Phosphatidic Acid Is an Intermediate in Phosphoglyceride Synthesis

Phosphoglycerides are synthesized in the cytoplasm and endoplasmic reticulum (ER) of all cells. Phosphatidic acid, which is synthesized from glycerol phosphate, is the key intermediate. Its biosynthesis is shown in Figure 24.1.

Figure 24.1 Synthesis of phosphatidic acid.

De novo synthesis of phosphoglycerides occurs via two pathways. In the phosphatidic acid pathway, phosphatidate is activated as cytidine diphosphate (CDP)-diacylglycerol. This strategy is used for the synthesis of phosphatidylinositol (Fig. 24.2) and cardiolipin.

Figure 24.2 Synthesis of phosphatidylinositol by the phosphatidic acid pathway.

In the salvage pathway, phosphate is removed from phosphatidate to form 1,2-diacylglycerol. As shown in Figure 24.3 for the synthesis of phosphatidylcholine, choline is activated as the CDP derivative, and phosphocholine is then attached to the 3-hydroxyl group of 1,2-diacylglycerol. Phosphatidylethanolamine is synthesized in a similar way. Use of CDP-activated precursors for the synthesis of membrane lipids is analogous to use of uridine diphosphate–activated precursors for the synthesis of glycogen and other complex carbohydrates. However, in the case of the phosphoglycerides, one of the two phosphates in the CDP derivative remains in the product.

Figure 24.3 Synthesis of phosphatidylcholine by the salvage pathway.

Phosphoglycerides Are Remodeled Continuously

Phospholipases are used to remodel the phosphoglycerides by changing the fatty acids in positions 1 and 2 (Fig. 24.4). They are named according to their cleavage specificity:

Figure 24.4 Exchange of a fatty acid in a phosphoglyceride by successive action of phospholipase A₂ and an acyltransferase. CoA, Coenzyme A; CoA-SH, uncombined CoA.

The acyltransferases that replace the cutout fatty acid usually place a saturated fatty acid in position 1 and an unsaturated fatty acid in position 2. The unsaturated fatty acid is most often arachidonic acid for phosphatidylinositol and oleic acid or linoleic acid for the other phosphoglycerides.

The alcoholic substituent of phosphatidic acid is exchangeable as well. Most phosphatidylserine is synthesized by base exchange with ethanolamine in human tissues:

Phosphatidylethanolamine can be made by decarboxylation of phosphatidylserine, whereas phosphatidylcholine can be formed by methylation of phosphatidylethanolamine (Fig. 24.5).

Figure 24.5 Synthesis of phosphatidylethanolamine and phosphatidylcholine from phosphatidylserine. SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine.

Plasmalogens, which constitute up to 10% of the phosphoglycerides in muscle and brain, have an unsaturated fatty alcohol instead of a fatty acid in position 1 of the glycerol. Their synthesis is shown in Figure 24.6.

Figure 24.6 Synthesis of plasmalogens and platelet-activating factor (PAF). CDP, Cytidine diphosphate; CMP, cytidine monophosphate; CoA-SH, uncombined coenzyme A; P_i, inorganic phosphate.

Platelet-activating factor (PAF) (see Fig. 24.6) is formed by white blood cells as a mediator of hypersensitivity reactions and acute inflammation. In concentrations as low as 10⁻¹¹ to 10⁻¹⁰ mol/L, it induces platelet adhesion, vasodilation, and chemotaxis of polymorphonuclear leukocytes. The presence of an acetyl group in position 2, instead of a long-chain acyl group, makes PAF sufficiently water soluble to diffuse through an aqueous medium.

Sphingolipids Are Synthesized from Ceramide

Ceramide, consisting of sphingosine and a long-chain fatty acid, is the core structure of the sphingolipids:

The primary hydroxyl group at C-1 of the sphingosine moiety carries either phosphocholine (in sphingomyelin) or carbohydrate (in the glycosphingolipids) (see Fig. 12.5). Sphingosine is synthesized in the ER of most cells from palmitoyl-CoA and serine, and the fatty acid is introduced from its CoA-thioester. The fatty acid usually is saturated and can be very long, with 22 or 24 carbons.

During the synthesis of sphingolipids in the ER and Golgi apparatus, the hydroxyl group at C-1 of sphingosine is not activated. Instead, its substituent is introduced from an activated precursor. For example, sphingomyelin is synthesized with the help of phosphatidylcholine:

The oligosaccharide chains of the glycosphingolipids are synthesized by stepwise addition of monosaccharides from their activated precursors.

Deficiencies of Sphingolipid-Degrading Enzymes Cause Lipid Storage Diseases

Sphingolipids are degraded in the lysosomes. The breakdown of complex glycosphingolipids proceeds by stepwise removal of sugars from the end of the oligosaccharide (Fig. 24.8). Each of these enzymes is specific for the monosaccharide that it removes and the type of glycosidic bond that it cleaves.

Figure 24.8 Lysosomal degradation of sphingolipids. The numbered reactions refer to the storage diseases listed in Table 24.1. There are two different β-galactosidases, one for ganglioside G_M1 (reaction 1) and the other for galactocerebroside (reaction ). Lactosyl ceramide (Cer) is degraded by both (reaction ). Gal, Galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; NANA, N-acetylneuraminic acid.

A deficiency of any of these enzymes leads to the accumulation of its substrate in the lysosomes. The resulting disease is called a lipid storage disease or sphingolipidosis (Table 24.1). The enzyme deficiency is expressed in all tissues. The nervous system is seriously affected in essentially all cases because of its high sphingolipid content and turnover. Hepatosplenomegaly is another common finding in these diseases because phagocytic cells in spleen and liver remove erythrocytes from the circulation, and nondegradable lipid from the red blood cell membrane accumulates in these tissues.

Table 24.1 Examples of Lipid Storage Diseases

The inheritance is autosomal recessive except for Fabry disease, which is X-linked recessive. For diagnosis and genetic counseling, enzyme activities are determined in cultured leukocytes, skin fibroblasts, or, for prenatal diagnosis, amniotic cells. In the more severe diseases, affected homozygotes have near-zero enzyme activity. These diseases are progressive and lead to early death. In milder variants of lipid storage diseases, affected homozygotes have greatly reduced but not completely absent enzyme activity. Heterozygotes can be identified because their enzyme activity is reduced to about half of normal.

CLINICAL EXAMPLE 24.1: ABO Incompatibility

Blood group substances are genetically polymorphic antigens on the surface of the erythrocyte membrane. People cannot form antibodies to their own blood group substances, but they can form antibodies against those of other people. This can result in dangerous transfusion reactions.

The antigens of the ABO blood group system are glycosphingolipids whose antigenic specificities are caused by variations in the terminal sugar of the oligosaccharide (Fig. 24.7). The glycosyl transferase that adds the last monosaccharide comes in three alleles. The A allele codes for an enzyme that adds N-acetylgalactosamine, the B allele codes for an enzyme that adds galactose, and the O allele has a nonsense mutation and produces no enzyme.

Figure 24.7 Synthesis of the ABO blood group substances. N-acetylgalactosamine (GalNAc) transferase (present in people with blood group A) and galactose (Gal) transferase (present in people with blood group B) are encoded by allelic variants of the same gene. A third variant of this gene does not produce an active enzyme. Homozygosity for this nonfunctional allele produces blood group O (only the H substance is present). Cer, Ceramide; Fuc, fucose.

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