Chapter 5 Cellular Respiration & Metabolism Cell Respiration and Metabolism

5.1: Glycolysis and the Lactic Acid Pathway

Glycogen in liver

107

Glucose from digestive tract Glucose in blood plasma

Glucose from liver

Capillary

Interstitial fluid Plasma membrane Glucose in cell cytoplasm Glycolysis Pyruvic acid Anaerobic Metabolism in skeletal muscle into mitochondrion Krebs cycle Electron transport Aerobic Respiration CO2 + H2O Mitochondrion Lactic acid Cytoplasm

re 5.1 Overview of energy metabolism using glucose. of The blood glucose may be obtained from food via the ~30 ATP Complete combustion of blood a molecule glucose requires oxygen and yields ve tract, or the liver may produce it from stored glycogen. Plasma glucose enters the cytoplasm of cells, where it can be used for Absence of oxygen, energy is obtained by pathway leading to production of lactic by either anaerobic metabolism or aerobic cell respiration. In this schematic diagram, the size of the plasma membrane is greatly Metabolism - structures (anabolic catabolic) reactions body involve energy transformation rated compared to the size of the other andand the interstitial (extracellular tissue) in fluid.

acid

ch pyruvic acid molecule contains 3 carbons, 3 oxyAlthough the overall equation for glycolysis is exergonic, break of glucose, fatty glucose acids,must andbe amino acids serve as primary sources of energy for and 4 hydrogens (see fig. 5.4).down The number of carbon activated at the beginning of the pathway xygen atoms in 1 molecule of glucoseC H O can before energy can be obtained. This activation requires the synthesis of ATP 6 12 6 be accounted for in the 2 pyruvic acid molecules. addition of two phosphate groups derived from 2 molecules some chem. bonds energy in glucose transferred to energy bonds in ATP, some lost as heat se the 2 pyruvic acids together account for only 8 of ATP. Energy from the reaction ATP ADP + Pi is thereAnabolic reactions - require input of energy and include synthesis of larger energy-storage ens, however, it is clear that 4 hydrogen atoms are fore consumed at the beginning of glycolysis. This is shown molecules (glycogen, protein) ed from the intermediates in glycolysis. Each pairfat of andas an up-staircase in figure 5.2. Notice that the Pi is not hydrogen atoms is used to reduce a molecule of NAD. oxidation-reduction shown in these reactions in figure 5.2; this is because the Energy transfer involves reactions. process, each pair of hydrogen atoms donates 2 elecphosphate is not released, but instead is added to the interOxidation - molecule loses election o NAD, thereby reducing it. The reduced NAD binds mediate molecules of glycolysis. The addition of a phosphate Reduction - molecule accepts the election that was lost on from the hydrogen atoms, leaving 1 proton unbound group is known as phosphorylation. Besides being essential nal election acceptor an oxygen in animal cell (see chapter 4, fig. 4.17). Starting from 1glucose mol- is always for glycolysis, the phosphorylation of glucose (to glucose therefore, glycolysis results in thecell production of 2 mol6-phosphate) has an important side benefit: it traps the gluAerobic respiration of NADH and 2 H+. Themetabolic H+ will follow the NADH coseoxygen within the cell.converts This is because phosphorylated pathway involving that glucose or fatty organic acid to carbon dioxide sequent reactions, so for simplicity we can refer to molecules cannot cross plasma membranes. and water d NAD simply as NADH. At later steps in glycolysis, 4 molecules of ATP are proSmall amount ofof chem-bond glucose is released atreduced) early steps in metabolic pathway, ycolysis is exergonic, and a portion the energy energy duced of (and 2 molecules of NAD are as energy is released is used some to drive the endergonic reaction liberated (theATP down-staircase in in fig. 5.2). The 2 molecules tissue cells can obtain energy from production temporary absence of oxygen + Pi ATP. At the Glucose end of the glycolytic pathway, there of ATP used the beginning, therefore, representconverting an energy undergoes metabolic pathway ofin glycolysis in cell cytoplasm into pyruvic acid et gain of 2 ATP molecules per glucose molecule, as investment; the net gain of 2 ATP and 2 NADH molecules Skeletal muscles often convert pyruvic acid into lactic acid under Anaerobic metabolism ed in the overall equation for glycolysis: by the end of the pathway represents an energy profit. The overall equation for glycolysis obscures the fact that this is Glucose + 2 NAD + 2 ADP + 2 Pi a metabolic pathway consisting of nine separate steps. The 2 pyruvic acid + 2 NADH + 2 ATP individual steps in this pathway are shown in figure 5.3.

Catabolic reactions - release energy by breakdown of larger organic molecules

Lactic Pyruvic acid as H 1 (see chapter 4, fig. 4.17). Starting fromas 1glucose molfor glycolysis, the phosphoryl 1proton from the hydrogen atoms, leaving proton unbound group known phosphorylation. Besides being essential Because the 2 pyruvic acids together account for only is 8acid of ATP. Energy from the reaction ATP ADP + Pi is t ecule, therefore, glycolysis results in the production of 2 mol6-phosphate) an important as H+ (see chapter 4, fig. 4.17). Starting from 1glucose mol- Metabolism for glycolysis, the phosphorylation of glucose (tohas glucose hydrogens, however, it is clear that 4 hydrogen atoms are fore consumed at the beginning of glycolysis. This is s in 2 skeletal muscle ecules of NADH H+. 6-phosphate) The H+ will has follow the NADHside benefit: cose within thethe cell. This is be ecule, therefore, glycolysis results in the production of 2 and molan important it traps gluremoved from the intermediates in glycolysis. Each pair of as an up-staircase in figure 5.2. Notice that the Pi i into in subsequent socose for within simplicity refer to molecules cannot cross plasma ecules of NADH and 2mitochondrion H+. The H+ will follow the reactions, NADH the we cell.can This is because phosphorylated organic these hydrogen atoms is used to reduce a molecule of NAD. shown in these reactions in figure 5.2; this is becaus Aerobic reduced NAD as NADH. At later steps in glycolysis, in subsequent reactions, so for simplicity we can simply refer to molecules cannot cross plasma membranes. In this process, eachKrebs pair of hydrogen atoms donates 2 elecphosphate is not released, but instead is added to the Electron is exergonic, and a Mitochondrion CO H2O of Glycolysis portion the energy4 molecules duced (and 2 molecules reduced NAD simply as NADH. At later in glycolysis, of ATP are pro- of NA 2 + steps cycle transport trons to NAD, thereby reducing it. The reduced NAD binds mediate molecules of glycolysis. The addition of a phos Respiration that is released is used to duced drive the endergonic reaction down-staircase Glycolysis is exergonic, and a portion of the energy (and 2 molecules of NAD are liberated reduced)(the as energy is 1proton from the hydrogen atoms, leaving 1 proton unbound group is known as phosphorylation. Besides being ess ADP + Pi ATP. At therespiration endliberated of the glycolytic pathway, therein fig.of ATP used the beginning, t that is released is usedcells to drive the endergonic reaction (the down-staircase 5.2 ). The 2 in molecules Most body obtain energy by aerobic in mitochondria + as H (see chapter 4, fig. 4.17). Starting from 1glucose molfor glycolysis, the phosphorylation of glucose (to glu Pi ATP. At the end of the glycolytic there of ATP per used in the beginning, therefore, represent the an energy is a net pathway, gain ofglucose. 2 ATP molecules glucose molecule, as investment; net gain of 2 gure ADP 5.1+ Glycolysis Overview of energy metabolism The blood glucose6-phosphate) may be obtained from food via theside benefit: it traps the ecule, therefore, glycolysis using resultsblood in the production of 2 molhas an important is a net gain of 2 ATP molecules per glucose molecule, as equation investment; the net gain of 2 ATP and NADH molecules indicated in the overall for glycolysis: by 2 the end of the pathway rep + + estive tract, or the liver may produce from stored glucose enters the cytoplasm cells, where it can beis used for phosphorylated or ecules of NADH and 2 for Hglycogen. . energy, The HPlasma will follow NADH cose of within the cell. This because Breakdown ofitglucose begins in the cytoplasm indicated in the overall equation for glycolysis: by the end of the pathway represents an energy profit. The overall equation for glycolysis rgy by either anaerobic metabolism or aerobic cell respiration. In this schematic diagram, the size of the plasma membrane is greatly in subsequent reactions, so for simplicity we can refer to molecules cannot cross plasma membranes. glucose (six-carbon sugar) is converted into 2 pyruvic acid (pyruvate) overall equation for glycolysis obscures the fact that this Glucose + 2 NAD + 2 ADP + 2 Pi a metabolic pathway is consisting ggerated compared toreduced the size of the other structures and the interstitial (extracellular tissue) fluid. At later steps in glycolysis, 4 molecules of ATP are NAD simply as NADH. Glucose + 2 NAD + 2 ADP + 2 Pi 2 pyruvic acid + a2 metabolic separate steps. NADH +pathway 2 ATP consisting of nine individual steps in The this pathway Glycolysis exergonic, and a portion of the energy duced (and 2 glycolysis molecules NAD are reduced) as ener Each pyruvic acid contains 3 carbons, 3 oxyAlthough the overall equation for isof exergonic, 2 molecule pyruvic acid + is 2 NADH + 2 ATP individual steps in this pathway are shown in figure 5.3. that is released is used to drive the of endergonic reaction is used liberated (the down-staircase in fig. 5.2). The 2 mole Glycolysis is exergonic, portion energy released to drive endergonic reaction s, and 4 hydrogens (see fig. 5.4). The number of carbon glucose must be activated at the beginning of the pathway ADP + Pi ATP. At the end of the glycolytic pathway, there of ATP used in the beginning, therefore, represent an e oxygen atoms in 1 molecule of glucoseC6H12O6can before energy can be obtained. This activation requires the is a net gain of 2 ATP molecules per glucose molecule, as investment; the net gain of of two 2 ATP and 2 NADH mole beacid activated at beginning of glycolysis and requires addition phosphate s be accounted for Glucose in the 2 must pyruvic molecules. addition of two phosphate groups derived from 2 molecules indicated in the overall equation for glycolysis: by the end of the pathway represents an energy profit ause the 2 pyruvic group acids together account for only 8 of ATP. Energy from the reaction ADP + Pi is from 2 ATP. 2 ATP represent an energy investment. 2 equation X ATP for is thereconsumed overall glycolysis obscures the at fact that t rogens, however, it beginning is clear that 4 hydrogen atoms are fore consumed at the beginning of glycolysis. This is shown fox78119_ch05_105-127.indd 107 of glycolysis Glucose + 2 NAD + 2 ADP + 2 Pi a metabolic pathway consisting of nine separate steps moved from the asATP an up-staircase in individual figure 5.2. steps Notice the Pi is are notshown ch05_105-127.indd 107 intermediates in glycolysis. Each pair of 25/06/10 9:10 PM 2 pyruvic acid + 2 NADH +2 in that this pathway in figure 5.3 Phosphorylation - addition of phosphate group se hydrogen atoms is used to reduce a molecule of NAD. shown in these reactions in figure 5.2; this is because the NAD is reduced to donates 2 NADH. 4 ADP phosphate converts is tonot 4 ATP his process, each2 pair of hydrogen atoms 2 elecreleased, but instead is added to the interFrom 1 Glucose molecule results in Production of: ns to NAD, thereby reducing it. The reduced NAD binds mediate molecules of glycolysis. The addition of a phosphate 2 molecules of 1 NADH 4 ATP. group is known as phosphorylation. Besides being essential roton from the hydrogen atoms, leaving proton and unbound H+ (see chapter 4, fig. 4.17). Starting from 1glucose molfor glycolysis, the phosphorylation of glucose (to glucose net gain of 2 ATP le, therefore, glycolysis results in the production of 2 mol6-phosphate) important side H benefit: it traps the used glu- to 1. Glucose phosphorylated 2. Converted 3. Formhas 4. an Split 5. 2 pairs removed and fox78119_ch05_105-127.indd 107 les of NADH and 2 H+. The H+ will follow the NADH cose within the cell. This is because phosphorylated organic reduced NAD to 2 NADH + H 6. Phosphate group removed to from ATP 7 and 8 isomerizations. 9. subsequent reactions, so for simplicity we can refer to molecules cannot cross plasma membranes. 109 Cell Respiration Metabolism and produced 2 and pyruvic acid uced NAD simplyphosphate as NADH. group removed to form 2 ATPAt later steps in glycolysis, 4 molecules of ATP are pro+H NAD Glucose (C H of O ) the energy Glycolysis is exergonic, and a portion duced (andNADH 2 molecules of NAD are reduced) as energy is H O H OH O O t is released is used to drive the endergonic reaction liberated (the down-staircase in fig. 5.2 ). The 2 molecules H C C C H C C C ATP 1 pathway, there OH in the OH LDH beginning, therefore, P + Pi ATP. At the end of the glycolytic of H ATP used represent an energy H H ADP glucose molecule, as net gain of 2 ATP molecules per investment; the net gain Lactic of 2 ATP and 2 NADH molecules Pyruvic acid acid Glucose 6-phosphate icated in the overall equation for glycolysis: by the5.4 endThe of formation the pathway represents Figure of lactic acid. The addition an energy profit. The of 2 hydrogen atoms (colored boxes) from reduced NAD to 2 overall equation for glycolysis obscures the fact that this is pyruvic acid produces lactic acid and oxidized NAD. This reaction is by lactic acid dehydrogenase (LDH) and is reversible Glucose + 2 NAD + 2 ADP + 2 Pi a catalyzed metabolic pathway consisting of nine separate steps. The Fructose 6-phosphate under the proper conditions. 2 pyruvic acid + 2 NADH + 2 ATP individual steps in this pathway are shown in figure 5.3.
+ 6 12 6

ATP

3 Dihydroxyacetone phosphate

ADP Fructose 1,6-biphosphate 4

3Phosphoglyceraldehyde Pi NAD 2H NADH 1,3Biphosphoglyceric acid ADP ATP 6 5

3Phosphoglyceraldehyde Pi NAD 2H NADH 1,3Biphosphoglyceric acid ADP ATP 6 5

ndd 107

3Phosphoglyceric acid 7 2Phosphoglyceric acid 8 Phosphoenolpyruvic acid ADP ATP 9

3Phosphoglyceric acid 7 2Phosphoglyceric acid 8 Phosphoenolpyruvic acid ADP ATP 9

Red blood cells, which lack mitochondria, can use only the lactic acid pathway; therefore (for reasons described in the next section), they cannot use oxygen. This spares the oxygen they carry for delivery to other cells. Except for red blood cells, anaerobic metabolism occurs for only a limited period of time in tissues that have energy requirements in excess of their aerobic ability. Anaerobic metabolism occurs in the skeletal muscles and heart when the ratio of oxygen supply to oxygen need (related to the concentration of NADH) falls below a critical level. Anaerobic metabolism is, in a sense, an emergency procedure that provides some ATP until the emergency (oxygen deficiency) has passed. It should be noted, though, that there is no real emergency in the case of skeletal muscles, where lactic acid fermentation is a normal, daily occurrence that does not harm muscle tissue or the individual. Excessive lactic acid production by muscles, however, is associated with pain and muscle fatigue. (The metabolism of skeletal muscles is discussed in chapter 12, section 12.4.) In contrast to skeletal muscles, the heart normally respires only aerobically. If anaerobic conditions do occur in the heart, a potentially dangerous situation may be present.

25/06/10 9:10 PM

CLINICAL APPLICATION
Ischemia refers to inadequate blood flow to an organ, such that the rate of oxygen delivery is insufficient to maintain aerobic respiration. Inadequate blood flow to the heart, or myocardial ischemia, may occur if the coronary blood flow is occluded by atherosclerosis, a blood clot, or by an artery spasm. People with myocardial ischemia often experience angina pectoris severe pain in the chest and left (or sometimes, right) arm area. This pain is associated with increased blood levels of lactic acid which are produced by the ischemic heart muscle. If the ischemia is prolonged, the cells may die and produce an area called an infarct. The degree of ischemia and angina can be decreased by vasodilator drugs such as nitroglycerin, which improve blood flow to the heart and also decrease the work of the heart by dilating peripheral blood vessels.

Pyruvic acid (C3H4O3)

Pyruvic acid (C3H4O3)

Figure 5.3

Glycolysis. In glycolysis, 1 glucose is converted into 2 pyruvic acids in nine separate steps. In addition to 2 pyruvic acids, the products of glycolysis include 2 NADH and 4 ATP. Because 2 ATP were used at the beginning, however, the net gain is 2 ATP per glucose. Dashed arrows indicate reverse reactions that may occur under other conditions.

Cell Respiration and Metabolism

109

Lactic Acid Pathway

NADH + H+ H H C H Pyruvic acid O C C OH LDH O H NAD H C H OH C H C OH O

Lactic acid

Dihydroxyacetone phosphate

glyceraldehyde

hoglyceric acid 6

oglyceric acid 7

oglyceric acid 8

olpyruvic acid

cid (C3H4O3)

ose is s. In addition e 2 NADH and however, the te reverse

When oxygen not available, NADH +H produced Figure 5.4 is The formation of lactic acid. The addition in glycolysis is oxidized in cytoplasm by of 2 hydrogen atoms (colored boxes) from donating electrons to pyruvic acidreduced NAD to pyruvic acid produces lactic and oxidized NAD. This reaction result in reformation of acid NAD and addition of 2 H atoms to pyruvic acid is catalyzed by lactic acid dehydrogenase (LDH) and is reversible addition of 2 H atoms to pyruvic acid produces lactic acid under the proper conditions. Anaerobic metabolism - aka: lactic acid fermentation; glucose converted into lactic acid where oxygen is not used in process Red molecule blood cells, is which lack electron mitochondria, can use only organic the last acceptor in both lactic acid and ethanol production the lactic acid pathway; therefore (for reasons described in Yields a net gain of 2 ATP per glucose molecule. the next section), they cannot use oxygen. This spares the Cell can survive as long as sufcient can be produced for its need and lactic oxygen they carry w/ for oxygen delivery to other cells. Except for energy red acid concentrations is not excessive blood cells, anaerobic metabolism occurs for only a limited period of time in tissuesanaerobic that have energy requirements in Survive longer under conditions excess of their aerobic ability. Anaerobic metabolism occurs Skeletal muscles > cardiac muscle > brain in the skeletal muscles and heart when the ratio of oxyRBCs, lack mitochondria and can only use lactic acid pathway gen supply to oxygen need (related to the concentration of except for RBC, anaerobic metabolism occurs only for a limited period NADH) falls below a critical level. Anaerobic metabolism is, Anaerobic metabolism is an emergency procedure in a sense, an emergency procedure that provides some ATP to provide some ATP until emergency has passed until the emergency (oxygen deficiency) has passed. It should be noted, though, that acid there fermentation is no real emerSkeletal muscles perform lactic on a daily occurrence that does not harm gency in the case of skeletal muscles, where lactic acid fermuscle tissue or individual mentation is a normal, occurrence does not harm fatigue excessive lactic acid daily associates w/ that pain and muscle muscle tissue or the individual. Excessive lactic acid producGlycogenesis and Glycogenolysis tion by muscles, however, is associated with pain and muscle Liver, skeletal muscles, heart storeiscarbohydrates in form of glycogen, abundance of glucose fatigue. (The metabolism ofand skeletal muscles discussed in molecules would 12.4.) exertIn an osmotic pressure and the would draw dangerous amount of water into cells chapter 12, section contrast to skeletal muscles, heart normally respires only aerobically. If anaerobic condiGlycogenesis - formation of glycogen from glucose tions do occur in the heart, a potentially dangerous situation Glucose converts to glucose 6-phosphate which then converts into its isomer, glucose may be present. 1-phosphate. Glycogen synthase removes phosphate group to polymerize glucose into glycogen Glycolysis -A conversion glucose into 2 molecules of pyruvic acid CLINIC L A P P Lof IC ATION Glycogenesis - production of glycogen, mostly in skeletal muscles and liver Ischemia refers to inadequate blood flow to an organ, such Glycogenolysis - Hydrolysis (breakdown) of glycogen; yields glucose 6-phosphate for glycolysis, that the rate of oxygen delivery is insufficient to maintain aerobic or (in liver only) free glucose that can be secreted into blood respiration. Inadequate blood flow to the heart, or myocardial glycogen phosphorlyase catalyzes breakdown of glycogen to glucose 1-phosphate which then ischemia, may occur if the coronary blood flow is occluded by converts to a glucose 6-phosphate atherosclerosis, blood clot, or by an artery spasm. People Gluconeogenesis - production of glucose from noncarbohydrate molecules with myocardial ischemia often experience angina pectoris Lipogenesis - formation of triglycerides (fat), primarily in adipose tissue severe pain in the chest and left (or sometimes, right) arm area. This pain is associated with(breakdown) increased blood of levels of lactic acid primarily in adipose tissue Lipolysis - hydrolysis triglycerides, which are produced by the ischemic heart muscle. If the Ketogenesis - formation of ketone bodies, four-carbon-long organic acids, from fatty acids, ischemia is prolonged, the cells may die and produce an area occurs in liver called an infarct. The degree of ischemia and angina can be Organic molecules w/ phosphate groups cannot cross plasma membranes decreased by vasodilator drugs such as nitroglycerin, which
improve blood flow to the heart and also decrease the work of the heart by dilating peripheral blood vessels.

Fructose 6-phosphate

GLYCOLYSIS

can be used as a source for new glucose 6-phosphate (2) in a process called glycogenolysis. The liver contains an enzyme that can remove the phosphate from glucose 6-phosphate; liver glycogen thus serves as a source for new blood glucose.

The liver contain enzyme, glucose 6-phosphatase, able to remove phosphate groups and produce free glucose able to be transported through plasma membrane Glucose 6-phosphate in liver and cells can then be used as an 111 Cell and | C H blood EC KRespiration POIN TMetabolism intermediate for secrete glycogen synthesis, or into it can blood, be converted Liver can glucose andto thereby supply glucose for use by other organs
free glucose that is secreted into the blood. The conversion of noncarbohydrate molecules (not just lactic acid, but also GLYCOGEN amino acids and glycerol) through pyruvic acid to glucose is Pi i an extremely important process called gluconeogenesis. P The 1 2 significance of this process in conditions of fasting will be discussed together with amino acid metabolism (section 5.3). Glucose 1-phosphate During exercise, some of the lactic acid produced by skeletal muscles may in Pi be transformed through gluconeogenesis ADP ATP the liver to blood glucose. This new glucose can serve as an Glucose Glucose 6-phosphate energy source during exercise and can be used after exercise (blood) Many Liver to help replenish only the depleted muscle glycogen. This twotissues way traffic between skeletal muscles and the liver is called the Cori cycle (fig. 5.6). Through the Cori cycle, gluconeoFructose 6-phosphate genesis in the liver allows depleted skeletal muscle glycogen to be restored within 48 hours.
GLYCOLYSIS

1. Define the term glycolysis in terms of its initial substrates and products. Explain why there is a net gain of 2 molecules of ATP in this process. 2. What are the initial substrates and final products of anaerobic metabolism?

Figure 5.5 Glycogenesis andof lactic acid 3. Describe the physiological functions glycogenolysis. Blood glucose entering tissue fermentation. In which tissue(s) is anaerobic cells is phosphorylated to glucose 6-phosphate. metabolism normal? In which tissue is it abnormal?
This intermediate can be metabolized for energy

Glucose 4. Describe the pathways byconverted which glucose and in glycolysis, or it can be to glycogen (blood)

glycogen can be whyGlycogen only the liver can (1) interconverted. in a process called Explain glycogenesis. represents a storage form of carbohydrates that secrete glucose derived from its stored glycogen.
can be used as a source for new glucose

12

Chapter 5

5. Define the term gluconeogenesis and explain how this 6-phosphate (2) in a process called process replenishes the glycogen stores of skeletal glycogenolysis. The liver contains an enzyme that muscles following exercise. can remove the phosphate from glucose
6-phosphate; liver glycogen thus serves as a source for new blood glucose. H

5.2 AEROBIC RESPIRATION

Cori Cycle

H H C H H C H n the aerobic respiration of glucose, pyruvic acid is Skeletal muscles Liver Glucose 6-phosphate in liver cells can then be used as an CoA C O | + CS C O + CO2 ormed by glycolysis andGlycogen then converted into acetyl Glycogen H E C K P O I N T intermediate for glycogen synthesis, or it can be converted to oenzyme A. This begins cyclic metabolic pathway 5.6 The Cori cycle. During C 1. Define the term glycolysisFigure CoA S free glucose a that is secreted into the blood. The conversion in terms of its initial substrates Exercise Rest of noncarbohydrate molecules (not just lactic acid, but also exercise, muscle glycogen serves as a and products. Explain why there is a net gain of HO O alled the Krebs cycle. As 1 a result 9 of these pathways, a amino acids and glycerol) through pyruvic acid to glucose is source of glucose 6-phosphate for the Blood 2 molecules of ATP in this process. Glucose 6-phosphate Glucose 6-phosphate Glucose The arge amount of an reduced NAD and FAD (NADH and extremely important process called gluconeogenesis. Coenzyme A Acetyl coenzyme Athrough 3). Pyruvic acid lactic and acid pathway (steps 2. What are the initial substrates final products of 1 7 significance of this process in conditions8 of fasting will be anaerobic metabolism? This lactic acid is carried by the blood reduced coenzymes proADH2) is generated. These 6 5.7 discussed2together with amino acid metabolism (section 5.3). Figure The formation of acetyl coenzyme A in (step 4) to the where 3. Describe the physiological functions ofliver, lactic acid it is converted exercise, some of thethe lactic acid produced by skelide electrons for a During process that drives formation aerobic respiration. Notice that NAD is reduced to NADH (steps in back to glucose 6-phosphate 5 and Pyruvic acid Pyruvic acid fermentation. In which tissue(s) is anaerobic etal muscles may be transformed through gluconeogenesis in this process.metabolism normal? In which 6). This is next converted into free glucose f ATP. tissue is it abnormal? the liver to blood glucose. This new glucose can serve as an

NAD

NADH + H+

5 3 (step 7), glucose which can be carried by the blood 4. Describe the pathways by which and glycogen energy source during exercise and can be used after exercise (step 8) back to the skeletal can be interconverted. Explain why only the liver can muscles. Blood to help replenish the depleted muscle glycogen. This twoLactic acid glucose derived During Lactic acid this glucose can be used to secrete from itsrest, stored glycogen. way traffic between skeletal muscles and the liver is called 4 EARNING OUTCOMES converts 1 glucose molecule into how 2 molecules restore muscle glycogen (step the Cori cycle (fig. 5.6). Through the Cori cycle, gluconeo- Glycolysis 5. Define the term gluconeogenesis and explain this 9). of pyruvic acid. Since eachthe pyruvic molecule genesis in the liver allows depleted skeletal muscle glycogen process replenishes glycogenacid stores of skeletal is conAfter studying this section, you should be able to: In and mammals, lactic acids produced anaerobic metabolism eliminated by aerobic to humans be restored within 48 hours. muscles following exercise. verted into in 1 molecule of acetyl CoA and is 1 CO , 2 molecules
2

glucose. to These acetyl acid to pyruvic acid and NAD is reduced NADH + CoA H. molecules serve as substrates for mitochondrial enzymes in the(lactic aerobicacid, pathway, while the car- conversion amino acids, glycerol) the Gluconeogenesis electron transport system and oxidative of noncarbohydrate molecules Describe fox78119_ch05_105-127.indd 111 Skeletal muscles Liver is a waste product that is carried by the blood to 25/06/10 9:10 PM bon dioxide phosphorylation, explaining the role of oxygen in this through pyruvic acid to glucose Glycogen Glycogen the lungs for elimination. It is important to note that the oxyprocess. During exercise, some lactic acid produced by skeletal muscles may be transformed through Figure 5.6 Cori cycle. During is derived from pyruvic acid,The not from oxygen gas. gen in CO 2 Exercise Rest can be produced from glycogen Explain how glucose exercise, muscle glycogen serves as a glucogenogenesis in liver to blood glucose. New glucose can serve as energy source during 1 9 source of glucose 6-phosphate for the Blood and from noncarbohydrate molecules, and how thehelp liver replenish depleted muscle exercise and after exercise to glycogen Glucose 6-phosphate Glucose 6-phosphate Glucose lactic acid pathway (steps 1 through 3). produces free glucose for secretion. 8 7 Cori cycle - gluconeogenesis in liver allows depleted skeletal muscle to restore in 48hrs This lactic acidglycogen is carried by the blood Krebs Cycle 6 2 (step 4) to the liver, where it is converted 5.2: Aerobic Respiration back to glucose the 6-phosphate and acid Pyruvic acid Once Pyruvic acetyl CoA has been formed, acetic (steps acid 5subunit The aerobic respiration of glucose (C6H12 O6) is given Glucose used to formed pyruvic acidin by glycolysis and then converted into acetyl coezyme A 6). This is next converted into free glucose (2 carbons long) combines with oxaloacetic acid (4 carbons he following overall equation: 5 3 (step 7), which can provide be carried byelectrons the blood generate large amount of reduced NAD and FAD (NADH and FADH2) and long) to form a molecule of citric acid (6 carbons long). Coen- for ATP
the Krebs cycle. lactic

of lacticof acid to carbon and water. Lactic acid dehydrogenase converts of acetyl CoA and 2 molecules of CO2 are derived (LDH) from each aerobic cell respiration glucose through dioxide Describe the respiration

acid only as a transporter zyme Lactic A acts of acetic from During rest, this glucose canacid be used to one 4 restore muscle glycogen (step 9). enzyme to another (similar to the transport of hydrogen by of ATP Aerobic respiration equivalent combustion in terms (38-40%) released is captured in high-energy bonds Energy is released isto small, and a portion NAD). The formation of citric acid begins a cyclic metabolic f its final products (CO2 and H2O) and terms ofbegins the totalw/ glycolysis Aerobic respiration ofin glucose pathway known as the citric acid cycle, or TCA cycle (for trimount of energy Glycolysis liberated. In in aerobic respiration, however, anaerobic metabolism andcarboxylic aerobic acid; respiration results in 2 pyruvic acid acid, 2 ATP, 2 citric acid has three carboxylic groups). he energy is released in small, enzymatically controlled oxiMost commonly, however, this cyclic pathway is called the ation reactions, and a portion (38% to 40%) of the energy Krebs cycle, after its principal discoverer, Sir Hans Krebs. A PM fox78119_ch05_105-127.indd 111 25/06/10 9:10 eleased is captured in the high-energy bonds of ATP. simplified illustration of this pathway is shown in figure 5.8. The aerobic respiration of glucose begins with glycolysis. Through a series of reactions involving the elimination Glycolysis in both anaerobic metabolism and aerobic respiraof 2 carbons and 4 oxygens (as 2 CO2 molecules) and the on results in the production of 2 molecules of pyruvic acid, removal of hydrogens, citric acid is eventually converted to ATP, and 2 NADH + H+ per glucose molecule. In aerobic

C6H12O6 + O2 6 acid CO2 + 6 H2O Lactic

Blood

(step 8) back to the skeletal muscles.

NADH + H per glucose molecule. In aerobic resp, electrons in NADH are not donated to pyruvic acid and lactic acid is not formed. Pyruvic acids will move to diff. cellular location and undergo diff. rxn In aerobic resp, pyruvic acid leaves cell cytoplasm, enter interior (matrix) of mitochondria Once pyruvic acid is inside mitochondrion, carbon dioxide is enzymatically removed from pyruvic acid form acetic acid by combining acetic acid w/ a coenzyme called coenzyme A. This produce acetyl Coenzyme A, Acetyl CoA.
H H C C C HO O Coenzyme A Acetyl coenzyme A H O H + S CoA NAD NADH + H+ H H C C S H O + CO 2 CoA

ruvic acid is d into acetyl olic pathway pathways, a (NADH and nzymes prohe formation

Pyruvic acid

ble to:

Figure 5.7 The 1 formation of acetyl coenzyme A in Glycolysis converts glucose into 2 pyruvic acid aerobic respiration. Notice that NAD is reduced to NADH each pyruvic acid is converted into 1 acetly CoA in and 1 CO2 (2 acetyl CoA and 2 CO2 are derived) this process. Acetyl CoA serve as substrates for mitochondrial enzymes in aerobic pathway Carbon dioxide is waste produced carried by blood to lungs for elimination Oxygen in CO2 is derived from pyruvic not from oxygen gas Cell Respiration and Metabolism 113 Glycolysis converts 1 glucose molecule into 2 molecules Krebs of Cycle pyruvic acid. Since each pyruvic acid molecule is contheir fate will be described a little later. The oxidized forms verted into 1 molecule of acetyl CoA and 1 CO2, 2 molecules of NAD and FAD are thus regenerated and can continue of acetyl CoA and 2 molecules of CO2 are derived from each electrons from the Krebs cycle to the electronto shuttle glucose. These acetyl CoA molecules serve as substrates for transport chain. The first molecule of the electron-transport chain turn becomes reduced when it accepts the electron mitochondrial enzymes in the aerobic pathway, while thein carC3 Pyruvic acid from NADH. When the cytochromes receive a pair of bon dioxide is a waste product that is carried by thepair blood to CYTOPLASM electrons, 2 ferric ions (Fe3+) become reduced to 2 ferrous the lungs for elimination. It is important to note that the oxy2+ ions (Fe ). gas. gen in CO2 is derived from pyruvic acid, not from oxygen The electron-transport chain thus acts as an oxidizing
Glycolysis NAD

cose through

d oxidative ygen in this

m glycogen d how the liver

O6) is given in

ustion in terms ms of the total tion, however, controlled oxiof the energy of ATP. with glycolysis. erobic respiraf pyruvic acid, ule. In aerobic re not donated as happens in cids will move different reaceventually be

simplified illustration 2of this pathway is shown in figure 5.8. Figure 5.8 ACoA simplified diagram of the Krebs acid Through a series offormed, reactions involving the elimination Once acetyl has acetic subunit combines w/ oxaloacetic acid to form citric acid. cycle. This diagram shows how the original four-carbon-long C L Ithe NICAL APPLICATION of 2 carbons and 4 oxygens (as 2 CO molecules) and Coenzyme A acts as transporter of acetic acid from one enzyme to another 2 oxaloacetic acid is regenerated at the end of the cyclic pathway. removal of hydrogens, citric acid is eventually converted to Free radicals are molecules with unpaired in contrast Only the numbers of carbon atoms in the Krebs cycle formation of citric acid begins cyclic metabolic pathways known as citric electrons, acid cycle or TCA cycle to molecules oxaloacetic acid, the which completes the cyclic metabolic path- that are not free radicals because they have two intermediates are shown; numbers of hydrogens and oxygens (tricarboxylic acid) aka Krebs cycle areway not accounted for this simplified scheme. (fig. 5.9 ). in In this process, these events occur: electrons per orbital. A superoxide radical is an oxygen molecule
with 4 anoxygens extra, unpaired electron. These can be generated in Reactions involve elimination of 2 carbons and (as CO2) and removal of hydrogens, electron-transport system. Superoxide radicals have some Electron Transport anda phosphate group to of fig. 5.9 ), which donates ADP to known physiological functions; for example, they are produced Oxidative producePhosphorylation one ATP. in phagocytic white blood cells where they are needed for the

agent for NAD and FAD. Each element in the chain, however, also functions as a reducing agent; one reduced cytochrome transfers its electron pair to the next cytochrome in the chain CO2 + NADH + H (fig. 5.10). In this way, the iron ions in each cytochrome Mitochondrial matrix CoA alternately become reduced (from Fe3+ to Fe2+) and oxidized C2 Acetyl CoA Once acetyl CoA has been formed, the acetic acid subunit (from Fe2+ to Fe3+). This is an exergonic process, and the energy derived is used to phosphorylate ADP to ATP. The (2 carbons long) combines with oxaloacetic acid (4 carbons production of ATP through the coupling of the electronlong) to form a molecule of citric acid (6 carbons long). CoenOxaloacetic acid C4 transport system with the phosphorylation of ADP is zyme A acts only as a transporter of acetic acid from one appropriately termed oxidative phosphorylation. enzyme to another (similar to the transport of hydrogen CO2 The by coupling is not 100% efficient between the energy 3 NADH + H+ NAD). The formation a cyclic metabolic Krebs cycleof citric acid begins released by electron transport (the oxidative part of oxidaCitric acid C6 1 FADH2 tive phosphorylation) and the energy incorporated into the pathway known as the citric acid cycle, or TCA cycle (for tri1 ATP chemical bonds of ATP (the phosphorylation part of the C5 carboxylic acid; citric acid has three carboxylic acid groups). -Ketoglutaric acid term). This difference in energy escapes the body as heat. Most commonly, however, this cyclic pathway is called the Metabolic heat production is needed to maintain our internal Krebs cycle, after its principal discoverer, Sir Hansbody Krebs. A temperature.

Krebs Cycle

CO

1. One guanosine triphosphate (GTP) is producedmitochondria (step 5

through the leakage of electrons from the

the cell cytomitochondria. rbon dioxide is n-long pyruvic

Three molecules of NAD are reduced to NADH (steps 4, 5, of bacteria. However, the production of free radicals destruction Built2. into the foldings, or cristae, of the inner mitochondrial and other molecules classified as reactive oxygen species membrane are series molecules that serve as an electronand 8aof fig.of 5.9 ). (including the superoxide, hydroxyl, and nitric oxide free transport system during aerobic respiration. This electron3. One molecule of FAD is reduced to FADH2 (step 6). radicals) have been implicated in many disease processes, transport chain of molecules consists of a protein containing atherosclerosis (hardening of the arterieschapter13, flavin mononucleotide (abbreviated FMN andFADH derived by from The production of NADH and each including turn of 2 ironsection 13.7). Accordingly, reactive oxygen species have been the vitamin riboflavin), coenzyme Q, and a group of

H Acetyl CoA (C2) H COOH C O C H COOH

114
Chapter 5

HO H2O 1 H

C COOH C H COOH 2 H

COOH C H C COOH C H COOH 3 H H H COOH C H C COOH C OH cis-Aconitic acid (C6) H2O

Citric acid (C6)

citric acid is converted to oxaloacetic acid 8

H H O

Oxaloacetic acid (C4)

H H C OH C

C C S

COOH

CoA +

H2O COOH C O H C H COOH 8

HS

CoA

COOH H C H + H+ NADH HO H NAD C COOH C H COOH 2

H2O COOH H C H C COOH C H COOH H2O

2H
H2O 1

Acetyl ) H CoA (C2 H

COOH Isocitric acid (C6) NADH + H+

3 H H H COOH C H C COOH C OH

COOH Malic acid (C4) 7 H2O HH

Citric acid (C6)

2H

Oxaloacetic acid (C4)

cis-Aconitic acid (C6)

NAD

COOH C OH

COOH

2H

NADH + H+ NAD NADH + H+

H CC H COOH C Malic acid (C4)

COOH Isocitric acid (C6)

HOOC
H2O

Fumaric acid (C4)

H COOH C C HOOC H Fumaric acid (C4)

2H ATP
2H ATP FADH2 FAD

FADH2 FAD

2H

NAD

CO2 COOH

COOH

ADP 2H GDP
2H NADH + H+ NAD CO2

H H

C 6 H C H
COOH

CO NADH 2

+ H+

H H

C H C H C O COOH

GTP ADP
GTP GDP

NAD H
H

COOH C H CO2 C H C O COOH

H H

COOH C H
C H COOH

Succinic acid (C4)

Succinic acid (C4)

-Ketoglutaric acid (C5)

5
5 H2O

-Ketoglutaric acid (C5)

H2O
2

The completeKrebs Krebs cycle. Notice that, for that, each turn of the cycle, 1 ATP, 3 NADH, and 1 1 FADH produced.and 1 FADH are produced. Figure Figure 5.9 5.9 The complete cycle. Notice for each turn of the cycle, ATP,are 3 NADH, 2

system mitothat form a stemThe and a respiratory globular subunit. The stem contains into the chondrial space membranes. between The the electron-transport inner and outer assemblies consist of a group of proteins ADP produced one is grouped into three to complexes that serve as ATP proton a channel through the inner mitochondrial membrane that chondrial membranes. The electron-transport system that form a stem and a globular subunit. The stem contains + pumps (fig. 5.11). The first pump (the NADH-coenzyme permits the passage of protons (H ). The globular subunit, Steps 4, 5, and three NAD are is grouped into three complexes serve as proton a channel through the mitochondrial membrane that Q reductase complex) transports 4 that H+ 8: from the matrix which reduced protrudes into to the NADH matrix, contains an inner ATP synthase to the intermembrane space for every pair of electrons to enzyme that permits catalyzes the reaction ADP + Pi ATP when it +). The globular subunit, Step 6: pump one FAD is reduced FADH2 pumps (fig. 5.11 ). The first (the NADH-coenzyme the passage of protons (H moved along the electron-transport system. The second is activated by the diffusion of protons through the respira+ Q reductase transports H from the matrix which protrudes into the matrix, contains an ATP synthase production of4complex) NADH and FADH2 by each of Krebs cycle is way, more signicant in terms of pump complex) (the cytochrome c reductase also transtory assemblies andturn into the matrix (fig. 5.11 ). In this ports 4 protons into the intermembrane space, and the phosphorylation (the addition of phosphate the to ADP) is cou- ADP + P ATP when it to the intermembrane space for every pair of electrons enzyme that catalyzes reaction energy production than singlepled GTP produced directly by cycle i third pump (the cytochrome c oxidase complex) transto oxidation (the transport of electrons) in oxidative moved along electron-transport system. is activated by the diffusion of protons through the respiraports 2 the protons into the intermembrane space. As a The result, second phosphorylation. Electron Transport and Oxidative Phosphorylation there is a higher concentration of H+ in complex) the intermembrane pump (the cytochrome c reductase also transtory assemblies and into the matrix (fig. 5.11). In this way, system a series of molecule Function of Oxygen build into foldings (cristae) of inner space An than electron in the matrix, transport favoring the diffusion of H+ is back ports 4 protons into the intermembrane space, and the phosphorylation (the addition of phosphate to ADP) is couout into the matrix. The inner mitochondrial membrane, If the last cytochrome remained in a reduced state, it would mitochondrial membrane + third pump (the cytochrome c oxidase complex) transpled to oxidation (the transport however, does not permit diffusion of H , except through be unable to accept more electrons. Electron transportof electrons) in oxidative Electron transport chain consist of protein containing avin mononucleotide (FMN from vitamin structures called respiratory assemblies. would then progress only to the next-to-last cytochrome. ports 2 protons into the intermembrane space. As a result, phosphorylation. + riboavin), coenzyme Q, and cytochromes (group of iron containing pigments) there is a higher concentration of H in the intermembrane Function ofoxidation-reduction Oxygen space than in theCytochromes matrix, favoring the diffusionelectrons of H+ back to oxygen a3 donates in nal reaction) out into the matrix. The inner mitochondrial membrane, the last cytochrome remained in atransport reduced state, it would Electron-transport system pick up electronsIffrom NADH and FADH2 and them in dinite + however, does not permit diffusion of H , except through be unable to accept more electrons. Electron transport sequence and direction fox78119_ch05_105-127.indd 114 25/06/10 9:10 PM structures called respiratory assemblies. would then progress only to the next-to-last cytochrome. Aerobic respiration

into the space between the inner and outer mito-

The respiratory assemblies consist of a group of proteins Step 5: 1 GTP (guanosine triphosphate) is produced, which donates a phosphate group to

78119_ch05_105-127.indd 114

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Cell Respiration and Metabolism

115

NADH NAD 2 H+

FMN FMNH2 2 e Fe2+ Cytochrome b Fe3+ 2 e

FADH2
Electron energy

Oxidized CoQ Reduced

FAD

Fe2+ Cytochrome c1 and c 3+ Fe

Fe3+ Cytochrome a Fe2+ 2e

Fe2+ Cytochrome a3 Fe
3+

H2O 2e

2 H+

1 O 2 2

Figure 5.10 The electron transport system. Each element in the electron-transport chain alternately becomes reduced and oxidized as it transports electrons to the next member of the chain. This process provides energy for the pumping of protons into the intermembranous space of the mitochondrion, and the proton gradient is used to produce ATP (as shown in fig. 5.11). At the end of the electron-transport chain, the electrons are donated to oxygen, which becomes reduced (by the addition of 2 hydrogen atoms) to water.

NADH and FADH2 become oxidized by transferring pairs of electrons to electron transport This process would continue until all of the elements of the ATP Balance Sheet system of cristae. electron-transport chain remained in the reduced state. At NAD and FAD, oxidized forms, are regenerated Overview and continue to shuttle electrons from Krebs this point, the electron-transport system would stop functioning and no ATP could be produced in the mitochondria. There are two different methods of ATP formation in cycle to ETC With the electron-transport system incapacitated, NADH and cell respiration. One method is the direct (also called First molecule of electron-transport chain substrate-level becomes )reduced when itoccurs accepts electron pair from FADH could not become oxidized by donating their electrons phosphorylation that in glycolyto the chain and, through inhibition of Krebs cycle enzymes, sis (producing a net gain of 2 ATP) and the Krebs cycle NADH no more NADH and FADH could be produced in the mitochondria. cytochromes The Krebs cycle would stop anda only anaerobic When receive pair of electrons, 2 ferric ions (Fe3+) become reduced to 2 metabolism could occur. ferrous ions (Fe2+) CLINICAL APPLICATION Oxygen, from the air we breathe, allows electron transport to continue by functioning as the final electron acceptor ETC acts as oxidizing agent for NAD and Cyanide FAD is a fast-acting lethal poison that produces such of the electron-transport chain. This oxidizes cytochrome a , symptoms as rapid heart rate, tiredness, seizures, and headache. One reduced cytochrome its allowing electron transport and oxidative transfers phosphorylation to electron pair to next cytochrome in ETC, functioning as a Cyanide poisoning can result in coma, and ultimately death, in continue. At the very last step of aerobic respiration, therereducing agent the absence of quick treatment. The reason that cyanide is so fore, oxygen becomes reduced by the 2 electrons that were deadly is that it has very specific action: it blocks the transfer this is an exergonic process and energy derived isone used to phosphorylate ADP to ATP reduced passed to the chain from NADH and FADH . This of electrons from cytochrome a to oxygen. The effects are thus oxygen binds 2 protons, and a molecule of water is formed. Oxidative phosphorylation - Production of ATP through coupling of electron-transport system the same as would occur if oxygen were completely removed Because the oxygen atom is part of a molecule of oxygen gas aerobic cell respiration and the production of ATP by oxidative of (O ),w/ thisphosphorylation last reaction can be shown as ADP follows: phosphorylation comes to a halt. Coupling of Electron Transport O + 4 e + 4 H 2 H O to ATP Production
2 2 3 2
3

fox78119_ch05_105-127.indd 115

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116

Chapter 5

Outer mitochondrial membrane

Inner mitochondrial membrane

H+ Intermembrane space H+

H+

Second pump

Third pump

1 First pump e 1 4 H+

2 H+

H2O 3 ADP + Pi

2 H + 1/2 O2

ATP synthase

H+

ATP

4 H+ NADH

NAD+ Matrix

Figure 5.11 The steps of oxidative phosphorylation. (1) Molecules of the electron-transport system function to pump H+ from the matrix to the intermembrane space. (2) This results in a steep H+ gradient between the intermembrane space and the cytoplasm of the cell. (3) The diffusion of H+ through ATP synthase results in the production of ATP.

Chemiosmotic theory - electron transport system, powered by transport of electrons, pumps protons (H) from mitochondrial matrix into space between inner and outer mitochondrial mem. (producing 1 ATP per cycle). These numbers are certain ADP and Pi, which are transported into the mitochondrion. Electron-transport system is grouped into three complexes serves as proton pumps. and constant. In the second method of ATP formation, Thus, it effectively takes 4 protons to produce 1 ATP that First pump (NADH-coenzyme Q reductase complex) transports 4H from matrix to oxidative phosphorylation, the numbers of ATP molenters the cytoplasm. ecules produced vary space under different conditions for To summarize: The theoretical ATP yield is 36 to 38 ATP inermembrane for every pair of and electrons moved along the electron-transport system. different kinds of cells. For many years, it was believed per glucose. The actual yield, allowingspace for the costs Second pump (cytochrome c reductase complex) transports 4H into ATP intermembrane that 1 NADH yielded 3 ATP and that 1 FADH2 yielded 2 of transport into the cytoplasm, is about 30 to 32 ATP per Third pump (cytochrome c oxidase complex) transports 2H into intermembrane space ATP by oxidative phosphorylation. This gave a grand total glucose. The details of how these numbers are obtained are results in higher [H] in intermembrane space than in matrix, favoring diffusion of H back into of 36 to 38 molecules of ATP per glucose through cell resdescribed in the following section. pirationmatrix (table 5.2). Newer biochemical information, however, suggests that these numbers may be overestimates, inner mitochondrial membrane does not permit diffusion of H, except through respiratory Detailed Accounting because, of the 36 to 38 ATP produced per glucose in the assemblies mitochondrion, only 30 to 32 ATP actually enter the cytoEach NADH formed in the mitochondrion donates 2 electrons repiratory assemblies consist of group of proteins formstransport stem system and globular plasm of the cell. to that the electron at the firstsubunit. proton pump (see Stem passage of protons (H). Roughly 3 permits protons must pass through the respiratory fig. 5.11). The electrons are then passed to the second and assemblies and activate ATP synthase to produce 1 ATP. Howthird proton pumps, activating them in turn until the Globular subunit contain ATP synthase enzyme that catalyzes ADP + each P toof ATP by diffusion ever, the newly formed ATP is in the mitochondrial matrix 2 electrons are ultimately passed to oxygen. The first and of H through the respiratory assemblies into matrix and must be moved into the cytoplasm; this transport also second pumps transport 4 protons each, and the third pump Function of Oxygen uses the proton gradient and costs 1 more proton. The ATP transports 2 protons, for a total of 10. Dividing 10 protons + remain in reduced state, unable to accept electrons. Electron transport and If H last are cytochrome transported into the cytoplasm in exchange for by the 4 it takesmore to produce an ATP (in the cytoplasm) gives would then progress only to the next-to-last cytochrome and continue til all elements remain in

fox78119_ch05_105-127.indd 116

25/06

electron-transport chain remained in the reduced state. At Overview this point, the electron-transport system would stop functioning and no ATP could be produced in the mitochondria. There are two different methods of ATP formation in With the electron-transport system incapacitated, NADH and cell respiration. One method is the direct (also called FADH2 could not become oxidized by donating their electrons substrate-level) phosphorylation that occurs in glycolyto the chain and, through inhibition of Krebs cycle enzymes, sis (producing a net gain of 2 ATP) and the Krebs cycle no more NADH and FADH2 could be produced in the mitochondria. The Krebs cyclestate. would At stop and only electron-transport anaerobic reduced this point, system would stop functioning and no ATP metabolism could occur. produced CLINICAL APPLICATION Oxygen, from the ETC air weincapacitated, breathe, allows electron With NADH transand FADH2 could not oxidized, and through inhibition of Krebs port to continue by functioning as the final electron acceptor Cyanide is be a fast-acting lethal poison that produces such cycle enzymes, no more NADH and FADH2 could not be produced in mitochondria. Krebs of the electron-transport chain. This oxidizes cytochrome a3, symptoms occur. as rapid heart rate, tiredness, seizures, and headache. cycle would stop and only anaerobic metabolism allowing electron transport and oxidative phosphorylation to Cyanide can electron result in coma, and ultimately death, in electron transport to continue by poisoning being nal acceptor in ETC. continue. At theOxygen very last allows step of aerobic respiration, therethe absence of quick treatment. The reason that cyanide is so fore, oxygen becomes reduced by the 2 electrons that were electron transport and oxidative phosphorylation to This oxidizes cytochrome a3, allowing deadly is that it has one very specific action: it blocks the transfer . This reduced passed to the chain from NADH and FADH continue. 2 of electrons from cytochrome a3 to oxygen. The effects are thus oxygen binds 2 protons, and a aerobic molecule respiration, of water is formed. Last step of oxygen become reduced by 2 electrons were removed passed to the same as would occur if oxygen werethat completely Because the oxygen atom is part of a molecule of oxygen gas the chain from NADH and FADH2. aerobic cell respiration and the production of ATP by oxidative (O2), this last reaction can be shown as follows: comes to a halt. Oxygen binds 2H, and a mole of water isphosphorylation formed + O2 + 4 e + 4 H 2 H2O

05_105-127.indd

ATP Balance Sheet 2 different methods of ATP formation in cell respiration Direct (substrate-level) phosphorylation occurs in glycolysis (producing net gain of 2 ATP) and Krebs cycle (producing 1 ATP per cycle) 115 25/06/10 9:10 PM These numbers are certain and constant Oxidative phosphorylation ATP produced vary under different conditions and for different kinds of cells. only 30 to 32 ATP actually enter cytoplasm of cell It takes 4 protons to produce 1 ATP that enters cytoplasm Theoretical ATP yield is 36 to 38 ATP per glucose. Actual ATP yield, allowing for costs of transport into cytoplasm is about 30-32 ATP per glucose Detail Accounting Each NADH formed in mitochondrion donates 2 electrons to ETC at rst proton pump. Electrons are then passed to second and third proton pumps, activating each until 2 electrons are passed to oxygen. First and second pumps transport 4 proton each Third pump transports 2 protons Total of 10 Dividing 10 protons by the 4 it takes to produce an ATP (in the cytoplasm) gives 2.5 ATP produced for every pair of electrons donated by NADH Three molecules of NADH are formed w/ each Krebs cycle One NADH is also produced when pyruvate is converted into acetyl CoA One glucose, two Krebs cycle (producing 6 NADH) and 2 pyruvate converted to acetyl CoA (producing 2 NADH) yield 8 NADH 8 NADH multiply by 2.5 ATP gives 20 ATP Electrons from FADH2 are donated later in ETC and activate only second and third H pumps. Electrons passed from FADH2 result in pumping of only 6 proton (4 by second and 2 by third) 1 ATP is produced for every 4 proton pump, electron derived from FADH2 result in formation of 1.5 ATP Each Krebs cycle produces 1 FADH2 and we get two Krebs cycle from 1 glucose, there are 2 FADH2 that gives 3 ATP 23 ATP subtotal from oxidative phosphorylation from only NADH and FADH2 produced in the

mitochondrion. Glycolysis also produces 2 NADH, but cannot directly enter mitochondrion, but can be shuttled in. the 2 NADH is translated into 2 FADH2 when shuttled into mitochondrion and yield 2 X1.5ATP = 3ATP This total to 26 ATP produced by oxidative phosphorylation from glucose. 117 Cell Respiration and Metabolism Adding 2 ATP from direct (substrate-level) phosphorylation in glycolysis and 2 ATP directly by two Krebs cycle gives a grand total of 30 ATP produced by aerobic respiration of glucose
Table 5.2 | ATP Yield per Glucose in Aerobic Respiration
Phases of Respiration
Glucose to pyruvate (in cytoplasm)

ATP Made Directly

2 ATP (net gain)

Reduced Coenzymes
2 NADH, but usually goes into mitochondria as 2 FADH2

ATP Made by Oxidative Phosphorylation Theoretical Yield

If from FADH2: 2 ATP ( 2) = 4 ATP or if stays NADH: 3 ATP ( 2) = 6 ATP 3 ATP ( 2) = 6 ATP 3 ATP ( 6) = 18 ATP 2 ATP ( 2) = 4 ATP 32 (or 34) ATP

Actual Yield
If from FADH2: 1.5 ATP ( 2) = 3 ATP or if stays NADH: 2.5 ATP ( 2) = 5 ATP 2.5 ATP ( 2) = 5 ATP 2.5 ATP ( 6) = 15 ATP 1.5 ATP ( 2) = 3 ATP 26 (or 28) ATP

Pyruvate to acetyl CoA ( 2) Krebs cycle ( 2) Total ATP

None 1 ATP ( 2) = 2 ATP 4 ATP

1 NADH ( 2) = 2 NADH 3 NADH ( 2) = 6 NADH 1 FADH2 ( 2) = 2 FADH2

5.3 Metabolism of Lipids and Proteins Pyruvic acid and Krebs cycle acids serve as common intermediates in interconversion of glucose, lipids and amino acids 2.5 ATP that are produced for every pair of electrons donated We now have a total of 26 ATP (or, less commonly, by not an NADH. no such in thing as half an ATP; the 28 ATP) produced by oxidative phosphorylation from gluCells do store(There extrais energy form of extra ATP decimal fraction simply indicates an average.) cose. We can add the 2 ATP made by direct (substrate-level) When cellular ATP rise due to more energy (from food) is available than can be immediately used, Three molecules of NADH are formed with each Krebs phosphorylation in glycolysis and the 2 ATP made directly by ATP production is inhibited and glucose is converted into glycogen and fat a grand total of 30 ATP (or, less cycle, and 1 NADH is also produced when pyruvate is conthe two Krebs cycles to give verted into acetyl CoA (see fig. 5.7 ). Starting from 1 glucose, commonly, 32 ATP) produced by the aerobic respiration of Lipid Metabolism two Krebs cycles (producing 6 NADH) and 2 pyruvates conglucose ( table 5.2 ). Glucose converted into fat verted to acetyl CoA (producing 2 NADH) yield 8 NADH. glycolysis occurs pyruvic acid converted into acetyl CoA Multiplying by 2.5 ATPand per NADH gives 20 ATP. Some glycoltic intermediates (phosphoglyceraldehyde and dihydroxyacetone phosphate) do Electrons from FADH are donated later in the electron2 | C HEC KP OIN T transport system than those donated by NADH; consenot complete conversion to pyruvic acid and acetyle CoA does not enter Krebs cycle. quently, these electrons activate only the second and third 6. Compare the fate of pyruvate in aerobic and anaerobic instead they are used to produced variety of lipids, including cholesterol (used in synthesis of proton pumps. Since the first proton pump is bypassed, the cell respiration. bile salts and from steroid hormones), ketone of bodies, and fatty acids electrons passed FADH result in the pumping only 2 7. acid Draw chain. a simplified Krebs cycle and indicate the high6 protons (4 by the secondare pump and 2 by the third pump). Acetic acid subunits joined together to from fatty energy products. Because 1 ATP is produced every 4 protons pumped, six acetyl CoA will for produce a fatty acid of 12 carbons long. electrons derived from FADH2 result in the formation of 8. Explain how NADH and FADH2 contribute to oxidative Lipogenesis formation of fat, occurs in adipose tissue and in liver when concentration of 6 4 = 1.5 ATP. Each Krebs cycle produces 1 FADH and phosphorylation. 2 blood glucose is elevated following aare meal we get two Krebs cycles from 1 glucose, so there 2 FADH2 9. Explain how ATP is produced in oxidative thatAdipose give 2 1.5 ATP = 3 ATP. White Tissue phosphorylation. The 23 ATP subtotal from oxidative phosphorylation White fat - where most triglycerides in body are stored we have at this point includes only the NADH and FADH2 Lipolysis - lipase enzyme hydrolyze into glycerol and free fatty acids to be used produced in the mitochondrion. Remember thattriglycerides glycolysis, which occurs in the cytoplasm, also produces 2 NADH. These as energy source 5.3 METABOLISM OF LIPIDS cytoplasmic NADH cannot directly enter the mitochondrion, glycerol released into blood is mostly taken up by AND liver which converts into glucose through PROTEINS but there is a process by which their electrons can be gluconeogenesis shuttled in. The net effect of the most common shuttle Triglycerides can be hydrolyzed into glycerol and fatty Most energy carriers provided by lipolysis are free fatty acids is that signicant a molecule of NADH in the cytoplasm is translated acids. The latter are of particular importance because they into a molecule of FADH in the mitochondrion. The 2 NADH Brown Adipose Tissue 2 can be converted into numerous molecules of acetyl CoA
produced in glycolysis, therefore, usually become 2 FADH2 and yield 2 1.5 ATP = 3 ATP by oxidative phosphorylation. (An alternative pathway, where the cytoplasmic NADH is transformed into mitochondrial NADH and produces 2 2.5 ATP = 5 ATP, is less common; however, this is the dominant pathway in the liver and heart, which are metabolically highly active.)

that can enter Krebs cycles and generate a large amount of ATP. Amino acids derived from proteins also may be used for energy. This involves the removal of the amine group and the conversion of the remaining molecule into either pyruvic acid or one of the Krebs cycle molecules.

Brown fat - from different cells major site for thermogenesis (heat production) in newborn Ketone Bodies triglycerides in adipose tissue are continuously being broken down and resynthesized to ensure blood will normally contain sufcient level of fatty acids for aerobic resportion by skeletal muscles, liver and other organs When rate of lipolysis exceeds rate of fatty acid utilization (starvation, deting, and diabetes mellitus) blood concentration of fatty acids increases If liver cells contain sufcient ATP, some acetyl CoA derived from fatty acids is channeled and convert into acetoacetic acid and beta-hydroxybutyric acid. Adding acetone, produces ketone bodies Amino Acid metabolism Nitrogen ingest as protein, enters body as amino acid and excreted as urea in urine Childhood excrete less nitrogen because amino acid incorporated into protein during growth and are in state of positive nitrogen balance Negative nitrogen balance - excrete more nitrogen than they ingest because they are breaking down their tissue proteins Healthy adults maintain nitrogen balance by excreting equal amount of nitrogen ingested Transamination Essential amino acids - 8 proteins (9 in children) cannot be produced by body and must obtained in diet Nonessential - body can produce them if provided w/ sufcient carbohydrates and essential amino acids Transamination - Keto acid - pyruvic acid and Krebs cycle acids, can be converted to amino acid w/ addition of amine (NH2) group by cannibalizing another amino acid 121 Cell Respiration and Metabolism Transamination is catalyzed by enzyme transaminase which requires vitamin B6 (pyridoxine) as coenzyme. Table 5.3 | The Essential and Nonessential Amino Acids is required to
Essential Amino Acids
Lysine Tryptophan Phenylalanine Threonine Valine Methionine Leucine Isoleucine Histidine (in children)

roteins that are hildren) cannot ned in the diet. 3). The remaine sense that the fficient amount s. are collectively ne group; these odies (derived s section. Keto addition of an lly obtained by process, a new cannibalized is ction, in which no acid to form

Nonessential Amino Acids

Aspartic acid Glutamic acid Proline Glycine Serine Alanine Cysteine Arginine Asparagine Glutamine Tyrosine

d by a specific in B6 (pyridoxutamic acid, for acid or oxaloby the enzyme is catalyzed by e names reflect

Oxidative Deamination
As shown in figure 5.16, glutamic acid can be formed through transamination by the combination of an amine group with -ketoglutaric acid. Glutamic acid is also produced in the

Pyruvic acid

Acetyl CoA

Amino acids

Protein

Oxidative Deamination Urea C6 Removes amine groups from amino acids - leaving a keto acid and ammonia (which is Krebs converted to urea) C4 cycle more amino acid than are needed for protein synthesis, amine group from glutamic acid may C5 be removed and excreted as urea in urine of Different Energy Sources gen, fat, and Uses protein. These simplified metabolic pathways show how glycogen, Blood contains variety of energy e most reactions are reversible, the reaction from pyruvic acid sources to acetyl CoA is not. ly plants, in a phase ofglucose photosynthesis called the dark reaction, can use CO2 fatty to and ketone bodies from liver, acids from adipose tissue, and lactic acid and amino acids from muscle Brain uses blood glucose as its major energy source Table 5.4 | Relative Importance of Different Molecules in the Blood with Respect to the Energy Requirements of Different Organs UES
Organ
Brain

one dies

nger after

Glucose
+++

Fatty Acids
+++ +++ ++

Ketone Bodies
+ + ++ +

Lactic Acid
+ +

se

help outs?

Skeletal muscles + (resting) Liver Heart + +

pathway dicate only e steps of

d explain, ergy.

d explain

ain, in of energy.

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