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The symbol Fuc represents the sugar fucose.Chapter 9 LipidsBOX 9-2253Some Inherited Human Diseases Resulting fromAbnormal Accumulations of Membrane LipidsThe polar lipids of membranes undergo constantmetabolic turnover, the rate of their synthesis normally being counterbalanced by an equal rate ofbreakdown. The breakdown of lipids is promotedby hydrolytic enzymes, each capable of hydrolyzinga specific covalent bond. For example, the degradation of phosphatidylcholine, a major membranelipid, takes place by the action of several differentphospholipases (see Fig.
9-12).The metabolism of membrane sphingolipids,including sphingomyelin, cerebrosides, and gangliosides, is prone to genetic defects of enzymes involved in their degradation. When they are synthesized at a normal rate but their degradation isimpaired, sphingolipids or their partial breakdownproducts accumulate in the tissues. For example,in Niemann-Pick disease, sphingomyelin accumulates in the brain, spleen, and liver.
The diseasefirst becomes evident in infants, causing mentalretardation and early death. Niemann-Pick disease is caused by a rare genetic defect in the hydrolytic enzyme sphingomyelinase, which cleavesphosphocholine from sphingomyelin.Much more common is Tay-Sachs disease, inwhich a specific ganglioside accumulates in thebrain and spleen owing to the lack of the lysosomalenzyme hexosaminidase A, a degradative enzymethat normally hydrolyzes a specific bond betweenan Af-acetyl-D-galactosamine and a D-galactose residue in the polar head of the ganglioside (see Fig.9-9). As a result, the partially degraded gangliosides accumulate, causing degeneration of the nervous system.
The symptoms of Tay-Sachs diseaseare progressive retardation in development, paralysis, blindness, and death by the age of 3 or 4 yr.Tay-Sachs disease is rare in the population atlarge (1 in 300,000 births) but has a very high incidence (1 in 3,600 births) in Ashkenazic Jews (thoseof Eastern European extraction), who make upmore than 90% of the Jewish population of theUnited States.
One in 28 Ashkenazic Jews carriesthe defective gene in recessive form, which meansthat when both parents are carriers, there is a onein four probability that a child will develop TaySachs disease. Genetic counseling of parents hasbecome important in averting the occurrence ofthis disease. Tests have been devised to determinethe presence of the recessive gene in prospectiveparents. These tests involve measuring the level ofhexosaminidase A in skin cells.
Carriers of the defective gene have a reduced (but for these individuals, functional) level of the enzyme. Tests of theFigure 1 (a) A 1-year-old infant with Tay-Sachsdisease, (b) Electron micrograph of a portion of anaffected brain cell, showing the abnormal ganglioside deposits in the lysosomes.fetus can also be made during pregnancy by takinga sample of amniotic fluid, the fluid surroundingthe growing fetus, in a process known as amniocentesis.
The activity of hexosaminidase A can bemeasured in fetal cells contained in this fluid.Part II Structure and Catalysis254Figure 9—12 The specificities of phospholipases.Phospholipases A^ and A2 hydrolyze the ester bondsof intact glycerophospholipids at C-l and C-2 ofglycerol, respectively. Phospholipases C and D eachsplit one of the phosphodiester bonds in the headgroup, as indicated. Some phospholipases act onlyon one type of glycerophospholipid, such as phosphatidylinositol or phosphatidylcholine; others areless specific.
When one of the fatty acids has beenremoved by a type-A phospholipase, the secondfatty acid is cleaved from the molecule by alysophospholipase.Phospholipase A13Phospholipase CCH 2IPhospholipase A2IO=P—O—CH 2 —CH 2 —N(CH 3 ) 3I10VPhospholipase DSpecific Phospholipases Degrade Membrane PhospholipidsMost cells continually degrade and replace their membrane lipids. Foreach of the bonds in a glycerophospholipid, there is a specific hydrolyticenzyme (Fig. 9-12).
Phospholipases of the A type remove one of the twofatty acids, producing a lysophospholipid; these esterases do not attackthe ether link in plasmalogens. Lysophospholipases remove the remaining fatty acid.Phospholipid breakdown is part of at least two signaling processesin animal cells. Extracellular signals (certain hormones, for example)activate a phospholipase C that specifically cleaves phosphatidylinositols, releasing diacylglycerol and inositol phosphates, which serve asintracellular signals.
Other extracellular stimuli activate a phospholipase A that releases arachidonic acid from membrane lipids;arachidonate serves as a precursor in the synthesis of one of theeicosanoids that act as intracellular messengers. These messengerroles for lipids are discussed later in this chapter.PolarheadSteroidnucleusFigure 9-13 Cholesterol. To simplify reference toderivatives of the steroid nucleus, the rings are labeled A through D and the carbon atoms are numbered (in blue) as shown.
The hydroxyl group onC-3 represents the polar head group. For storageand transport of the sterol, this hydroxyl groupcondenses with a fatty acid to form a sterol ester.CH.3.C—NH-CH2—CH2-SO,3OOHTaurocholic acid(a bile acid)Sterols Have Four Fused Hydrocarbon RingsSterols are structural lipids present in the membranes of most eukaryotic cells. Their characteristic structure is the steroid nucleus consisting of four fused rings, three with six carbons and one with five(Fig.
9-13). The steroid nucleus is almost planar, and relatively rigid;the fused rings do not allow rotation about C—C bonds. Cholesterol,the major sterol in animal tissues, is amphipathic, with a polar headgroup (the hydroxyl group at C-3) and a nonpolar hydrocarbon body(the steroid nucleus and the hydrocarbon side chain at C-17) about aslong as a 16-carbon fatty acid in its extended form.
Similar sterols arefound in other eukaryotes: stigmasterol in plants and ergosterol infungi, for example. With rare exceptions, bacteria lack sterols. Thesterols of all species are synthesized from simple five-carbon isoprenesubunits (as are the fat-soluble vitamins, quinones, and dolichols described below).In addition to their roles as membrane constituents, the sterolsserve as precursors for a variety of products with specific biologicalactivities. Bile acids, in which the side chain at C-17 is hydrophilic, actas detergents in the intestine, emulsifying dietary fats to make themmore readily accessible to digestive lipases.
A variety of steroid hormones (described below) are also produced from cholesterol by oxidation of the side chain at C-17.255Chapter 9 LipidsOn receiving the Nobel Prize in 1985 for their work on cholesterolmetabolism, Michael Brown and Joseph Goldstein recounted in theirlecture the extraordinary history of cholesterol:Cholesterol is the most highly decorated small molecule in biology.
Thirteen Nobel Prizes have been awarded to scientists who devoted majorparts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination forscientists from the most diverse areas of science and medicine.We shall return to cholesterol later, to consider its role in biologicalmembranes, its remarkable biosynthetic pathway, and its role as precursor to the steroid hormones.Amphipathic Lipids AggregateWe have noted that glycerophospholipids, sphingolipids, and sterolsare virtually insoluble in water. When mixed with water, these amphipathic compounds form microscopic lipid aggregates in a phase separate from their aqueous surroundings.
Lipid molecules cluster togetherwith their hydrophobic moieties in contact with each other and theirhydrophilic groups interacting with the surrounding water. Recall thatlipid clustering reduces the amount of hydrophobic surface exposed towater and thus minimizes the number of molecules in the shell of ordered water at the lipid-water interface (see Fig. 4-7), resulting in anincrease in entropy.
Hydrophobic interactions among lipid moleculesprovide the thermodynamic driving force for the formation and maintenance of these structures.Depending on the precise conditions and the nature of the lipidsused, three types of lipid aggregates can form when amphipathic lipidsare mixed with water (Fig. 9-14). Micelles are relatively small, spherical structures involving a few dozen to a few thousand molecules arranged so that their hydrophobic regions aggregate in the interior,excluding water, and their hydrophilic head groups are at the surface,in contact with water.
Micelle formation is favored when the crosssectional area of the head group is greater than that of the acyl sidechain(s) (Fig. 9-14a), as it is in free fatty acids, lysophospholipids(which lack one fatty acid), and the detergent SDS.Individual units arewedge-shaped(cross-section of headgreater than thatof side chain)(a)ol| i Individual units areilcylindrical (cross-section>vij of head equals that of side chain)(b)Figure 9-14 Amphipathic lipid aggregates thatform in water, (a) In spherical micelles, the hydrophobic chains of the fatty acids are sequestered atthe core of the sphere. There is virtually no waterin the hydrophobic interior of the micelle, (b) Ina bilayer, all acyl side chains except those at theedges of the sheet are protected from interactionwith water, (c) When an extensive two-dimensionalbilayer folds on itself, it forms a liposome, a threedimensional hollow vesicle enclosing an aqueouscavity.Aqueouscavity(c)256Part II Structure and CatalysisA second type of lipid aggregate in water is the bilayer, in whichtwo lipid monolayers combine to form a two-dimensional sheet.
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