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75,8 CHAPTER 24 Carbohydratesin Living Organisms thiamine pyrophosphate, lipoic acid, FAD, NAD*, and coenzyme A-are also present.Thiamine was mentioned previously (Sec.21.B)asvitamin 81. Now we see that there is a need for it, as its pyrophosphate, in converting pyruvate to acetyl CoA. H NH, I I *// NZc-c-cH, -N' rll CH3-C\. C-S \l | I o- o- C:C-CH,CH,O-P-O-P-O_ /.C l-tl CH. Thiamine pynophosphate Lipoic acid is not classifled as a vitamin. Evidently humans can make their ornmlipoic acid. No caseof lipoic acid deficiency in a human being has ever been reported. HO ( ) < l l -cH2cH2cH2cH2c-oH \ / S-S Lipoicacid PRACTICE EXERCISE 24.I Acetyl CoA is often considered an energy-rich compound Explainwhy. like ATP 24.5 Thecitric ocid cycle AIM: To list the stepsfor the degradotionof one ocetylgroup in the citric ocid cycle. Focus ' The oxidation of glucose carbons is completed in the citric acid cycle. The two molecules of acetyl CoA from one molecule of glucosenow pass into the citric acid cycle. Figure 24.4 shows the complete cycle,which rbkes place in the mitochondria of eukaryotic cells. As in other metabolicfathways, all the reactions of the citric acid cycle are catalyzed by enzymes. Some of the necessaryenzyrnesare located in the fluid contained inside the mitochondrial inner membrane; others are attached to the inner surface of the interior membrane. As we go through the steps of the cycle, be especially alert to the fates of the carbons of the reacting molecules, the various types of transformations that are occurring, and the production of NADH, FADH2,andAIP 24.5 The Citric Acid Cycle o il CH.-C-S-CoA Acetyl CoA Uttvr^/Wt CO,- o:c tftvl I- \,/s-coA 'ft' tl,o ( lLu+ar ,io"cts,1luL CH, t- CH, CO, t' neP CO2 Oxaloacetate (or- Cot- t- HO -C- HC-OH Ma]ate \n, CO; I tz ,rA -l Hro l- , Citric acid cycle l COr- COr- , l' cis-Aconitate HC tl t: CH2 .c- co,tl CH Fumarate cot i felHa CO2- Citrate. co^'\ I t fl 9Ht l- H-CH o '' u i o' Citryl CoA I -t"q4t7 ior.^ CH y*' Hzoo.' "--.\ ,_4j:"succinate cr-Ketoglutarate COrI CH, t.fHz NAD* ,/l Hto # Figure24.4 Thecitricacidcyclebeginsat the l2 o'clockposition.Aswe followthe fateof the carbonatomsof the acetylgroupof acetylCoA"we seethat they arenot the ones Iostascarbondioxidein oneturn of the cycle.Wll eitherof thesecarbonatomsbe oxidizedto carbondioxideduringtheirsecondpassthroughthe cycle? l^ - ,4O CHAFIER24 Carbohydratesin Living Organisms ' The citric acid cycle begins when an acetyl-group of acetyl CoA condenses with a molecule of oxaloacetate to give a niolecule of citryl CoA. O S-CoA \ .'c / 9o'I O:C O till CH, + CH3-C-S-CoA 9H, t,.l i.---. HO-Q-COz- co'- f", Cozoxaloacetate- AcetldcoA tcoeffirl$o",1t ut"l The thioester bond of citryl CoA is rapidly hydrolyzed to give citrate and CoA. O. .S-CoA \./ c co,- CH, CH, + t- ll HO-C-CO2tl CH, + HzO i- HO-C-COzCH, t- t- cor- coz- Citryl CoA . + HS-CoA Citrate The early discovery of citrate is the reason the pathway is called the.citric ""*rT"'?"ostep of the rycle involves the dehydration of citrate to c,s- aconitate. -tt co,l-r- co,- t", f", tl HO-C-CO2-: ttl H-C-H tl , cozCitrate 9-COr- + 4rO CH cozcls-Aconitate Water \ Now a hydration reaction occurs in which water is added to the Ao,[Ut" bond. Isocitrate is the product of the rehydration. , Qor- ?o'.l f"' f-"o,CH rl cozcis-Aconitate fo,- f", +H2o.-H-?-corHC-OH cozIsocitrate 24.5 TheCitricAcidCycle 741 At this point the production of reducing power andAIP is about to begin as isocitrate is oxidized to a-ketoglutarate. CozCOr I I CH, CH, I HC-CO2I HC-OH I 9H, I --Z---NAD. NADH + CO2 C:O I I Coz- Coza-Ketoglutarate Isocitrate NAD+ is the coen4rme in the reaction, and for every molecule of isocitrate oxidized, one molecule of NAD+ is reduced to NADH. The oxidation also involves the loss of a molecule of carbon dioxide, but notice that the carbon dioxide comes from the oxaloacetate and not from the acetyl group that entered the cycle. The next step in the cycle results in the loss of carbon dioxide, reduction of a second NAD+, and phosphorylation of ADP to AIP (a substrate-level phosphorylation). Succinate is the product. Note that once again the carbon dioxide comes from oxaloacetateinstead of acetyl CoA. A second NADH and oneAIP are produced. co,I CozI CHz CHt ATP ADP+ 4 I I CH, CH, I Coz- I C:O I + co2 CorSuccinate d-Ketoglutarate Succinate is next oxidized to fumarate. Recall that oxidation-reduction enzyrnesthat catalyzethe formation of carbon-carbon double bonds usually use FAD as the coenzyrne.That is the case here, where one FADH2 is produced. coz- coztl HC HC-H I --Z----= H-!H I eio enbH, coz- CH I corFumarate Succinate A second hydration reaction now occurs as fumarate is converted to malate. Corcort- I HC-OH HC CH I CozFumarate + HrO =- I H-CH Cot- 742 CHAPTER 24 Carbohydratesin Living Organisms Malate is oxidized back to oxaloacetate in the final step of the cycle, and NAD+ is simultaneously reduced. A third NADH is produced. CO, COr I HC-OH I CHr t- Cor- --z--NAD* Malate NADH'H I c- o I Yii, I CorOxaloacetate The oxaloacetate molecule is now available to start another turn of the cycle by reacting with another molecule of acetyl CoA. This is what happens in the citric acid cycle: 1. Acetyl CoA and oxaloacetatecombine to form citrate. 2. Citric acid eventually loses two carbon atoms as carbon dioxide. The carbons in the two molecules of carbon dioxide are not the same carbons that entered the citric acid cycle as acetyl groups of acetyl CoA. Nevertheless, the net effect of the cycle is the same as if these carbons were oxidized. 3. At the end of the pathway, a molecule of oxaloacetateremains, which is why the pathway is called a cycle. (The original oxaloacetate molecule could have come from several places in metabolism, but we need not worry about that here.) 4. Each turn of the citric acid cycle yields three molecules of NADH, one of FADH2,and one of AIP PRACTICE EXERCISE 24.4 Write a net equation that summarizes one turn of the citric acid cycle. 24.6ATPyield AIM: Togive on occountingof the ATPproducedby the complete oxidation of o moleculeof glucose. \ Focus The complete oxidation of I molecule of glucose yields 38ATP molecules. Two turns of the citric acid cycle are necessaryto oxidize completelir the equivalent of two molecules of acetyl CoA (obtained from one molecule of glucose) to four molecules of carbon dioxide. Using this information, alongwith the yields ofATP and NADH obtained in glycolysis,we can calculate the total amount of ATP generatedby the aerobic catabolism of one molecule of glucose.Remember that each NADH molecule can generate three ATP molecules and each FADH2 molecule can generate two ATP molecules by oxidative phosphorylation. TabIe 24.2 summarizes the 24.7 LacticFermentation 74t of AerobicCatabolism from Complete Table24.2ATPProduction Molecule OneGlucose Pathway Burning a mole of glucoseto form CO2and H2Oproduces686 kcal of energy. \v\rhenwe oxidize a mole of glucose,the 38 mol of ATPrepresents 277 kcal of stored energy.Our bodies,then, are about277 kcal/686 kcal x 100 : 40% efficient. glycolysis (4ATPgenerated minus 2 invested) citric acid cycle (2 acetyl groups of acetyl CoA oxidized to carbon dioxide) oxidative phosphorylation: 2NADH from glycolysis 2NADH from acetyl CoA formation 6NADH from the citric acid cycle zFADH2from the citric acid rycle ATPyield 2 2 6 6 1B A 3B results.The data show that enough of the energyreleasedin the complete oxidation of I molecule of glucoseis trapped by aerobic cells to generate 3BAIP molecules. 24.7 LacticFermentstion AIM: To exploin why cells sometimesuseloctic fermentotionfor energyproduction. Focus Aerobic cells switch to lactic or alcoholic fermentation in the absenceofoxygen. So far our discussion of glucose metabolism has assumed that the cell doing the metabolism has plenty of oxygen available.\Mhat if it does not? We know that the mitochondria of aerobic cells need oxygen so that the electron transport chain can opelate. \Mhen there is no oxygen available to drain electrons from NADH and FADH2 in respiration, the electron carriers of the electron transport chain become completely reduced. More electrons cannot be passed down the chain, and oxidative phosphorylation stops. However,the levels of NADH and FADH2in the mitochondrion increase as the citric acid cycle continues to operate. Soon, not enough NAD+ and FAD are regeneratedby respiration to sustain the operation of the citric acid cycle, and the mitochondrial power plant shuts down ,/ Now the only place that ATP is being produced is in the cytoplasm. Here,two molecules ofATP are produced for every glucosemolecule converted to two molecules of pyruvate in glycolysis. Cytoplasmic NAD+ is also being reduced to NADH, and NAD+ is needed for glycolysisto continue. (It is needed to change glyceraldehyde3-phosphateto 1,3-bisphosphoglycerate.)If there were no way to regenerateNAD+, glycolysis too would stop.With no energyproduction, the cell would die' In such an emergency,the cells of many aerobic organismsregenerate NAD+ from the NADH formed in glycolysis by using the NADH to reduce