Phosphatidyl Amine

Inositol Moiety

Figure 3-5. Line models of some phospholipids. If R = hydrogen, the compound is the phosphatidic acid as indicated. If the polar moieties shown below are substituted at R, the compound is the corresponding phosphatidyl-R (i.e., if R is choline, the compound is phosphatidylcholine).

When one of the acyl groups of a glycer-olphospholipid is removed, a phospholipid with a single hydrocarbon chain is formed; this is called a "lyso" compound. Lysophos-pholipids are detergents because of their strong water-soluble head group and their lipid-soluble hydrocarbon chain. A rare genetic deficiency of the enzyme lecithin:cho-lesterol acyltransferase (LCAT), which transfers the fatty acid on the sn-2 position of lecithin (PC) to cholesterol to form a cholesterol ester and lysolecithin, has been described. Deficiency of this enzyme results in accumulation of lecithin (PC) and free cholesterol in plasma lipoproteins. Most phospholipids are part of the main structure of membranes but some, such as PS and PI, may have more specific functions. PS seems to be a marker for apoptotic cells, and PI plays a role in generating two second messengers, inositol triphosphate (IP3) and diacylglycerol, at the membrane surface. Glucosyl phosphatidylino-sitols are a recently described class of lipid moieties that are attached to certain proteins (Englund, 1993) and act as membrane anchors for the protein (e.g., alkaline phosphatase). Such proteins may be released from the membranes by phospholipase C, which hydrolyzes the PI, leaving diacylglycerol in the membrane.

Sphingolipids

Sphingolipids (Bell et al., 1993) are formed by the addition of fatty acids to the base sphingosine. Ceramide is formed when a fatty acid is linked to sphingosine through an amide bond at the 2 position. Substituted cera-mides are important constituents of skin lipids (Elias, 1991). (See Chapter 15 for the role of essential fatty acid in skin ceramides.) Elevated ceramide concentrations have been found in a disorder characterized by the inability of lysosomes to catabolize ceramide, known as Farber's disease. When ceramide is esterified with phosphocholine, sphingomyelin is formed. When sphingomyelin catabolic enzymes are absent, sphingomyelins accumulate in tissue, giving rise to Niemann-Pick disease.

Sphingosine can react with sugars to form psychosine, in which a monosaccharide is linked to the 1 carbon of sphingosine. When a monosaccharide is linked to the one position of a ceramide, a cerebroside such as galactocerebroside is formed (Fig. 3-6). Different sugars may be added to form a variety of neutral glycosphingolipids. Complex-charged glycocerebrosides, called gangliosides, are formed when sialic acid (negatively charged) is added to the sugars. Gangliosides in low

Sphingosine

Sphingosine

Phosphatidyl Amine Dag

Galactose

Galactocerebroside

Figure 3-6. Line model of a cerebroside. Sphingosine is d-erythro-2-amino-4-octadecene-1,3-diol. The ceramide shown is 2-stearoyl sphingosine, and the galactocerebroside is 1-galactosyl ceramide. The fatty acid is attached to sphingosine through an amide bond.

Galactose

Galactocerebroside

Figure 3-6. Line model of a cerebroside. Sphingosine is d-erythro-2-amino-4-octadecene-1,3-diol. The ceramide shown is 2-stearoyl sphingosine, and the galactocerebroside is 1-galactosyl ceramide. The fatty acid is attached to sphingosine through an amide bond.

concentration are firmly anchored to; the outer surfaces of many plasma membranes and appear to act as both antigens and receptors for certain toxins, antibodies, and lectins. Specific enzymes are necessary for the catab-olism of each of these glycolipids; when an enzyme is either absent or defective, the non-metabolized glycolipid molecule accumulates, resulting in a lipid storage disease.

Sphingolipid precursors or breakdown products such as sphingosine and ceramide may have important roles as cellular second messengers (Hannun, 1996). Sphingomyelin may also have a role in the intracellular movement of cholesterol.

Steroids

Steroids (Gunstone et al., 1994; Hamilton, 1995) are defined as "all those substances that are structurally related to the sterols and bile acids to the extent of possessing the characteristic perhydro-1,2-cyclopentano-phenanthrene ring system." This polycyclic structure, consisting of four linked rings, is illustrated in the structure of cholesterol (Fig. 3-7), a molecule that may modulate membrane fluidity, permeability fusibility, and thickness. Although cholesterol appears in low amounts in some primitive animals such as sponges, it is the predominant sterol in higher animals. Steroid hormones (i.e., testosterone, androgens, estrogens, progesterones, Cortisol, cortisone, aldosterone, and vitamin D hormone) are formed from cholesterol. These molecules exert major effects in regulating metabolism in higher ani mals. Plant sterols are present in vegetable oils. Normally, plant sterols are not absorbed by the intestine of humans, as discussed in Chapter 7. However, a rare genetic condition that permits their absorption leads to p-sito-sterolemia, a disease in which large amounts of plant sterols are deposited in the body tissues. More complex molecules with a steroid nucleus, such as digitalis, are also found in plants. Digitalis is a strong stimulant for heart contractions and has been used for centuries to combat heart failure.

Cholesteryl esters are formed from fatty acids and cholesterol. These interesting molecules are often stored in organs, such as the adrenal gland and the corpus luteum of the ovary where they serve as precursors for steroidal hormones. They also accumulate in certain disorders (e.g., cholesteryl ester storage disease, atherosclerosis, familial hypercholesterolemia, and Tangier disease). Cholesteryl esters form liquid crystals, which have been identified by polarizing microscopy in living tissues (Small, 1988; Waugh and Small, 1984).

Cholesteryl Ester

Cholest-5-en-3(3-ol (Cholesterol)

Figure 3-7. Line drawing of cholesterol (cholest-5-en-3/3-oD.

Cholest-5-en-3(3-ol (Cholesterol)

Figure 3-7. Line drawing of cholesterol (cholest-5-en-3/3-oD.

Bile acids (Nair and Kritchesky 1971; Ca-bral and Small, 1989) are formed by degrading the terminal side chain of cholesterol from 27 carbon atoms to 24 carbon atoms and by adding hydroxyl (-OH) groups to various positions in the ring. Thus, bile acids such as cholic and chenodeoxycholic acids are formed (Fig. 3-8). The alkali metal salts of hydroxylated bile acids conjugated with taurine or glycine are natural detergents synthesized in the liver and secreted into bile. They solubilize phospholipid and cholesterol in the bile of higher animals, thus permitting secretion of cholesterol into the gut. The excretion of both cholesterol and bile acids is the major way cholesterol is removed from the body

Bile salts also aid in the digestion and absorption of fat and fat-soluble vitamins in the intestine (Carey et al., 1983). Bile salt deficiency caused by intestinal pathology [e.g., mutant ileal bile acid transporter (Oelk-ers et al, 1997), celiac disease, tropical sprue, bacterial overgrowth, or ileal resection] can cause fat malabsorption and malnutrition. This problem is especially serious in children, in whom growth may be impaired. Bile acid deficiency may also lead to cholesterol gallstone formation, because bile salt is required for cholesterol solubilization in bile. Abnormal bile acid metabolism is associated with accumulation of cholestanol (the saturated analog of cholesterol) in the disease cerebro-tendinous xanthomatosis.

Other Lipids

Eicosanoids are oxygenated fatty acids principally derived from the 20-carbon fatty acids, arachidonic acid, eicosatrienoic acid, and ei-cosapentaenoic acid (see Table 3-2). These oxygenated derivatives are present in low concentration, are chemically unstable, have a very short lifetime, and act as autocoids to influence contractility, membrane permeability, and many other cellular functions.

Acyl coenzyme A and acylcarnitine are key intermediates in fatty acid metabolism; they are usually present in low concentrations, but under certain conditions they may accumulate and disrupt cellular functions. Cytidine diphosphate-diacylglycerol (CDP-DAG) is an intermediate in phospholipid synthesis and probably partitions into membranes.

Lipopolysaccharides (endotoxin) are a large class of bacterial glycolipids, present in the outer leaf of the outer membrane of gram-negative organisms, that are complex in nature and may act in higher animals as toxins,

Bile Acid

ri

r2

r3

Lithodeoxycholic

aOH

H

H

Deoxycholic

cxOH

H

aOH

Chenodeoxycholic

aOH

aOH

H

Ursodeoxycholic

aOH

POH

H

Cholic

aOH

aOH

aOH

Ursocholic

aOH

POH

otOH

Chenodeoxycholic Acid Synthesis

Figure 3-8. Molecular structure of common bile acids, showing the common steroid ring and side chain structure. The location and orientation of hydroxyl group(s) are given for each bile acid.

activators of phagocytic cells, transforming factors, and mutagens.

THE GENERAL PROPERTIES OF LIPIDS

The physical properties of lipids (see Small, 1986, for in-depth review), coupled with the reactivity of their substituent groups, determine the biological properties of lipids. The aliphatic hydrocarbon chain is an important constituent of many lipid molecules. A knowledge of the properties of the hydrocarbon chain is fundamental to understanding the behavior of any given lipid class, because there are striking similarities between chain packing in normal alkanes and chain packing in more complex aliphatic lipids. Most lipids, because of their hydrocarbon chains, are elongated molecules that align along their long axis and pack in layers more or less perpendicular to their molecular axis. X-ray diffraction has been extensively used to study the structure of the hydrocarbon chain, the packing between chains, and the crystalline and liquid crystalline packing of lipid molecules. The hydrocarbon chain, in its rigid, most stable crystalline state, forms a zigzag, a\\-trans arrangement from carbon to carbon (Fig. 3-9). The distance between carbons is about 1.533 A, similar to the carbon-carbon distance in the diamond. The carbon-carbon bond angle slightly varies but approximates

112°. Thus, the distance between every other carbon atom is 2.54 A, and the increment along the chaiin for each carbon atom is 1.27 A.

Packing of Lipids in the Solid State

Crystalline hydrocarbons and the hydrocarbon chains of more complex lipids pack into two distinct classes of subcells. The first class is characterized by dense, tightly packed chains in which there is specific chain-chain interaction. In the second class, the chains are more loosely packed, and specific chain-chain interaction is weakened because of partial rotation of the chain and/or of its methylene (~CH2-) groups. The tightly packed class includes lipids packed in orthorhombic, tri-clinic, or monoclinic subcells, which are important in such food products as chocolate but probably do not occur in vivo. The second class, with more loosely packed chains aligned hexagonally, may occur as microdo-mains in membrane subcells and may occasionally be present in pathological deposits in living organisms (Edidin, 1997).

The Liquid Crystalline State of Lipids

In nature, lipid aggregates are not usually crystalline but rather are found as liquid crystallike arrays. The liquid crystal state (Small, 1986) is the fourth state of matter (the others

Figure 3-9. Line and space-filling models of the hydrocarbon chain in its most stable zigzag, all-trans conformation. Carbon-carbon distances and bond angles are given. Projections down the chain are shown on the right. The space-filling models show the outlines of the minimal van der Waals radii, i.e., they show the shape of the chain. Carbon atoms are black and hydrogen atoms are white. Projections down the chain show the lumps and grooves formed by the chain and that the chain is a little wider in the direction vertical to the page than in that horizontal to the page. (Modified from Small, D. M. 11986] The Physical Chemistry of Lipids from Alkanes to Phospholipids. Handbook of Lipid Research, vol. 4. Plenum Press, New York.)

c h2

c h2

Longitudinal Section

"A

Space-filling Model

Projection Down Long Axis

Line Model

Space-filling Model

Longitudinal Section

Projection Down Long Axis being gas, liquid, and solid), and it has properties of both crystals and liquids. This intermediate state combines both order and fluidity and thus is particularly suited to cellular function, especially the formation of membranes and other ordered structures such as retinal rods and cones, myelin, and chloro-plasts. At least four factors can induce liquid crystalline formation in a particular lipid: temperature, pressure, magnetic field, and electrostatic field. Furthermore, certain molecules may be induced to form liquid crystals by the addition of water.

Many biological lipids form liquid crystals. For instance, when heated, cholesteryl esters, phospholipids, soaps (Na or K salts of long-chain fatty acids, e.g., K+-stearate), and glycosphingolipids transform from crystals to liquid crystals. Hydration causes most phospholipids, monoacylglycerols, sphingosine, and glycosphingolipids to form hydrated liquid crystals at body temperature, and thus liquid crystals are the predominant state of these lipids in vivo. Fatty acids (RCOOH) exist only in low pH (<6), whereas Na and K acyl carboxylates (soaps) exist only at high pH (>8). At neutral pH, fatty acids exist as "acid-soaps," which are composed of 1 acid and 1 soap [e.g., K+H+ (RCOO-)2]. These compounds form liquid crystals in water.

Liquid crystals formed by lipids have been classified and are illustrated in Fig. 3-10 depending on their degree of long-range order as determined by x-ray diffraction (Small, 1986). Liquid crystals that have three-dimensional (3D) long-range order pack in a cubic lattice (Fig. 3-10, upper left) and could be considered crystalline. However, because the chain packing is liquid (melted), they are classified as liquid crystals. Lipids that form cubic crystals (the viscous isotropic state) include hydrated soaps, hydrated monoacylglycerols, and some hydrated phospholipids. Cubic structures of phospholipids may be efficient structures in which to store intracellular membrane phospholipids. Two-dimensional liquid crystals are ordered in either rectangular or hexagonal 2D lattices. The rectangular lattice is also called the "ribbon-like structure," in which finite bundles of polar head groups pack in ribbons of infinite length. Hexagonal 2D liquid crystalline states are composed of long rods or cylinders packed in a hexagonal array When no or little water is present, the polar parts of the molecules align (with small amounts of water if present) to form the cores of the rods, and the liquid hydrocarbon chains are the continuous matrix. This is called the "Hex II phase." Lipids forming Hex II phases include some anhydrous soaps, dry and hydrated phospholipids, and acid-soaps. Hex II phospholipid phases have been implicated as intermediate structures in cellular membrane fusion processes.

In higher water concentration, particularly when the polar group tends to interact strongly with water and the hydrocarbon part is a single chain, a hexagonal phase forms in which the hydrocarbon chains form the center of the rod and the polar groups are on the exterior of the rod, with water as the continuous matrix (Fig. 3-10, upper right). Lipids forming this so-called Hex I phase include many micelle-forming molecules, such as sphingosine-HCl, hydrated soaps, detergents, and some lysophosphatides.

Lamellar liquid crystals (also called smectic liquid crystals) are ordered in one dimension (ID), i.e., the only order is the stacking between the lamellae. In ID liquid crystals, the acyl chains may be either crystalline (gel state) or liquid. In the gel state, the chains are packed in a hexagonal lattice. Molecules that form the gel state include hydrated K, rubidium (Rb), and cesium (Cs), soaps, and many phospholipids, especially the lung surfactant dipalmitoyl PC. Dipalmitoyl PC forms a bilayered gel (Fig. 3-10, lower left), whereas K, Rb, and Cs soaps, lyso PC, and platelet-activating factor form interdigitated gels. Thus one polar group covers two chains in both types of gel (Fig. 3-10). Phospholipids with one short-chain and one long-chain fatty acid form an interdigitated "1 per 3" structure in which the short chains from two opposing phospholipids lie end to end (Fig. 3-10), and one polar group covers 3 chains. When the chains are melted (liquid), the state is called La; synonyms are lamellar liquid crystalline and smectic A. The lamellar liquid crystalline phase (La) is formed by hydrated soaps, acid-soaps, phospholipids, monoacylglycerols, and glycosphingolipids, and it is the progenitor of all membrane structure.

Gel Interdigitated Gel "1 per 3" La |

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  • TILLY
    How lysolecithin biochemically acts as a detergent?
    7 years ago

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