| Biosynthesis of phospholipids
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The biosynthesis of lecithin (phosphatidylcholine) from DAG requires activation of choline to a cytidine diphosphate (CDP) nucleotide derivative. In this series of reactions, shown in Figure 26.4, the choline 'head-group' is converted to phosphocholine, and then activated to CDP-choline by a pyrophosphorylase reaction. The pyrophosphate bond is cleaved, and phosphocholine is then transferred to DAG to form lecithin. This reaction is analogous to the transfer of glucose from UDP-glucose to glycogen, except that both the choline and phosphate groups are transferred to DAG. Phosphatidylethanolamine is formed by a similar pathway using cytidine triphosphate (CTP) and phosphoethanolamine, to form CDP-ethanolamine.
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| Figure 26.2 Pathway of formation of phosphatidic acid and its conversion to diacylglycerol (DAG) and major phospholipids. CDP, cytidine diphosphate; CTP, cytidine triphosphate; CoASH, coenzyme A; DHAP, dihydroxyacetone phosphate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate. |
| Both phosphatidylcholine and phosphatidylethanolamine can react with free serine by an exchange reaction to form phosphatidylserine and the free base, choline or ethanolamine (Fig. 26.5). In a secondary pathway, phosphatidylcholine can also be formed by methylation of phosphatidylethanolamine with the methyl donor, S-adenosylmethionine (SAM) (Fig. 26.6). The methylation pathway involves the sequential transfer of three activated methyl groups from three different molecules of SAM. Liver also has another route to phosphatidylethanolamine, involving decarboxylation of phosphatidylserine by a specific mitochondrial decarboxylase.
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| PLATELET ACTIVATING FACTOR AND HYPERSENSITIVITY |
| Platelet activating factor (PAF; Fig. 26.3) contains an acetyl group at carbon-2 of glycerol and a saturated 18-carbon alkyl ether group linked to the hydroxyl group at carbon-1, rather than the usual long-chain fatty acids of phosphatidylcholine. It is a major mediator of hypersensitivity reactions, acute inflammatory reactions, and anaphylactic shock, and affects the permeability properties of membranes, increasing platelet aggregation and causing cardiovascular and pulmonary changes, including edema and hypotension. In allergic persons, cells involved in the immune response become coated with immunoglobulin E (IgE) molecules that are specific for a particular antigen or allergen, such as pollen or insect venom. When these individuals are re-exposed to that antigen, antigen-IgE complexes form on the surface of the inflammatory cells and initiate the synthesis and release of PAF. |
| Figure 26.3 Platelet activating factor and hypersensitivity. PAF is a major mediator of acute inflammatory reactions, such as the anaphylactic response to bee venom seen in this patient. (Courtesy of Professor Jonathan Brostoff.) |
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| Figure 26.4 Formation of phosphatidylcholine by the CDP-choline pathway. CYT, cytosine; CDP, cytidine diphosphate, CMP, cytidine monophosphate; DAG, diacyl glycerol; Rib, ribose. CTP, cytidine triphosphate. |
| SURFACTANT FUNCTION OF PHOSPHOLIPIDS |
| Acute respiratory distress syndrome (ARDS) accounts for 15-20% of neonatal mortality in Western countries. The disease affects only premature infants and its incidence is directly related to the degree of prematurity. |
| Comment. Immature lungs do not have enough type II epithelial cells to synthesize sufficient amounts of the phospholipid, dipalmitoylphosphatidylcholine (DPPC). This phospholipid makes up more than 80% of the total phospholipids of the extracellular lipid layer that lines the alveoli of normal lungs. DPPC decreases the surface tension of the aqueous surface layer of the lungs, facilitating opening of the alveoli during inspiration. Lack of surfactant causes the lungs to collapse during the expiration phase of breathing, leading to ARDS. The maturity of the fetal lung can be determined by measuring the lecithin:sphingomyelin ratio in amniotic fluid. If there is a potential problem, a mother can be treated with a glucocorticoid to accelerate maturation of the fetal lung. ARDS is also seen in adults in whom the type II epithelial cells have been destroyed as a result of the use of immunosuppressive drugs or certain chemotherapeutic agents. |
| Figure 26.5 Pathways of interconversion of phospholipids by exchange of head groups, by methylation or by decarboxylation. E, ethanolamine, DAG, diacylglycerol; PC, phosphatidylcholine; PS, phosphatidylserine; SAM, S-adenosylmethionine. |
| Figure 26.6 Structures of the methyl and sulfate donors involved in the synthesis of membrane lipids. SAM, S-adenosylmethionine; PAPS, 3'-phosphoadenosine-5'-phosphosulfate (active sulfate). |
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| Figure 26.7 Formation of phosphatidylglycerol by activation of phophatidic acid to form CDP-DAG, and transfer of DAG to glycerol. CMP, cytidine monophosphate; CTP, cytidine triphosphate. |
| Phospholipids that have an alcohol as the head group, e.g. phosphatidylglycerol and phosphatidylinositol, are synthesized by an alternative pathway, which also involves activation by cytidine nucleotides. In this case, the phosphatidic acid is activated, rather than the head group, yielding
CDP-DAG (Fig. 26.7). The phosphatidic acid group is then transferred to free glycerol or inositol, to form phosphatidylglycerol or phosphatidylinositol, respectively. A second phosphatidic acid may also be added to phosphatidylglycerol to form diphosphatidylglycerol (DPG) (see Fig. 26.1).
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