BIOCHEMISTRY: TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

CHAPTER 8. LIPID METABOLISM

VIII. Metabolism and Functions of Phospholipids

Phospholipid METABOLISM is closely linked to numerous physiological processes, including the formation and degradation of Cellular Membrane Structures, the assembly of Lipoproteins and Bile micelles, and The production of a surface layer in pulmonary alveoli that prevents alveolar collapse during expiration. Disruption of phospholipid metabolism underlies various pathologies, notably respiratory distress syndrome in newborns, Fatty Liver disease (hepatic steatosis), and hereditary disorders associated with glycolipid accumulation, known as lysosomal storage diseases. These lysosomal disorders are characterized by diminished activity of lysosomal Hydrolases involved in glycolipid degradation.

A. Glycerophospholipid Metabolism

Synthesis of Phosphatidylcholines, Phosphatidylethanolamines, and Phosphatidylserines

The Initial Stages of glycerophospholipid and neutral fat synthesis follow the same pathway up to The formation of phosphatidic acid. Phosphatidic acid can be synthesized via two distinct routes: through glyceraldehyde-3-phosphate and through dihydroxyacetone phosphate (Fig. 8-57).

Class="center">Fig. 8-57. Pathway of glycerophospholipid synthesis. R₁ — saturated fatty acid residue; R₂ — polyunsaturated fatty acid residue; SAM — S-adenosylmethionine.

In the next step, phosphatidase cleaves the phosphate group from phosphatidic acid, yielding diacylglycerol. Further transformations of diacylglycerol can also proceed through different pathways. One major route involves the activation of the phospholipid's "polar HEAD group": Choline, Serine, or ethanolamine is converted into CDP-choline, CDP-serine (Fig. 8-58), or CDP-ethanolamine.

Fig. 8-58. Synthesis of CDP-choline. The polar head group of phosphatidylcholine is converted, utilizing ATP energy, into its active form—phosphocholine—which then reacts with CTP with the simultaneous release of PP_i, driving the reaction equilibrium forward. The resulting CDP-choline serves as a choline donor for phosphatidylcholine synthesis. CDP-choline — cytidine diphosphate choline; CMP — cytidine monophosphate; P — phosphoric acid residue.

Subsequently, diacylglycerol reacts with CDP-derivatives with the release of CMP, yielding the corresponding phospholipid, such as phosphatidylcholine. Various interconversions occur among Glycerophospholipids. Phosphatidylcholine can also be synthesized via an alternative pathway: through the sequential transfer of three methyl groups from SAM to phosphatidylethanolamine. Phosphatidylserine can be converted into phosphatidylethanolamine by decarboxylation, whereas phosphatidylethanolamine can be converted back into phosphatidylserine via the exchange of ethanolamine for serine.

Dipalmitoylphosphatidylcholine — The Main Component of Pulmonary Surfactant

Surfactant is an extracellular lipid layer containing a minor fraction of hydrophobic Proteins that lines The surface of pulmonary alveoli and prevents their walls from sticking together during expiration (Fig. 8-59). The primary component of surfactant is dipalmitoylphosphatidylcholine, which accounts for up to 80% of all constituent Phospholipids. Additionally, surfactant contains hydrophobic proteins, the total amount of which does not exceed 10–20%.

Fig. 8-59. Effect of surfactant on alveolar function. A — surfactant reduces the surface tension of the fluid lining the alveoli, preventing alveolar walls from collapsing during expiration. Less air pressure is required to inflate the alveoli; B — in the absence of surfactant or when its production is deficient (in premature infants), alveolar walls collapse during expiration, requiring a tenfold higher air pressure for inflation.

The synthesis of dipalmitoylphosphatidylcholine (lecithin) in type II pneumocytes begins during embryonic development and increases sharply between 32 and 36 weeks of gestation.

An important indicator of normal surfactant maturation is a phosphatidylcholine/sphingomyelin ratio >4 (Fig. 8-60). This ratio can be determined by analyzing the composition of Amniotic Fluid. Insufficient surfactant production in premature infants after birth leads to respiratory distress syndrome, the leading cause of death in this group of newborns. A phosphatidylcholine/sphingomyelin ratio <2 indicates a high risk of developing respiratory distress syndrome. When necessary, prenatal corticosteroid Treatment stimulates surfactant synthesis in the fetal Lungs and reduces the risk of respiratory distress syndrome.

Fig. 8-60. Changes in the amniotic fluid phosphatidylcholine/sphingomyelin ratio across different stages of Pregnancy. By the 35th week of gestation, the concentration of phosphatidylcholine increases 4-fold relative to sphingomyelin, indicating normal lung maturation.

Synthesis of Phosphatidylinositol and Cardiolipin

Another metabolic fate of diacylglycerol involves the formation of an active intermediate, CDP-diacylglycerol, which leads to the synthesis of phosphatidylinositol and cardiolipin (see scheme below).

Phosphatidylinositol can subsequently be phosphorylated to form phosphatidylinositol 4,5-bisphosphate, a membrane phospholipid localized in the inner leaflet of Cell/30.html">The Plasma Membrane that participates in intracellular hormonal signal Transduction (see Chapter 5). Cardiolipin is located primarily in The inner mitochondrial membrane, with trace amounts found in pulmonary surfactant.

Catabolism of Glycerophospholipids

Various types of phospholipases localized in cell membranes or Lysosomes catalyze the Hydrolysis of glycerophospholipids (see Section 5). The hydrolysis of certain glycerophospholipids by phospholipases is important not only as a catabolic pathway, but also as a mechanism for generating secondary messengers or precursors in the synthesis of bioactive substances known as Eicosanoids. In addition, phospholipases A₁ and A₂ are involved in remodeling the fatty acid composition of glycerophospholipids, for instance, during the embryonic synthesis of dipalmitoylphosphatidylcholine, a key component of pulmonary surfactant.

B. Functions and Metabolism of Sphingolipids

Sphingolipids are derivatives of ceramide, which is formed by condensing the amino alcohol sphingosine with a fatty acid. The sphingolipid family includes sphingomyelins and glycosphingolipids (see Table 8-4, Fig. 8-61).

Sphingomyelins are found in the membranes of various tissues, with the highest concentrations occurring in Nervous Tissue. Sphingomyelins of myelin sheaths predominantly contain long-chain Fatty acids, namely lignoceric (24:0) and nervonic (24:1) acids, whereas sphingomyelin from the Brain Gray matter is rich in stearic acid.

Glycosphingolipids — Glycolipids composed of a ceramide moiety linked to one or more carbohydrate residues and sialic acid (N-acetylneuraminic acid) (see Figs. 8-5, 8-8, 8-61).

Scheme

Fig. 8-61. Structures of glycosphingolipids. A — general structural scheme of glycosphingolipids; B — Structure OF THE radicals attached to ceramide, and names of specific glycosphingolipids. Abbreviations: cer — ceramide; glc — glucose; gal — galactose; gal-NAc — N-acetylgalactosamine; N-ANA — N-acetylneuraminic acid.

Glycosphingolipids are localized in the Plasma Membranes of Cells such that the carbohydrate portion of the molecule faces The Cell surface and frequently exhibits antigenic properties. This extracellular moiety mediates cell-Cell Recognition and interaction. Interestingly, the carbohydrate structure of Blood Group Antigens on the erythrocyte surface (the ABO system) can be attached either to ceramide or to proteins; in the latter case, the antigenic structure is a glycoprotein rather than a glycolipid.

Certain gangliosides act as receptors for Bacterial toxins. For example, G_M1, located On the surface of intestinal epithelial cells, serves as the attachment site for cholera toxin, a protein secreted by the causative agents of cholera.

Functions of glycosphingolipids can be summarized as follows:

Interactions between:

✵ cells;

✵ cells and the Extracellular matrix;

✵ cells and microbes.

Modulation of:

✵ protein kinase activity;

✵ growth factor receptor activity;

✵ antiproliferative effects (apoptosis, Cell Cycle).

Provision of:

✵ membrane structural rigidity;

✵ membrane protein conformation.

Synthesis of ceramide and its derivatives. The Biosynthesis of sphingolipids begins with the formation of ceramide. Serine undergoes Condensation with palmitoyl-CoA. The resulting intermediate is first reduced by the coenzyme NADPH, after which a fatty acid, typically containing 24 carbon atoms, is attached to the amino group of dihydrosphingosine via an amide bond. Subsequent oxidation by an FAD-dependent dehydrogenase yields ceramide. Ceramide serves as the precursor for a large group of sphingolipids: carbohydrate-free sphingomyelins and glycosphingolipids (Fig. 8-62). Subsequent synthetic reactions are catalyzed by specific transferases, the Complement of which varies across different tissues. The conjugation of phosphorylcholine with ceramide by sphingomyelin synthase produces sphingomyelin. The addition of carbohydrate moieties is catalyzed by specific Glycosyltransferases, utilizing activated sugars—UDP-galactose and UDP-glucose—as carbohydrate Donors. Galactocerebroside is the principal lipid of myelin sheaths, whereas glucocerebroside is a constituent of membranes in many cell types and acts either as a precursor for more complex glycolipids or as an intermediate in their Catabolic pathways.

Fig. 8-62. Synthesis of sphingolipids from ceramide. Abbreviations: gal — galactose; glc — glucose; gal-NAc — N-acetylgalactosamine; N-ANA — N-acetylneuraminic acid; UDP-galactose, UDP-glucose — activated sugar donors transferred by specific glycosyltransferases; CMP-N-ANA — activated form of N-acetylneuraminic acid; PAPS — phosphoadenosine phosphosulfate, the active form of sulfuric acid. Phosphocholine or CARBOHYDRATES are attached to the hydroxymethyl group of ceramide (highlighted by a dashed line). Each carbohydrate residue is added by a specific glycosyltransferase located in the cisternae of the rough Endoplasmic reticulum and the Golgi apparatus.

Sphingomyelin catabolism and its disorders.

Lysosomes contain Enzymes capable of hydrolyzing any cellular component. These enzymes are called acid hydrolases because they function actively in an acidic environment. An optimal pH of 5 is maintained by a proton pump that uses ATP energy to transport hydrogen ions into lysosomes. The catabolism of sphingomyelins and glycolipids takes place in lysosomes. The breakdown of sphingomyelins involves two enzymes: sphingomyelinase, which cleaves off phosphorylcholine, and ceramidase, whose action yields sphingosine and a fatty acid (Fig. 8-63).

Fig. 8-63. Sphingomyelin hydrolysis.

A genetic defect in sphingomyelinase is the underlying cause of Niemann-Pick disease. Children with this defect die at an early age. Symptoms of the disorder include enlargement of The Liver and Spleen (hepatosplenomegaly), with lysosomes accumulating sphingomyelin, as well as intellectual disability. A genetic defect in another enzyme, ceramidase, leads to Farber disease, characterized by hepatosplenomegaly and joint involvement (pain and Swelling).

Catabolism of glycosphingolipids. The catabolism of glycosphingolipids begins with their translocation from the cell surface into the Cytoplasm via endocytosis. Consequently, molecules located on the membrane surface end up in endocytic vesicles within the cytoplasm and fuse with lysosomes. Lysosomes house all the enzymes required for the hydrolysis of complex glycosphingolipid molecules: α- and β-galactosidases, β-glucosidases, neuraminidase (sialidase), and ceramidase. Through sequential hydrolysis reactions, complex glycosphingolipids are broken down into monomers: glucose, galactose, fatty acids, sphingosine, and other metabolites.

Genetic defects of lysosomal enzymes in glycosphingolipid catabolism. Under normal conditions, the Synthesis and catabolism of glycosphingolipids are balanced so that The amount of these components in membranes remains constant. If There is a genetic defect in any lysosomal enzyme involved in glycosphingolipid catabolism, non-depolymerized substrate accumulates in the lysosomes forming so-called "residual bodies". This causes lysosomes to enlarge, potentially leading to membrane rupture, release of enzymes into the Cytosol, and impaired cellular function. Genetic Disorders resulting from a deficiency in any of the glycosphingolipid catabolic enzymes are termed sphingolipidoses, or lysosomal storage diseases. These disorders are rare, but their incidence is remarkably high in certain human populations. For instance, Gaucher disease, caused by a deficiency of β-glucosidase (Fig. 8-64), occurs with a frequency of 166 per 100,000 among Ashkenazi Jews, whereas Tay-Sachs disease (a deficiency of β-hexosaminidase) has an incidence of 33 per 100,000. Sphingolipidoses are typically fatal in early childhood due to severe damage to Nerve Tissue cells, where glycosphingolipids are concentrated. However, patients with Gaucher and Fabry diseases have a relatively normal life expectancy.

Fig. 8-64. Glycosphingolipid catabolism. The diagram indicates the enzymes whose genetic defects cause hereditary disorders known as sphingolipidoses.