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Chapter24SUMMARY - @mary 24.1 HOW Are Fatty Acids...

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Unformatted text preview: @mary 24.1 HOW Are Fatty Acids Synthesized? The synthesis of fatty acids and other lipid components is different from their degradation. Fatty acid synthesis involves a set of reactions that follow a strategy dif— ferent in several ways from the corresponding degradative process: 1, Intermediates in fatty acid synthesis are linked covalently to the sulf- hydryl groups of the acyl carrier proteins. In contrast, fatty acid break— down intermediates are bound to the ”-SH group of coenzyme A. 2. Fatty acid synthesis occurs in the cytosol, whereas fatty acid degrada- tion takes place in mitochondria. 3. In animals, the enzymes of fatty acid synthesis are components of one long polypeptide chain, the fatty acid synthase, whereas no sim- ilar association exists for the degradative enzymes. 4. The coenzyme for the oxidation—reduction reactions of fatty acid syn— thesis is NADPVNADPH, whereas degradation involves the NAD+/ NADH couple. 24.2 How Are Complex Lipids Synthesized? A common pathway operates in nearly all organisms for the synthesis of phOSphatidic acid, the precursor to other glycerolipids. Glycerokinase catalyzes the phosphory- lation of glycerol to form glycerol-S-phosphate, which is then acylated at both the 1- and 2—positions to yield phosphatidic acid. In eukaryotes, phosphatidic acid is converted directly either to diacylglycerol or to cyti- dine diphosphodiacylglycerol (or simply CDP—diacylglycerol). From these two precursors, all other glycerophospholipids in eukaryotes are derived. Phosphatidylethanolamine synthesis begins with phosphorylation of ethanolamine to form phosphoethanolamine. The next reaction involves transfer of a cytidylyl group from CT P to form CDP—ethanolamine and pyrophosphate. Eukaryotes also use CDP-diacylglycerol, derived from phosphatidic acid, as a precursor for several other important phospho— lipids, including phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin. 24.3 How Are Eicosanoids Synthesized, and What Are Their Functions? Eicosanoids are ubiquitous breakdown products of phos— pholipids. In response to appropriate stimuli, cells activate the break- down of selected phospholipids. Phospholipase A2 selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are un- saturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacylglycerols) and diacylglycerol lipase (which releases fatty acids). Animal cells can modify arachidonic acid and other polyunsaturated fatty acids to produce so-called local hor- mones. These substances include the prostaglandins (PC) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. 24.4 How Is Cholesterol Synthesized? The cholesterol biosyn— thetic pathway begins in the cytosol with the synthesis of mevalonate from acetyl—CoA. The first step is the condensation of two molecules of acetyl-CoA to form acetoacetyl—CoA. In the next reaction, acetyl—CoA and acetoacetyl-COA join to form 3-hydroxy—3-methylglutaryl-COA, which is abbreviated HMG-CoA, in a reaction catalyzed by HMG—CoA synthase. The third step in the pathway is the rate-limiting step in cho— lesterol biosynthesis; HMG-CoA undergoes two NADPH-dependent rev ductions to produce Eli-mevalonate. Biosynthesis of squalene involves conversion of mevalonate to isopentenyl pyrophosphate and dimethyl- allyl pyrophosphate, which join to yield farnesyl pyrophosphate and then squalene. A series of four reactions converts mevalonate to isopen- . tenyl pyrophosphate and then to dimethylallyl pyrophosphate. Con— densation of these two 5—carbon intermediates produces geranyl pyro- phosphate; addition of another 5-carbon isopentenyl group gives farnesyl pyrophosphate. Both steps in the production of farnesyl pyro— phosphate occur with release of pyrophosphate, hydrolysis of which drives these reactions forward. Two farnesyl pyrophosphatesjoin to pro- duce squalene. Squalene monooxygenase converts squalene to squalene- 2,3-epoxide. A second ER membrane enzyme produces lanosterol, and another 20 steps are required to convert lanosterol to cholesterol. 24.5 'How Are Lipids Transported Throughout the Body? Most lipids circulate in the body in the form of lipoprotein complexes. Simple, unesterified fatty acids are merely bound to serum albumin and other proteins in blood plasma, but phospholipids, triacylglycerols, cho- lesterol, and cholesterol esters are all transported in the form of lipo- proteins. At Various sites in the body, lipoproteins interact with specific receptors and enzymes that transfer or modify their lipid cargoes. 24.6 How Are Bile Acids Biosynthesized? The formation of bile salts represents the major pathway for cholesterol degradation. The firsl step involves hydroxylation at C-7. 7a-Hydroxylase is a mixed—function oxidase involving cytochrome P-450. Mixed—function oxidases use 02 as substrate. One oxygen atom goes to hydroxylate the substrate while the other is reduced to water. The function of cytochrome P450 is to acti- vate 02 for the hydroxylation reaction. Such hydroxylations are quite common in the synthetic routes for cholesterol, bile acids, and steroic hormones and also in detoxification pathways for aromatic compounds 24.7 How Are Steroid Hormones Synthesized and Utilized? Biosynthesis of steroid hormones begins with the desmolase reaction which converts cholesterol to pregnenolone. Desmolase activity include: two hydroxylases and utilizes cytochrome P—450. Pregnenolone is trans ported from the mitochondria to the ER, where a hydroxyl oxidatior and migration of the double bond yield progesterone. Progesterone i: also the precursor for synthesis of the sex hormone steroids and the cor ticosteroids. Testosterone is an androgen synthesized in males primarilj in the testes. B—Estradiol is the most important estrogen. Aldosterone the most potent of the mineralocorticoids, is involved in the regulatior of sodium and potassium balances in tissues. ...
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