厦大生化Chapter 22

1、Chapter 22 Fatty acid metabolismFats provide an efficient means for storing energy for later use. Studies of mice are revealing the interplay between fatty acid metabolism and the biochemical bases for appetite and weight control.1AdipocyteFour major physiological roles of fatty acids.Building block

2、s of phospholipids and glycolipids.2) Modification of protein.3) Fuel molecules.4) Hormone and intracellular messengers.222.0.1 An overview of fatty acid metabolismSteps in fatty acid degradation and synthesis.322.1 Triacylglycerols are highly concentrated energy storesBecause triacylglycerols are r

3、educed and anhydrous.Fatty acids: 9 kcal/g,Carbohydrates and protein: 4 kcal/g.Adipocyte are specialized for the synthesis, storage, and mobilization of triacylglycerols.Triacylglycerols fuel the long migration flights of the American Golden Plover.422.1.1 Dietary lipids are digested by pancreatic l

4、ipasesGlycocholate. Bile salts, such as glycocholate, facilitate lipid digestion in the intestine.5Action of pancreatic lipases. Lipases secreted by the pancreases convert triacylglycerols into fatty acids and monoacylglycerol for absorption into the intestine.622.1.2 Dietary lipids are transported

5、in chylomicronsChylomicron formation. The fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. Triacylglycerols are resyn-thesized and packaged with other lipids and apoprotein B-48 to form chylomicrons, which are then released into the lymph system.722.2 The utilization of

6、 fatty acids as fuel requires three stages of processingThe mobilization of lipids: Triacylglycerols are degraded to fatty acids and glycerol.The activation of fatty acids and transportation into mitochondria.The degradation of fatty acid.822.2.1 Triacylglycerols are hydrolyzed by cyclic AMP-regulat

7、ed lipasesLipolysis by lipase. Epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone induce lipolysis.Insulin inhibits lipolysis.9A hormone-sensitive lipase initiates the mobilization of triacylglycerol. 10Glycerol formed by lipolysis is absorbed by the liver and converted to glycer

8、aldehyde 3-phosphate, which is the intermediate of glycolysis and gluconeogenesis.1122.2.2 Fatty acids are linked to coenzyme A before they are oxidizedThe activation of fatty acid takes place on the outer mitochondrial membrane, and is catalyzed by acyl CoA synthetase.1222.2.3 Carnitine carries lon

9、g-chain activated fatty acids into mitochondrial matrixAcyl carnitine translocase. The entry of acyl carnitine into the mitochondrial matrix is mediated by a translocase. Carnitine returns to the cytosolic side of the inner mitochondrial membrane in exchange for acyl carnitine.13The transfer of acyl

10、 group between CoA and carnitine is catalyzed by carnitine acyltransferase and carnitine acyltransferase in the mitochondrial and cytosol, respectively. 1422.2.4 Acyl CoA, NADH, and FADH2 are generated in each round of fatty acid oxidationReaction sequence for the degradation of fatty acids. Fatty a

11、cids are degraded by the repetition of a four-reaction sequence consisting of oxidation, hydration, oxidation, and thiolysis.1516First three rounds in the degradation of palmitate -oxidation. Two-carbon units are sequentially removed from the carboxyl end of the fatty acid.1722.2.5 The complete oxid

12、ation of palmitate yields 106 molecules of ATP7 NADH: 7 2.5 = 17.5 ATP,7 FADH2: 7 1.5 = 10.5 ATP,8 acetyl CoA: 8 10 = 80 ATP,Activation of palmitate: -2 ATP (ATP AMP +2 Pi)Total 106 ATP.1822.3.1 Ketone bodies are formed from acetyl coenzyme A when fat breakdown predominatesThe acetyl CoA formed in f

13、atty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are balanced. In fasting, oxaloacetate is consumed to form glucose. Acetyl CoA is diverted to the formation of ketone bodies.Ketone bodies: acetoacetate, acetone, and D-3-hydroxybutyate.19Formation of ketone bo

14、dies. The ketone bodies are formed primarily in the liver2022.3.2 Ketone bodies are a major fuel in some tissuesUtilization of acetoacetate as a fuel. 22.3.3 Animals cannot convert fatty acids into glucose212222.4 Fatty acids are synthesized and degraded by different pathwaysSynthesis cytosol, Degra

15、dation mitochondrial matrix.Synthesis intermediates acyl carrier protein, Degradation intermediates Coenzyme A.Synthesis enzyme polypeptide, Degradation enzyme momopeptide.Synthesis elongation sequential addition of two-carbon units, malonyl ACP as active donor.Synthesis reductant NADPH, Degradation

16、 oxidants NAD + and FAD.Synthesis elongation stops palmitate (C16)2322.4.1 The formation of malonyl coenzyme A is the committed step in fatty acid synthesisCarboxylation of acetyl CoA is catalyzed by acetyl CoA carboxylase.2422.4.2 Intermediates in fatty acid synthesis are attached to an acyl carrie

17、r proteinPhosphopantetheine. Fatty acids are linked to the sulfhydryl terminus of phosphopantetheine group, which is, in turn, attached to a serine carrier protein.252622.4.3 The elongation cycle in fatty acid synthesisFatty acid synthesis. Fatty acids are synthesized by the repetition of the follow

18、ing reaction sequence: condensation, reduction, dehydration, and reduction.272829303132333435363738394022.4.4 Fatty acids are synthesized by a multifunctional enzyme complex in eukaryotesAnimal fatty acid synthase. Each chains in the homodimer contains: domain 1: acetyl transferase (AT), malonyl tra

19、nsferase (MT), condensing enzyme (CE); domain 2: acyl carrier protein (ACP), -ketoacyl reductase (KR), dehydratase (DH), enoyl reductase (ER); domain 3: thioesterase (TE).414222.4.5Citrate carries acetyl groups from mitochondria to the cytosol for fatty acid synthesisTransfer of acetyl CoA to the cy

20、tosol. Acetl CoA is transferred from mitochondria to the cytosol, and the reducing potential NADH is concomitantly converted into that of NADPH.4322.5 Acetyl coenzyme A carboxylase plays a key role in controlling fatty acid metabolismInsulin activates the carboxylase, whereas glucagon and epinephrin

21、e have the reverse effect.Citrate activates the carboxylase, palmity CoA and AMP, in contrast, inhibits the carboxylase.44Acetyl CoA carboxylase is inhibited by phosphorylation and activated by the binding of citrate.Global regulation.45Local regulationThe dephophorylatied form of the carboxylase is highly active even when citrate is absent. Citrate partly overcomes the inhibition of phosphorylation. Citrate facilitates the inactive polymerization form.46Response to dietIn starvation, the level of free fatty ac