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Transcript
25.3 FattyAcid Oxidation Stimulus (lowblood glucose) + Fat cell Epinephrine Fatty acids Figute25.2 Mobilizationof fatty acidsfrom adiposetissue. streanl. Fat mobilization is shor,rrnin Figure 25.2.The mobilized fatty acids become tightly attached to a plasma protein, serum albumin. The serum albumin transpofis the fatty acids to tissues where they are taken up by cells that need them. The glycerol produced by the hydrolysis of the triglyceride also enters these cells. 25., Fattyocid oxidation AIMS: Tonomeand describethe processof the cotobolismof fatty ocids,indicoting the end products.Topredict the hydrolysisproductsof typicol lipid molecules.Todetermine the number of moleculesof ocetylCoA,NADH,ond FADH, thot resultfrom the beto oxidotion of o given fotty ocid. Fatty acids are degraded to acetyl coenzymeA. Fatty acids enter tissue cells that need energy.Before a fatty acid molecule can be oxidized to produce energy,however,it must be converted to a fatty acyl CoA-a thiol esterformed from a fatty acid and CoA. o R-C o OH + I',S-CoA ------ R-C-S-CoA Fatty acid Fattyacyl CoA + H,O 25 Lioid Metabolism CHAPTER Lipid StorageDiseases Inborn errors associatedwith lipid metabolism include Tay-Sachsdisease,Gaucher's disease, and Niemann-Pick disease.All three conditions are lipid storage diseases. Normally, both triglycerides and complex lipids are constantly being broken down and synthesizedin the body. The lipid storage diseases seem to occur requiredto catbecausethe body lacksenzy.rnes lipids. complex alyze the breakdown of certain to accumulation This enzyme deficiency leads of abnormally high levels of complex lipids in specific tissues, particularly the brain, spleen, and liver. In all lipid storage diseases,there is retardation of mental and physical development for reasons that are not well understood. disease,in which lipids primarily Tay-Sachs accumulate in the brain, is characterized by paralysis, a deteriorated mental state, and the storedlipids are priblindness.In Tay-Sachs, marily gangliosides,the most complexmembers of the lipids containing sphingosine isee figure, part a). As shown in the figure, the gangliosides contain four different sugar units. Gaucher'sdiseasehas many variants with certain clinical features,including elevated concentrations of serum acid phosphatase. The structure of a typical cerebroside that accumulates in this disease is shown in part (b) of the figure. The spleen becomes enlarged because spleen cells accumulate cerebrosides(see Sec. 16.3). Gaucher's disease may progress rapidly and be fatal in infancy, but some patients live fairly norrnal life spans. This suggests that Gaucher's disease is a group of inheritable diseases.The inherited mutation may be different in each form of the disease,but all these mutations affect cerebroside metabolism. The chemical abnormality found in Niemann-Pick disease is an increased content of sphingolipids (see Sec. 16.3) in the organs, but especially the spleen (see figure, part c). As in Gaucher'sdisease,lhere are many variants of Niemann-Pick disease,indicating a variety of mutations affecting sphingolipid metabolism. At right: The three lipids whose excessivestorage disease,Caucher'sdisease,and causesTay-Sachs disease,the disease.ln Tay-Sachs Niemann-Pick the most complex storedlipidsare gangliosides, membersof the lipidscontainingsphingosine(a). The containglucose(CIu), sugarunits of the gangliosides galactose(Cal), and two unusual sugarstN-acetyl(Naga)and ff-acetylneurominic acid galactosamine (Nana).ln Gaucher'sand Niemann-Pick the diseases, lipids that cannot be broken down are the cerebrosides (b) and the sphingomyelins(c), respectively. The conversion of fatty acids to fatty acyl CoA occurs in the cytoplasm of cells, but the subsequent oxidation of fatty acyl CoA occurs in the mitochondria. This presentsa problem, since fatty acyl CoA molecules cannot passthrough the mitochondrial membrane.The passageof fatty acyl CoA from the cytoplasm into the mitochondria is done indirectly. The fatty acyl CoA is flrst converted into an ester of the amino alcohol carnitine. .l o tl --'-la- li:rr,-l ooH t-l R-C-SCoA Fatty acyl CoA R-C-O -l + (H3C)3N-CH2-CH-CO2H Carnitine ----- (H3C)gN-CH2-CH-CO2H Fatty acyl carnitine + H-SCoA 25.5 Fatty Acid Oxidation 767 cH2oH o OH CJI,OH I CHOH ul K*""') |,o---\Cnon HOOC\t t/ l---1 NHCCH3 o (a) A ganglioside(accumulatesin Tay-Sachsdisease) CH2OH OH l-o -\Q-CHz-QH-CH-CH:CH(CHz)rzCHs . /t 'l / \ \os/lo HO\ l/ | OH l_{ | | rtl l | NH-C-R (b) A cerebroside(accumulatesin Gaucher'sdisease) 9H. * t l- l l CH3 - N CH2CH2- | cHro-lo o oH O- P- | O- CH2' l- CH - CH - CH : CH(CHz) rzCHe ,l'"-8-,. (c) A sphingomyelin(accumulatesin Niemann-Pick disease) The fatty acyl carnitine passes through the mitochondrial membrane, where reaction with CoA converts it back to fatty aryl CoA. .- _ In mitochondrion o tl ,l R-C-O (H3C)3N-CHr-CH-CO2H Fattyaryl carnitine + H-SCoA + o tl R-C-SCoA Fattyacy|CoA OH *l + (H3C)3N-CH2-CH-CO2H iu*ititt" The fattyacyl camitine ls so important in the metabolism of fatty acids that a carnitine deficiency can be life-threatening. Clarence, the sick baby in the Casein Point earlier in this chapter, is an example. 758 2s LipidMetabolism CHAPTER ro rHECnsrlx Ponrr:Carnitinedeficiency Folr.ow-up Clarence was found to be suffering from a potentially fatal carnitine deflciency. This deficiency was the result of a defect in the genes responsible for fatty acid metabolism. Clarence's symptoms-vomlting, slow heart rate, and breathlng problemswere generai, and the condition ls rare. He was fortunate that his carnitine deficiency was diagnosed before it took its fatal course. Most of the symptoms of his disease disappeared when carnitine was added to his formula three times a day. Since his carnitine deficiency was accompanied by other defects in his fatty acid metabolism, Clarence also was placed on a low-fat diet. Clarence, whose prognosis was poor, seems to be thriving on his carnitine supplement and low-fat diet. Carnitinesupplements help in the oxidationof long-chainfatty acids. Fatty acid activation Formation of fatty acyl CoA molecules shows how the energy stored in the phosphatebonds of AIP can be used to drive chemical processesthat normally could not occur. Neither the fatty acid nor the CoA is sufficiently energetic to form the fatty acyl CoA directly, so the cell boosts the chemical ' reactivity of the fatty acid carboxyl group by investing ATP The triphosphate group of the AIP molecule is cleaved to give p1'rophosphate (PPi)' and the remaining adenosinemonophosphate (AMP)forms a high-energy anhydride bond with the fatty acid. LIioh-cnclq- an1'rt-dricie linkage oo tl o R-C-OH l r---tj-? a + P-C + PPr R-C-O-P-O o -,rll Mixed anhydride Fatty acid The anhydride linkage formed between the fatty acid and AMP in this reaction is energeticenough to be broken by reaction with the thiol group of CoA' o:. fil*l R-C-O-:-- O I Adenosine I o + HS_CoA -> R_C_S_CoA + oPo o Mixed anhydride CoA Eethz acyl CoA Adenosine monophosphate (AMP) 25.5 FattyAcid Oxidation 759 The thioester bond of the fatty acyl CoA is a high-energy bond, just as it is in acetyl CoA.Therefore,some of the energyinvested in the breakdor,mof ATP to AMP has been conserved in the thioester bond of the fatty acyl CoA. The cost to the cell of activating one molecule of fatty acid is the loss of two high-energy phosphoric acid anhydride bonds: one in the formation of the anhydride between the fatty acid and AMP and one when PP;is hydrolyzed to2P;. Beta oddation The formation of fatty acyl CoA molecules prepares fatty acids for entry into the mitochondria. In the mitochondria, fatty acyl CoA molecules are degraded to acetyl CoA in the catabolic processcalledbetaoxidation. During beta oxidation, the third (beta) carbon of the saturated fatty acid chain of the fatty acyl CoA molecule is oxidized to a ketone. H/ P q tt oo /O / /tl oxidarion C-C-C-C-C-C-S-CoA 6 5 4ls 2 r H | ^ ll o Fatty acyl CoA There are four reactions involved in beta oxidation. An example is the fatty acyl CoA formed from a 16-carbon acid, palmitic acid. Any NADH or FADH2produced in thesereactionsmust be'accountedfor, sincethe reducing power of thesemoleculesmay be used to produceATPin respiration.As in all the metabolic reactions we have discussed,every step of beta oxidation is catalyzedby enzymes. Step1:Dehydrogenation. A carbon-carbon double bond is formed between the second and third carbons of the palmitic acid chain. One molecule of FADH2is produced. o HHO IIil CH" - - l t ' : " C-C - S-CoA "+ CH,- +-C^- -,-=-_= tsAD HH tl CH3+CH2+zCH:CH-C-S a B FADrr, -CoA As we have seen, FAD is often the coen4/rne for en4rmes that catalyze the removal of hydrogen from saturated carbon compounds. This is the case here, and one FADH, molecule is producec. Step2: Hydration. A molecule of water is added to the double bond of the fatty acyl CoA.This step is the hydration reaction of beta oxidation. o CH3+CH,+'CH:CH-C-S-CoA OHHO + Ho-H -* CHr_FCrrb?B ttl ?;C-S-CoA HH Step3: Oxidation. The hydroxyl group is now oxidized to a ketone. NAD+ is the coenzyme that acts as the oxidizing agent in this second oxidation 770 25 Lipid Metabolism CHAPTER reaction of beta oxidation. Thus beta oxidation has now produced one molecule of FADH2and one molecule of NADH. oHo i l-t t l - OHHO llll CH3+ CH2Jrz- C6- l' HHH Ca C- S- CoA --Z---I NAD CH3+ CH2JrT C C C- S- CoA I -\ADH-H Step 4: Carbon-carbon bond cleauage. The carbon-carbon bond between the second and third carbons is cleaved to give acetyl CoA and a new fatty acyl CoA that is two carbons shorter than the starting thioester: This reaction involves another molecule of CoA, but no AIP is expended. o o oHo illll + HS-CoA CH"+CH,JlrC-C-C-S-CoA ------CHs-FCH2-lrrC-S-CoA I + CH3C-S-CoA 2carbons 14carbons H l6 carbons The fragmentation of fatty acyl CoA molecules into molecules of acetyl CoA is similar to other metabolic cycles.The steps of beta oxidation repeat over and over again until the fatty acyl CoA is completely degradedto aceryl CoA. Look at Figure 25.3. The fatty acyl CoA that starts each round of the o R-CH2-CH2-C-OH Activation AMP + 2P1 o il R-CH2-CH2-C-S-CoA FADH2 Cycle repeatswith fatty acyl CoA that is two carbons shorter than in previous round Dehydrogenation (oxidation) o tl R- CH: CH-C- S-CoA t -Hzo V $ R-C- To citric S-CoA acidcvcre OH o I R-CH-CHr-C-S-CoA n ,/ S-CoA CH.-CAcetyl CoA o 25.5 Figure Thefattyacidspiral. o il R-C-CH2-C-S-CoA Hydration lElq. 25.4ATPYield 771 beta-oxidation cycle is two carbons shorter than in the previous round. For this reason,the pathway for the degradation of fatty acids to acetyl CoA is ofien called thefatty acid spiral. Every round of the spiral produces one molecule each of acetyl CoA, NADH, and FADH2 until the fatty acyl CoA molecule is only four carbons long. At this point, the first three steps of the final round of beta oxidation produce the compound acetoacetyl CoA. The fourth step, the reaction of acetoacetyl CoA with CoA, produces an extra molecule of aceryl CoA from the tail end of the fatry acid without formation of NADH and FADHz. o o il CH3-C-CH2-C-S-CoA + HS-Cofi + Acetoaceryl CoA Studies have sholvn that exercising lessfrequently but for a longer duration is a good approach to burning body fat. After 40 minutes of exercising,the percentageof energy supplied by fat is greater than that supplied by carbohydrates.Still longer exerciseperiods lead to an even higher percentage of energybeing supplied by body fat. oo CH3-C-S-CoA + CH.-C-S-CoA In other words, the complete conversion of a fatty acyl CoA to two-carbon fragments of acetyl CoA always produces one more molecule of acetyl CoA than of NADH or FADHT.To summarize, the breakdo'vrrnof palmitic acid gives eight molecules of acetyl CoA,but only sevenmolecules of NADH and sevenmoleculesof FADH2are produced. PRACTICE EXERCISE 25.I Lauric acid is converted to acetyl CoA in beta oxidation. Determine the yields of (a) acetyl CoA, (b) NADH, and (c) FADH2. 25.4ATPyield AIM: To calculotethe numberof ATPmoleculesformedby the oxidotion of o fotty ocid molecule. Focus The complete oxidation of 1 molecule of palmitic acidyields 129 molecules ofATP. In Chapter 24 we saw that the carbons of the aceryl CoA produced by the catabolism of glucose can be completely oxidized to carbon dioxide in the citric acid cycle. Each molecule of acetyl CoA oxidized in this fashion yields enough energy to make one molecule of AIB one molecule of FADH2,and three molecules of NADH. The reducing power of each molecule of NADH can make three molecules of ATP by cellular respiration; FADH2produces two molecules of AIP in the same way. It was shor,rmthat 38 AIP molecules is the total useful energyyield of aerobic glucosecatabolism. Molecules of acetyl CoA are the same, regardlessof their source. Like acetyl CoA molecules produced from glucose,the acetyl CoA molecules formed in the fatty acid spiral can be oxidized in the citric acid cycle. Since we can find the yield of NADH, FADH2, and AIP from the beta-oxidation reactions of the fatty acid spiral and from the citric acid cycle, we can calculate how many molecules of AIP are produced by the total oxidation of one molecule of any fatty acid to carbon dioxide and water. Table 25.1 shows a calculation of this kind for palmitic acid. In calculating the totalAIP yield obtained from the complete oxidation of the fatty acid, we can count the investment of two high-energy phos-