1. Complex Lipid Metabolism
UNIT III:
Lipid Metabolism
Complex Lipid Metabolism
Part 3

2. 8. Prostaglandins and Related Compounds
Prostaglandins, and the related compounds thromboxanes and leukotrienes, are collectively known as eicosanoids to reflect their origin from polyunsaturated fatty acids with 20 carbons
They are extremely potent compounds that elicit a wide range of responses, both physiologic and pathologic
Although they have been compared to hormones in terms of their actions, eicosanoids differ from the true hormones in that:
They are produced in very small amounts in almost all tissues rather than in specialized glands
They also act locally rather than after transport in the blood to distant sites, as occurs with true hormones such as insulin

3. Eicosanoids are not stored, and they have an extremely short half-life, being rapidly metabolized to inactive products
Their biologic actions are mediated by plasma membrane G protein–coupled receptors, which are different in different organ systems
Prostaglandins are named as follows: PG plus a third letter (for example, A, D, E, F), which designates the type and arrangement of functional groups in the molecule. PGI2 is known as prostacyclin. The subscript number indicates the number of double bonds in the molecule.
Figure Examples of prostaglandin structures. Thromboxanes are designated by TX and leukotrienes by LT.

4. A- Synthesis of prostaglandins and thromboxanes
The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid.
It is elongated and desaturated to arachidonic acid, the immediate precursor of the predominant class of prostaglandins (those with two double bonds) in humans (Figure 17.22).
Note:
Arachidonic acid is released from membrane-bound phospholipids by phospholipase A2 in response to a variety of signals.

5. A- Synthesis of prostaglandins and thromboxanes
Synthesis of PGH2:
The first step in the synthesis of prostaglandins is the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase (PGH synthase).
This enzyme is an endoplasmic reticulum membrane-bound protein that has two catalytic activities: fatty acid cyclooxygenase (COX), which requires two molecules of O2, and peroxidase, which is dependent on reduced glutathione.
PGH2 is converted to a variety of prostaglandins and thromboxanes, as shown in Figure 17.23, by cell-specific synthases.

6. A- Synthesis of prostaglandins and thromboxanes
Isozymes of PGH synthase:
Two isozymes, usually denoted as COX-1 and COX-2, of the synthase are known.
COX-1 is made constitutively in most tissues, and is required for maintenance of healthy gastric tissue, renal homeostasis, and platelet aggregation.
COX-2 is inducible in a limited number of tissues in response to products of activated immune and inflammatory cells.
Note:
The increase in prostaglandin synthesis subsequent to the induction of COX-2 mediates the pain, heat, redness, and swelling of inflammation, and the fever of infection.

7. Figure Oxidation and cyclization of arachidonic acid by the two catalytic activities of prostaglandin endoperoxide synthase. G-SH = reduced glutathione; GS-SG = oxidized glutathione.

8. A- Synthesis of prostaglandins and thromboxanes
Inhibition of prostaglandin synthesis:
The synthesis of prostaglandins can be inhibited by a number of unrelated compounds.
For example, cortisol (a steroidal anti-inflammatory agent) inhibits phospholipase A2 activity and, therefore, the precursor of the prostaglandins, arachidonic acid, is not available.
Aspirin, indomethacin, and phenylbutazone (all nonsteroidal anti-inflammatory agents [NSAIDS]) inhibit both COX-1 and COX-2 and, therefore, prevent the synthesis of the parent prostaglandin, PGH2.
Note:
Systemic inhibition of COX-1, with subsequent damage to the stomach and the kidneys, and impaired clotting of blood, is the basis of aspirin's toxicity.

9. A- Synthesis of prostaglandins and thromboxanes
Inhibitors specific for COX-2 (for example, celecoxib1) were designed to reduce pathologic inflammatory processes while maintaining the physiologic functions of COX-1; however, their use has been associated with increased risk of heart attacks.

10. B. Synthesis of leukotrienes
Arachidonic acid is converted to a variety of linear hydroperoxy acids by a separate pathway involving a family of lipoxygenases.
For example, neutrophils contain 5-lipoxygenase, which converts arachidonic acid to 5-hydroxy-6,8,11,14 eicosatetraenoic acid (5-HPETE).
5-HPETE is converted to a series of leukotrienes, the nature of the final products varying according to the tissue.
Lipoxygenases are not affected by NSAIDS.
Leukotrienes are mediators of allergic response and inflammation.
Note:
Inhibitors of 5-lipoxygenase and leukotriene receptor antagonists are used in the treatment of asthma.

11. C. Role of prostaglandins in platelet homeostasis
In addition to their roles in mediating inflammation, fever, and allergic response, and ensuring gastric integrity and renal function, eicosanoids are involved in a diverse group of physiologic functions, including ovarian and uterine function, bone metabolism, nerve and brain function, smooth muscle regulation, and platelet homeostasis.
Thromboxane A2 (TXA2) is produced by activated platelets.
It promotes adherence and aggregation of circulating platelets, and contraction of vascular smooth muscle, thus promoting formation of blood clots (thrombi).

12. C. Role of prostaglandins in platelet homeostasis
Prostacyclin (PGI2), produced by vascular endothelial cells, inhibits platelet aggregation and stimulates vasodilation, and so impedes thrombogenesis.
The opposing effects of TXA2 and PGI2 limit thrombi formation to sites of vascular injury.

13. C. Role of prostaglandins in platelet homeostasis
Note:
Aspirin has an antithrombogenic effect.
It inhibits TXA2 synthesis from arachidonic acid in platelets by irreversible acetylation and inhibition of COX-1.
This irreversible inhibition of COX-1 cannot be overcome in anucleate platelets, but can be overcome in endothelial cells, because they have a nucleus and, therefore, can generate more of the enzyme.
This difference is the basis of low-dose aspirin therapy used to lower the risk of stroke and heart attacks by decreasing formation of thrombi.

14. Figure Overview of the biosynthesis and function of some important prostaglandins, leukotrienes, and a thromboxane from arachidonic acid.

15. Figure 17.24:
Irreversible acetylation of cyclooxygenase 1 by aspirin.

16. 9- Chapter Summary
Phospholipids are polar, ionic compounds composed of an alcohol (for example, choline or ethanolamine) attached by a phosphodiester bridge to either diacylglycerol (producing phosphatidylcholine or phosphatidylethanolamine) or to sphingosine
The alcohol sphingosine attached to a long-chain fatty acid produces a ceramide.
Addition of a phosphorylcholine produces the phospholipid sphingomyelin, which is the only significant sphingophospholipid in humans.
Phospholipids are the predominant lipids of cell membranes.

17. 9- Chapter Summary
Nonmembrane-bound phospholipids serve as components of lung surfactant and bile.
Dipalmitoylphosphatidylcholine (DPPC, also called dipalmitoyllecithin, DPPL) 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-bound PI 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 receptors.

18. 9- Chapter Summary
The products of this degradation, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol 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).
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.

19. 9- Chapter Summary
Sphingomyelin is degraded to a ceramide plus phosphorylcholine by the lysosomal enzyme sphingomyelinase.
A deficiency in sphingomyelinase causes Niemann-Pick (A + B) disease.
Glycolipids are derivatives of ceramides to which carbohydrates have been attached (glycosphingolipids).
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.

20. 9- Chapter Summary
Glycolipids are found predominantly in cell membranes of the brain and peripheral nervous tissue, with high concentrations in the myelin sheath.
They are very antigenic. Glycolipids are degraded in the lysosomes by hydrolytic enzymes.
A deficiency of one of these enzymes produces a sphingolipidosis, in each of which a characteristic sphingolipid accumulates.
Prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT) are produced in very small amounts in almost all tissues, and they act locally. They have an extremely short half-life.

21. 9- Chapter Summary
The dietary precursor of the eicosanoids is the essential fatty acid, linoleic acid.
It is elongated and desaturated to arachidonic acid—the immediate precursor of prostaglandins—which is stored in the membrane as a component of a phospholipid, generally phosphatidylinositol.
Arachidonic acid is released from the phospholipid by phospholipase A2.
Synthesis of the prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—an endoplasmic reticulum membrane protein that has two catalytic activities: fatty acid cyclooxygenase (COX) and peroxidase.
Opposing effects of PGI2 and TXA2 limit clot formation.
There are two isozymes of the synthase: COX-1 (constitutive) and COX-2.
Leukotrienes are linear molecules produced by the 5-lipoxygenase pathway.