in some cases and a phosphodiester in others

Steroid Hormones Carry Messages between Tissues

Steroids are oxidized derivatives of sterols; they have the sterol nucleus but lack the alkyl chain attached to ring D of cholesterol, and they are more polar than cholesterol. Steroid hormones move through the bloodstream (on protein carriers) from their site of production to target tissues, where they enter cells, bind to highly specific receptor proteins in the nucleus, and trigger changes in gene expression and thus metabolism.

Two main kinds of lipids

Storage and Membrane Lipids

Unsaturated

The double bonds of polyunsaturated fatty acids are almost never conjugated (alternating single and double bonds, as in —CH=CH—CH=CH—), but are separated by a methylene group: —CH=CH—CH2—CH=CH—. In nearly all naturally occurring unsaturated fatty acids, the double bonds are in the cis configuration.

Glycosphingolipids as determinants of blood groups

The human blood groups (O, A, B) are determined in part by the oligosaccharide head groups of these glycosphingolipids. The same three oligosaccharides are also found attached to certain blood proteins of individuals of blood types O, A, and B, respectively.

The physical properties of the fatty acids, and of compounds that contain them, are largely determined by the length and degree of unsaturation of the hydrocarbon chain.

The nonpolar hydrocarbon chain accounts for the poor solubility of fatty acids in water. The longer the fatty acyl chain and the fewer the double bonds, the lower is the solubility in water. The carboxylic acid group is polar (and ionized at neutral pH) and accounts for the slight solubility of short-chain fatty acids in water.

Triacylglycerols Are Fatty Acid Esters of Glycerol

The simplest lipids constructed from fatty acids are the triacylglycerols, also referred to as triglycerides, fats, or neutral fats.

Triacylglycerols

The simplest lipids constructed from fatty acids are the triacylglycerols, also referred to as triglycerides, fats, or neutral fats. An ester of glycerol with three molecules of fatty acid; also called a triglyceride or neutral fat. Triacylglycerols are composed of three fatty acids, each in ester linkage with a single glycerol. Most naturally occurring triacylglycerols are mixed; they contain two or three different fatty acids Because the polar hydroxyls of glycerol and the polar carboxylates of the fatty acids are bound in ester linkages, triacylglycerols are nonpolar, hydrophobic molecules, essentially insoluble in water

Three sub classes of sphingolipids

There are three subclasses of sphingolipids, all derivatives of ceramide but differing in their head groups: sphingomyelins, neutral (uncharged) glycolipids, and gangliosides

Vitamins E and K and the Lipid Quinones Are Oxidation-Reduction Cofactors

Vitamin E is the collective name for a group of closely related lipids called tocopherols, all of which contain a substituted aromatic ring and a long isoprenoid side chain (Fig. 10-22a). Because they are hydrophobic, tocopherols associate with cell membranes, lipid deposits, and lipoproteins in the blood. Tocopherols are biological antioxidants. The aromatic ring reacts with and destroys the most reactive forms of oxygen radicals and other free radicals, protecting unsaturated fatty acids from oxidation and preventing oxidative damage to membrane lipids, which can cause cell fragility. Tocopherols are found in eggs and vegetable oils and are especially abundant in wheat germ. Laboratory animals fed diets depleted of vitamin E develop scaly skin, muscular weakness and wasting, and sterility. Vitamin E deficiency in humans is very rare; the principal symptom is fragile erythrocyte

Glycerophospholipids Are Derivatives of Phosphatidic Acid

also called phosphoglycerides, are membrane lipids in which two fatty acids are attached in ester linkage to the first and second carbons of glycerol, and a highly polar or charged group is attached through a phosphodiester linkage to the third carbon. An amphipathic lipid with a glycerol backbone; fatty acids are ester-linked to C-1 and C-2 of the glycerol, and a polar alcohol is attached through a phosphodiester linkage to C-3. Glycerol is prochiral; it has no asymmetric carbons, but attachment of phosphate at one end converts it into a chiral compound The fatty acids in glycerophospholipids can be any of a wide variety, so a given phospholipid (phosphatidylcholine, for example) may consist of several molecular species, each with its unique complement of fatty acids.

Sphingomyelins

contain phosphocholine or phosphoethanolamine as their polar head group and are therefore classified along with glycerophospholipids as phospholipids no net charge on their head groups

free fatty acids vs not free

free fatty acids (unesterified fatty acids, with a free carboxylate group) circulate in the blood bound noncovalently to a protein carrier, serum albumin. However, fatty acids are present in blood plasma mostly as carboxylic acid derivatives such as esters or amides. Lacking the charged carboxylate group, these fatty acid derivatives are generally even less soluble in water than are the free fatty acids.

Chloroplasts Contain Galactolipids and Sulfolipids

he second group of membrane lipids includes those that predominate in plant cells: the galactolipids, in which one or two galactose residues are connected by a glycosidic linkage to C-3 of a 1,2-diacylglycerol Plant membranes also contain sulfolipids, in which a sulfonated glucose residue is joined to a diacylglycerol in glycosidic linkage. The sulfonate group bears a negative charge like that of the phosphate group in phospholipids.

The cellular oxidation of fatty acids (to CO2 and H2O)

is highly exergonic.

There are two significant advantages to using triacylglycerols as stored fuels,

the carbon atoms of fatty acids are more reduced than those of sugars, so oxidation of triacylglycerols yields more than twice as much energy, gram for gram, as the oxidation of carbohydrates. Second, because triacylglycerols are hydrophobic and therefore unhydrated, the organism that carries stored fuel in the form of fat does not have to carry the extra weight of water of hydration that is associated with stored polysaccharides In some animals, triacylglycerols stored under the skin serve not only as energy stores but as insulation against low temperatures

simplified nomenclature for unbranched fatty acids

the chain length and number of double bonds, separated by a colon. For example, the 16-carbon saturated palmitic acid is abbreviated 16:0, and the 18-carbon oleic (octadecenoic) acid, with one double bond is 18:1. Each line segment of the zigzag in the structure represents a single bond between adjacent carbons. The carboxyl carbon is assigned the number 1 (C-1), and the carbon next to it is C-2. The positions of any double bonds, designated Δ (delta), are specified relative to C-1 by a superscript number indicating the lower-numbered carbon in the double bond.

In addition to their roles as membrane constituents:

the sterols serve as precursors for a variety of products with specific biological activities. Steroid hormones, for example, are potent biological signals that regulate gene expression. Bile acids are polar derivatives of cholesterol that act as detergents in the intestine, emulsifying dietary fats to make them more readily accessible to digestive lipases.

SUMMARY 10.1 Storage Lipids

■ Lipids are water-insoluble cellular components, of diverse structure, that can be extracted from tissues by nonpolar solvents. ■ Almost all fatty acids, the hydrocarbon components of many lipids, have an even number of carbon atoms (usually 12 to 24); they are either saturated or unsaturated, with double bonds almost always in the cis configuration. ■ Triacylglycerols contain three fatty acid molecules esterified to the three hydroxyl groups of glycerol. Simple triacylglycerols contain only one type of fatty acid; mixed triacylglycerols, two or three types. Triacylglycerols are primarily storage fats; they are present in many foods. ■ Because trans fatty acids in the diet are an important risk factor for coronary heart disease, their use in prepared and processed foods has become highly regulated. ■ Waxes are esters of long-chain fatty acids and long-chain alcohols.

SUMMARY 10.3 Lipids as Signals, Cofactors, and Pigments

■ Some types of lipids, although present in relatively small quantities, play critical roles as cofactors or signals. ■ Phosphatidylinositol bisphosphate is hydrolyzed to yield two intracellular messengers, diacylglycerol and inositol 1,4,5-trisphosphate. Phosphatidylinositol 3,4,5-trisphosphate is a nucleation point for supramolecular protein complexes involved in biological signaling. ■ Prostaglandins, thromboxanes, leukotrienes, and lipoxins, all of which are eicosanoids derived from arachidonate, are extremely potent hormones. ■ Steroid hormones, such as the sex hormones, are derived from sterols. They serve as powerful biological signals, altering gene expression in target cells. ■ Vitamins D, A, E, and K are fat-soluble compounds made up of isoprene units. All play essential roles in the metabolism or physiology of animals. Vitamin D is precursor to a hormone that regulates calcium metabolism. Vitamin A furnishes the visual pigment of the vertebrate eye and is a regulator of gene expression during epithelial cell growth. Vitamin E functions in the protection of membrane lipids from oxidative damage, and vitamin K is essential in the blood-clotting process. ■ Ubiquinones and plastoquinones, also isoprenoid derivatives, are electron carriers in mitochondria and chloroplasts, respectively. ■ Dolichols activate and anchor sugars to cellular membranes; the sugar groups are then used in the synthesis of complex carbohydrates, glycolipids, and glycoproteins. ■ Lipidic conjugated dienes serve as pigments in flowers and fruits and give bird feathers their striking colors. ■ Polyketides are natural products widely used in medicine.

SUMMARY 10.2 Structural Lipids in Membranes

■ The polar lipids, with polar heads and nonpolar tails, are major components of membranes. The most abundant are the glycerophospholipids, which contain fatty acids esterified to two of the hydroxyl groups of glycerol, and a second alcohol, the head group, esterified to the third hydroxyl of glycerol via a phosphodiester bond. Other polar lipids are the sterols. ■ Glycerophospholipids differ in the structure of their head group; common glycerophospholipids are phosphatidylethanolamine and phosphatidylcholine. The polar heads of the glycerophospholipids are charged at pH near 7. ■ Chloroplast membranes are rich in galactolipids, composed of a diacylglycerol with one or two linked galactose residues, and sulfolipids, diacylglycerols with a linked sulfonated sugar residue and thus a negatively charged head group. ■ Some archaea have unique membrane lipids, with long-chain alkyl groups ether-linked to glycerol at each end and with sugar residues and/or phosphate joined to the glycerol to provide a polar or charged head group. These lipids are stable under the harsh conditions in which these archaea live. ■ The sphingolipids contain sphingosine, a long-chain aliphatic amino alcohol, but no glycerol. Sphingomyelin has, in addition to phosphoric acid and choline, two long hydrocarbon chains, one contributed by a fatty acid and the other by sphingosine. Three other classes of sphingolipids are cerebrosides, globosides, and gangliosides, which contain sugar components. ■ Sterols have four fused rings and a hydroxyl group. Cholesterol, the major sterol in animals, is both a structural component of membranes and precursor to a wide variety of steroids.