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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 26.1Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols

The first step in the synthesis of both phospholipids for membranes and triacylglycerols for energy storage is the synthesis of phosphatidate (diacylglycerol 3-phosphate). In mammalian cells, phosphatidate is synthesized in the endoplasmic reticulum and the outer mitochondrial membrane. It is formed by the addition of two fatty acids to glycerol 3-phosphate, which in turn is formed primarily by the reduction of dihydroxyacetone phosphate, a glycolytic intermediate, and to a lesser extent by the phosphorylation of glycerol. Glycerol 3-phosphate is acylated by acyl CoA to form lysophosphatidate, which is again acylated by acyl CoA to yield phosphatidate.

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These acylations are catalyzed by glycerol phosphate acyltransferase. In most phosphatidates, the fatty acyl chain attached to the C-1 atom is saturated, whereas the one attached to the C-2 atom is unsaturated.

The pathways diverge at phosphatidate. In the synthesis of triacylglycerols, phosphatidate is hydrolyzed by a specific phosphatase to give a diacylglycerol (DAG). This intermediate is acylated to a triacylglycerol in a reaction that is catalyzed by diglyceride acyltransferase. Both enzymes are associated in a triacylglycerol synthetase complex that is bound to the endoplasmic reticulum membrane.

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The liver is the primary site of triacylglycerol synthesis. From the liver, the triacylglycerols are transported to the muscles for energy conversion or to the adipocytes for storage.

26.1.1. The Synthesis of Phospholipids Requires an Activated Intermediate

Phospholipid synthesis requires the combination of a diacylglyceride with an alcohol. As in most anabolic reactions, one of the components must be activated. In this case, either of the two components may be activated, depending on the source of the reactants.

Synthesis from an Activated Diacylglycerol

The de novo pathway starts with the reaction of phosphatidate with cytidine triphosphate (CTP) to form cytidine diphosphodiacylglycerol (CDP-diacylglycerol) (Figure 26.1). This reaction, like those of many biosyntheses, is driven forward by the hydrolysis of pyrophosphate.

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Figure 26.1. Structure of CDP-Diacylglycerol.

Figure 26.1

Structure of CDP-Diacylglycerol. A key intermediate in the synthesis of phospholipids consists of phosphatidate and CMP joined by a pyrophosphate linkage.

The activated phosphatidyl unit then reacts with the hydroxyl group of an alcohol to form a phosphodiester linkage. If the alcohol is serine, the products are phosphatidyl serine and cytidine monophosphate (CMP).

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Likewise, phosphatidyl inositol is formed by the transfer of a diacylglycerol phosphate unit from CDP-diacylglycerol to inositol. Subsequent phosphorylations catalyzed by specific kinases lead to the synthesis of phosphatidyl inositol 4,5-bisphosphate, an important molecule in signal transduction. Recall that hormonal and sensory stimuli activate phospholipase C, an enzyme that hydrolyzes this phospholipid to form two intracellular messengers—diacylglycerol and inositol 1,4,5-trisphosphate (Section 15.2).

The fatty acid components of a phospholipid may vary, and thus phosphatidyl serine, as well as most other phospholipids, represents a class of molecules rather than a single species. As a result, a single mammalian cell may contain thousands of distinct phospholipids. Phosphatidyl inositol is unusual in that it has a nearly fixed fatty acid composition. Stearic acid usually occupies the C-1 position and arachidonic acid (Section 22.6.2) the C-2 position.

In bacteria, the decarboxylation of phosphatidyl serine by a pyridoxal phosphate-dependent enzyme yields phosphatidyl ethanolamine, another common phospholipid. The amino group of this phosphoglyceride is then methylated three times to form phosphatidyl choline. S-Adenosylmethionine is the methyl donor.

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In mammals, phosphatidyl ethanolamine can be formed from phosphatidyl serine by the enzyme-catalyzed exchange of ethanolamine for the serine moiety of the phospholipid.

Synthesis from an Activated Alcohol

In mammals, phosphatidyl ethanolamine can also be synthesized from ethanolamine through the formation of CDP-ethanolamine. In this case, the alcohol ethanolamine is phosphorylated by ATP to form the precursor, phosphorylethanolamine. This precursor then reacts with CTP to form the activated alcohol, CDP-ethanolamine. The phosphorylethanolamine unit of CDP-ethanolamine is then transferred to a diacylglycerol to form phosphatidyl ethanolamine.

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In mammals, a pathway that utilizes choline obtained from the diet ends in the synthesis of phosphatidyl choline, the most common phospholipid in these organisms. In this case, choline is activated in a series of reactions analogous to those in the activation of ethanolamine. Interestingly, the liver possesses an enzyme, phosphatidyl ethanolamine methyltransferase, that synthesizes phosphatidyl choline from phosphatidyl ethanolamine, through the successive methylation of ethanolamine. Thus, phosphatidyl choline can be produced by two distinct pathways, ensuring that this phospholipid can be synthesized even if the components for one pathway are in limited supply.

Note that a cytidine nucleotide plays the same role in the synthesis of these phosphoglycerides as a uridine nucleotide does in the formation of glycogen (Section 21.4.1). In all of these biosyntheses, an activated intermediate (UDP-glucose, CDP-diacylglycerol, or CDP-alcohol) is formed from a phosphorylated substrate (glucose 1-phosphate, phosphatidate, or a phosphorylalcohol) and a nucleoside triphosphate (UTP or CTP). The activated intermediate then reacts with a hydroxyl group (the terminus of glycogen, the side chain of serine, or a diacylglycerol).

26.1.2. Plasmalogens and Other Ether Phospholipids Are Synthesized from Dihydroxyacetone Phosphate

Glyceryl ether phospholipids contain an ether unit instead of an acyl unit at C-1 and are synthesized starting with dihydroxyacetone phosphate rather than glycerol 3-phosphate (Figure 26.2). Acylation by a fatty acyl CoA yields a 1-acyl derivative that exchanges with a long-chain alcohol to form an ether at C-1. NADPH reduces the keto group at C-2, and the resulting alcohol is acylated by a long-chain acyl CoA. Removal of the 3-phosphate group yields 1-alkyl-2-acylglycerol, which reacts with CDP-choline to form the ether analog of phosphatidyl choline.

Figure 26.2. Synthesis of an Ether Phospholipid.

Figure 26.2

Synthesis of an Ether Phospholipid. Steps in the synthesis include (1) acylation of dihydroxyacetone phosphate by acyl CoA, (2) exchange of an alcohol for the carboxylic acid, (3) reduction by NADPH, (4) acylation by a second acyl CoA, (5) hydrolysis (more...)

Image caduceus.jpg Platelet-activating factor (PAF) is an ether phospholipid implicated in a number of allergic and inflammatory responses.

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Subnanomolar concentrations of this 1-alkyl-2-acetyl ether analog of phosphatidyl choline induce the aggregation of blood platelets, smooth muscle contraction, and the activation of cells of the immune system. It is also a mediator of anaphylactic shock, a severe and often fatal allergic response. The presence of an acetyl group rather than a long-chain acyl group at C-2 increases the water solubility of this lipid, enabling it to function in the aqueous environment of the blood. PAF functions through a 7-TM receptor.

Plasmalogens are phospholipids containing an α,β-unsaturated ether at C-1. Phosphatidal choline, the plasmalogen corresponding to phosphatidyl choline, is formed by desaturation of a 1-alkyl precursor.

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The desaturase catalyzing this final step in the synthesis of a plasmalogen is an endoplasmic reticulum enzyme akin to the one that introduces double bonds into long-chain fatty acyl CoA molecules. In both cases, O2 and NADH are reactants, and cytochrome b5 participates in catalysis (Section 22.6).

26.1.3. Sphingolipids Are Synthesized from Ceramide

We turn now from glycerol-based phospholipids to another class of membrane lipid—the sphingolipids. These lipids are found in the plasma membranes of all eukaryotic cells, although the concentration is highest in the cells of the central nervous system. The backbone of a sphingolipid is sphingosine, rather than glycerol (Section 12.3.1). Palmitoyl CoA and serine condense to form dehydrosphingosine, which is then converted into sphingosine. The enzyme catalyzing this reaction requires pyridoxal phosphate, revealing again the dominant role of this cofactor in transformations that include amino acids.

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In all sphingolipids, the amino group of sphingosine is acylated: a long-chain acyl CoA reacts with sphingosine to form ceramide (N-acyl sphingosine) Figure 26.3). The terminal hydroxyl group also is substituted. In sphingomyelin, a component of the myelin sheath covering many nerve fibers, the substituent is phosphorylcholine, which comes from phosphatidyl choline. In a cerebroside, the substituent is glucose or galactose. UDP-glucose or UDP-galactose is the sugar donor. In a ganglioside, an oligosaccharide is linked to the terminal hydroxyl group of ceramide by a glucose residue (Figure 26.4).

Figure 26.3. Synthesis of Sphingolipids.

Figure 26.3

Synthesis of Sphingolipids. Sphingosine is converted into ceramide, which is an intermediate in the formation of sphingomyelin and gangliosides.

Figure 26.4. Ganglioside G M1.

Figure 26.4

Ganglioside G M1. This ganglioside consists of five monosaccharides linked to ceramide: one glucose (Glc) molecule, two galactose (Gal) molecules, one N-acetylgalactosamine (GalNAc) molecule, and one N-acetylneuraminate (NAN) molecule. The structures (more...)

26.1.4. Gangliosides Are Carbohydrate-Rich Sphingolipids That Contain Acidic Sugars

In gangliosides, the most complex sphingolipids, an oligosaccharide chain attached to the ceramide contains at least one acidic sugar. The acidic sugar is N-acetylneuraminate or N-glycolylneuraminate. These acidic sugars are called sialic acids. Their nine-carbon backbones are synthesized from phosphoenolpyruvate (a three-carbon unit) and N-acetylmannosamine 6-phosphate (a six-carbon unit).

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Gangliosides are synthesized by the ordered, step-by-step addition of sugar residues to ceramide. The synthesis of these complex lipids requires the activated sugars UDP-glucose, UDP-galactose, and UDP-N-acetylgalactosamine, as well as the CMP derivative of N-acetylneuraminate. CMP-N-acetylneuraminate is synthesized from CTP and N-acetylneur-aminate. The structure of the resulting ganglioside is determined by the specificity of the glycosyltransferases in the cell. More than 60 different gangliosides have been characterized (see Figure 26.4 for the structure of ganglioside GM1).

26.1.5. Sphingolipids Confer Diversity on Lipid Structure and Function

The structures of sphingolipids and the more abundant glycerophospholipids are very similar. Given the structural similarity of these two types of lipids, why are sphingolipids required at all? Indeed, the prefix “sphingo” was applied to capture the “sphinxlike” properties of this enigmatic class of lipids. Although the precise role of sphingolipids is not firmly established, progress toward solving the riddle of their function is being made. The most notable function attributed to sphingolipids is their role as a source of second messengers. For instance, ceramide derived from a sphingolipid may initiate programmed cell death in some cell types.

26.1.6. Respiratory Distress Syndrome and Tay-Sachs Disease Result from the Disruption of Lipid Metabolism

Image caduceus.jpg Respiratory distress syndrome is a pathological condition resulting from a failure in the biosynthetic pathway for dipalmitoyl phosphatidyl choline. This phospholipid, in conjunction with specific proteins and other phospholipids, is found in the extracellular fluid that surrounds the alveoli of the lung, where it decreases the surface tension of the fluid to prevent lung collapse at the end of the expiration phase of breathing. Premature infants may suffer from respiratory distress syndrome because their immature lungs do not synthesize enough dipalmitoyl phosphatidyl choline.

Tay-Sachs disease is caused by a failure of lipid degradation: an inability to degrade gangliosides. Gangliosides are found in highest concentration in the nervous system, particularly in gray matter, where they constitute 6% of the lipids. Gangliosides are normally degraded inside lysosomes by the sequential removal of their terminal sugars but, in Tay-Sachs disease, this degradation does not occur. As a consequence, neurons become enormously swollen with lipid-filled lysosomes (Figure 26.5). An affected infant displays weakness and retarded psychomotor skills before 1 year of age. The child is demented and blind by age 2 and usually dead before age 3.

Figure 26.5. Lysosome with Lipids.

Figure 26.5

Lysosome with Lipids. An electron micrograph of a lysosome containing an abnormal amount of lipid. [Courtesy of Dr. George Palade.]

The ganglioside content of the brain of an infant with Tay-Sachs disease is greatly elevated. The concentration of ganglioside GM2 is many times as high as normal because its terminal N-acetylgalactosamine residue is removed very slowly or not at all. The missing or deficient enzyme is a specific β-N-acetylhexosaminidase.

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Tay-Sachs disease can be diagnosed in the course of fetal development. Amniotic fluid is obtained by amniocentesis and assayed for β-N-acetylhexosaminidase activity.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK22405

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