Chapter Summary, Questions Answers - Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism

CHAPTER SUMMARY

Phospholipids are polar, ionic compounds composed of an alcohol (for example, choline or ethanolamine) attached by a phosphodiester bond to either diacylglycerol (DAG), producing phosphatidylcholine or phosphatidylethanolamine, or to the amino alcohol sphingosine (Figure 17.25 ). Addition of a long-chain fatty acid to sphingosine produces a ceramide. Addition of a phosphorylcholine produces the phospholipid sphingomyelin. Phospholipids are the predominant lipids of cell membranes. Nonmembrane phospholipids serve as components of lung surfactant and bile. Dipalmitoylphosphatidylcholine, also called dipalmitoyl lecithin, is the major lipid component of lung surfactant. Insufficient surfactant production causes respiratory distress syndrome. Phosphatidylinositol (PI) serves as a reservoir for arachidonic acid in membranes. The phosphorylation of membrane-boundPI produces phosphatidylinositol 4,5-bisphosphate (PIP2). This compound is degraded by phospholipase C in response to the binding of a variety of neurotransmitters, hormones, and growth factors to membrane G protein–coupled receptors. The products of this degradation, inositol 1,4,5-trisphosphate (IP3) and DAG mediate the mobilization of intracellular calcium and the activation of protein kinase C, which act synergistically to evoke cellular responses. Specific proteins can be covalently attached via a carbohydrate bridge to membrane-bound phosphatidylinositol (glycosyl phosphatidylinositol, or GPI), forming a GPI anchor. A deficiency in the synthesis of GPI in hematopoietic cells results in a hemolytic disease, paroxysmal nocturnal hemoglobinuria. The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice. Sphingomyelin is degraded to a ceramide plus phosphorylcholine by the lysosomal enzyme sphingomyelinase, a deficiency of which causes Niemann-Pick (A + B) disease. Glycosphingolipids are derivatives of ceramides to which carbohydrates have been attached. When one sugar molecule is added to the ceramide, a cerebroside is produced. If an oligosaccharide is added, a globoside is produced. If an acidic N-acetylneuraminic acid molecule is added, a ganglioside is produced. Glycosphingolipids are found predominantly in cell membranes of the brain and peripheral nervous tissue, with high concentrations in the myelin sheath. They are antigenic. Glycolipids are degraded in the lysosomes by acid hydrolases. A deficiency of any one of these enzymes produces a sphingolipidosis, in which a characteristic sphingolipid accumulates.

Prostaglandins (PGs) , thromboxanes (TXs), and leukotrienes (LTs) are produced in very small amounts in almost all tissues, act locally, and have an extremely short half-life. They serve as mediators of the inflammatory response. Arachidonic acid is the immediate precursor of the predominant class of PGs in humans (those with two double bonds). It is derived by the elongation and desaturation of the essential fatty acid linoleic acid and is stored in the membrane as a component of a phospholipid, generally PI. Arachidonic acid is released from the phospholipid by phospholipase A2 (inhibited by cortisol). Synthesis of the PGs and TXs begins with the oxidative cyclization of free arachidonic acid to yield PGH₂ by prostaglandin endoperoxide synthase (PGH synthase), an endoplasmic reticulum membrane protein that has two catalytic activities: fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of PGH synthase: COX-1 (constitutive) and COX-2 (nonconstitutive). Aspirin irreversibly inhibits both. Opposing effects of PGI2 and TXA2 limit clot formation. LTs are linear molecules produced from arachidonic acid by the 5-lipoxygenase pathway. They mediate allergic response and are not inhibited by aspirin or other NSAIDs.

Figure 17.25 Key concept map for complex lipids. PLA₂ = phospholipase A₂; SO₄²- = sulfate ion; NSAIDs = nonsteroidal anti-inflammatory drugs.

Study Questions

Choose the ONE best answer.

17.1 Aspirin-induced asthma (AIA) is a severe reaction to nonsteroidal anti-inflammatory drugs (NSAIDs) characterized by bronchoconstriction 30 minutes to several hours after ingestion. Which of the following statements best explains the symptoms seen in patients with AIA? NSAIDs:

A. inhibit the activity of the cystic fibrosis transmembrane conductance regulator protein, resulting in thickened secretions that block airways.

B. inhibit cyclooxygenase but not lipoxygenase, resulting in the flow of arachidonic acid to leukotriene synthesis.

C. activate the cyclooxygenase activity of PGH synthase, resulting in increased synthesis of prostaglandins that promote vasodilation.

D. activate phospholipases, resulting in decreased amounts of dipalmytoylphosphatidylcholine and alveolar collapse (atelectasis).

Correct answer = B. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase but not lipoxygenase, so any arachidonic acid available is used for the synthesis of bronchoconstricting leukotrienes. NSAIDs have no effect on the cystic fibrosis transmembrane conductance regulator protein protein, defects in which are the cause of cystic fibrosis. Steroids, not NSAIDs, inhibit phospholipase A2. Cyclooxygenase is inhibited by NSAIDs, not activated. NSAIDs have no effect on phospholipases.

17.2 An infant, born at 28 weeks of gestation, rapidly gave evidence of respiratory distress. Clinical laboratory and imaging (X-ray) results supported the diagnosis of infant respiratory distress syndrome. Which of the following statements about this syndrome is true?

A. It is unrelated to the baby’s premature birth.

B. It is a consequence of too few type II pneumocytes.

C. The lecithin/sphingomyelin ratio in the amniotic fluid is likely to be greater than two.

D. The concentration of dipalmitoylphosphatidylcholine in the amniotic fluid would be expected to be lower than that of a full-term baby.

E. It is an easily treated disorder with low mortality.

F. It is treated by administering surfactant to the mother just before she gives birth.

Correct answer = D. Dipalmitoylphosphatidylcholine (DPPC, or dipalmitoyl lecithin) is the lung surfactant found in mature, healthy lungs. Respiratory distress syndrome (RDS) can occur in lungs that make too little of this compound. If the lecithin/sphingomyelin ratio in amniotic is greater than two, a newborn’s lungs are considered to be sufficiently mature (premature lungs would be expected to have a ratio lower than two). The RDS would not be due to too few type II pneumocytes, which would simply be secreting sphingomyelin rather than DPPC at 28 weeks of gestation. The mother is given a glucocorticoid, not surfactant, prior to giving birth. Surfactant would be administered to the baby postnatally to reduce surface tension.

17.3 A 10-year-old boy was evaluated for burning sensations in his feet and clusters of small, red-purple spots on his skin. Laboratory studies revealed protein in his urine. Enzymic analysis revealed a deficiency of α-galactosidase, and enzyme replacement therapy was recommended. The most likely diagnosis is:

A. Fabry disease.

B. Farber disease.

C. Gaucher disease.

D. Krabbe disease.

E. Niemann-Pick disease.

Correct answer = A. Fabry disease, a deficiency of α-galactosidase, is the only X-linked sphingolipidosis. It is characterized by pain in the extremities, a red-purple skin rash, and kidney and cardiac complications. Protein in his urine indicates kidney damage. Enzyme replacement therapy is available.

17.4 Current medical advice for individuals experiencing chest pain is to call emergency medical services and chew a regular-strength, noncoated aspirin. What is the basis for recommending aspirin?

Aspirin has an antithrombogenic effect: It prevents formation of blood clots that could occlude heart vessels. Aspirin inhibits thromboxane A₂ synthesis by cyclooxygenase–1 in platelets through irreversible acetylation, thereby inhibiting platelet activation and vasoconstriction. Chewing a noncoated aspirin increases the rate of its absorption.