Chapter 5 Cell Respiration 501h67

Chapter 5 Cellular Respiration & Metabolism Cell Respiration and Metabolism

107

5.1: Glycolysis and the Lactic Acid Pathway Glycogen in liver

Glucose from digestive tract

Glucose from liver

Capillary

Glucose in blood plasma

Interstitial fluid Plasma membrane Glucose in cell cytoplasm Glycolysis

Anaerobic

Pyruvic acid

Metabolism in skeletal muscle

Lactic acid

Cytoplasm

into mitochondrion Krebs cycle

Electron transport

Aerobic Respiration

CO2 + H2O

Mitochondrion

re 5.1 Overview of energy metabolism using glucose. of Theglucose blood glucose may be obtained food via the ~30 ATP Complete combustion of blood a molecule requires oxygenfrom 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 (anabolic catabolic) reactions body involve energy transformation rated compared to the size of the other- structures andand the interstitial (extracellular tissue) in fluid.

Catabolic reactions - release energy by breakdown of larger organic molecules

acid

ch pyruvic acid molecule contains 3 carbons, 3 oxyAlthough the overall equation for glycolysis is exergonic, break of glucose, acids,must andbeamino acids serve as primary sources of energy for and 4 hydrogens (see fig. 5.4).down The number of carbonfatty glucose “activated” at the beginning of the pathway xygen atoms in 1 molecule of glucose—C H O —can before energy can be obtained. This activation requires the synthesis of ATP 6 12 6 be ed 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 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, ed from the intermediates in glycolysis. Each pairfat of andasprotein) an “up-staircase” in figure 5.2. Notice that the Pi is not hydrogen atoms is usedEnergy to reducetransfer a molecule of NAD. oxidation-reduction shown in these reactions in figure 5.2; this is because the involves reactions. process, each pair of hydrogen atoms donates 2 elehosphate 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 final election acceptor an oxygen in animal cell (see chapter 4, fig. 4.17). Starting from 1 glucose 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 thethat cell.converts This is because phosphorylated pathway involving 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 glucose is released atreduced) early steps in metabolic pathway, ycolysis is exergonic, andamount a portionofofchem-bond the energy energy duced of (and 2 molecules of NAD are as energy is released is used some to drive the endergonic liberated (theATP “down-staircase” fig.temporary 5.2). The 2 molecules tissue cells canreaction obtain energy from productioninin 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 ofinglycolysis 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.

Lactic Pyruvic acid as H 1 (see chapter 4, fig. 4.17). Starting fromas 1 glucose molfor glycolysis, the phosphoryl 1 proton from the hydrogen atoms, leaving proton unbound known phosphorylation. Besides being essential Because the 2 pyruvic acids together forgroup only is8acid of ATP. Energy from the reaction ATP → ADP + Pi is t ecule, results in the production of 2 mol6-phosphate) an important as H+ (see chapter 4, fig. 4.17). Starting fromtherefore, 1 glucoseglycolysis 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 into2mitochondrion in subsequent socose for within simplicity to molecules cannot cross plasma ecules of NADH and H+. The H+ will follow the reactions, NADH the we cell.can Thisrefer 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 as NADH. At later steps in glycolysis, in subsequent reactions, so for simplicity weNAD can simply refer to molecules cannot cross plasma membranes. In this process, eachKrebs pair of hydrogen atoms donates 2 elehosphate is not released, but instead is added to the Electron is exergonic, and aCOportion Mitochondrion H2O of Glycolysis 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 trons to NAD, thereby reducingtransport it. The reduced NAD binds mediate molecules of glycolysis. The addition of a phos Respiration that is released is used to duced drive the “down-staircase” Glycolysis is exergonic, and a portion of the energy (andendergonic 2 moleculesreaction of NAD are liberated reduced)(the as energy is 1 proton from the hydrogen atoms, leaving 1 proton unbound group is known as phosphorylation. Besides being ess + Pi → ATP. At therespiration endliberated of the glycolytic pathway, therein fig.of5.2 ATP used the beginning, t that is released isbody to drive theADP endergonic reaction (the “down-staircase” ). The 2 in molecules Most obtain energy by aerobic in mitochondria +usedcells as H (see chapter 4, fig. 4.17). Starting from 1 glucose molfor glycolysis, the phosphorylation of glucose (to glu Pi → ATP. At the end of the glycolytic of ATP per usedglucose in the beginning, therefore, represent the an energy is a net pathway, gain ofglucose. 2there ATP molecules molecule, as investment; net gain of 2 gure ADP 5.1+ Glycolysis Overview of energy metabolism Theofblood glucose6-phosphate) may be obtained food via theside benefit: it traps the ecule, therefore, glycolysis using resultsblood in the production 2 molhasfrom an important is a net gain of 2 ATP molecules perindicated glucose molecule, as equation investment; the net gain of 2 ATP and in the overall for glycolysis: by 2theNADH end ofmolecules the pathway rep + + estive tract, or the liver may produce from stored glucose enters the cytoplasm cells, where it can beisused for phosphorylated or ecules of NADH and 2 for Hglycogen. . energy, The HPlasma will follow NADH cose of within the cell. This because ofitglucose begins in the cytoplasm indicated inBreakdown the overall equation for glycolysis: by the end of the pathway representsoverall an energy profit.forThe equation 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 isconsisting Glucose + 2 NAD + 2 ADP + 2 Pi → a metabolic pathway 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 + a 2metabolic separatesteps steps. NADH +pathway 2 ATP consisting of nine individual in The this pathway Glycolysis is exergonic, and a portion of theindividual energy duced (and molecules NAD are reduced) as ener Each pyruvic acid2 molecule contains 3 carbons, 3 oxyAlthough the overall for2 glycolysis isof exergonic, pyruvic acid + 2 NADH + 2 ATP stepsequation in this pathway are shown in figure 5.3. that is released exergonic, is used to drive the of endergonic reaction is used liberated drive (the “down-staircase” in fig. 5.2). The 2 mole Glycolysis portion energy released endergonic reaction s, and 4 hydrogens (see fig. 5.4). is The number of carbon glucose must be “activated” atto 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 glucose—C6H12O6—can before energy can be obtained. This activation requires the is a net gain of 2be ATP moleculesatper glucose molecule, as investment; theaddition net gain of of two 2 ATP and 2 NADH mole activated and requires phosphate s be ed for Glucose in the 2 must pyruvic acid molecules. beginning additionofofglycolysis 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 for only 8 ofan ATP. Energyinvestment. from the reaction ADP + Pi is from 2 ATP. 2 ATP represent energy 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 notshown25/06/10 ch05_105-127.indd 107 intermediates in glycolysis. Each pair of 9:10 PM 2 pyruvic- addition acid + 2 NADH +2 in that this pathway in figure 5.3 Phosphorylation 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 istonot 4 ATP his process, each2pair 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 1NADH 4 ATP. group is known as phosphorylation. Besides being essential roton from the hydrogen atoms, leaving proton and unbound H+ (see chapter 4, fig.net 4.17). Starting from 1 glucose molfor glycolysis, the phosphorylation of glucose (to glucose 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 cannotCellcross plasma membranes. 109 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 HATP used represent an energy H H ADP glucose molecule, as net gain of 2 ATP molecules per investment; the net gain Lactic of 2acidATP and 2 NADH molecules Pyruvic 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.

ndd 107

+

6 12

ATP

6

3

ADP

Dihydroxyacetone phosphate

Fructose 1,6-biphosphate 4

3–Phosphoglyceraldehyde Pi

Pi

NAD 2H

5

NADH

NAD 2H

5

NADH

1,3–Biphosphoglyceric acid ADP ATP

3–Phosphoglyceraldehyde

1,3–Biphosphoglyceric acid ADP

6

ATP

6

3–Phosphoglyceric acid

3–Phosphoglyceric acid

7

7

2–Phosphoglyceric acid

2–Phosphoglyceric acid

8

8

Phosphoenolpyruvic acid

Phosphoenolpyruvic acid ADP

ADP ATP

9

Pyruvic acid (C3H4O3)

Figure 5.3

ATP

9

Pyruvic acid (C3H4O3)

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.

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 ed. 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.

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.

25/06/10 9:10 PM

109

Cell Respiration and Metabolism

Lactic Acid Pathway NADH + H+ H

H

O

C

C

O

Pyruvic acid

glyceraldehyde

5

hoglyceric acid 6

oglyceric acid 7

oglyceric acid 8

olpyruvic acid

9

cid (C3H4O3)

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

H

C

H

Dihydroxyacetone phosphate

NAD

OH

LDH

H

OH

C

C

H

H

O C OH

Lactic acid

When oxygen notformation available, NADH +H produced Figure 5.4 isThe 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 pyruvicin acid produces lactic andand oxidized NAD. This result reformation of acid NAD addition of 2reaction 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 useinonly organic the last acceptor 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 canthey survive asother longcells. as sufficient can be produced for its need and lactic oxygen carry w/ for oxygen delivery to Except for energy red acid is not excessive bloodconcentrations cells, anaerobic metabolism occurs for only a limited period oflonger time inunder tissuesanaerobic that have energy requirements in Survive conditions excess of their aerobic ability. Anaerobic metabolism occurs Skeletal muscles > cardiac muscle > brain in the skeletal muscles and heart when the ratio of RBCs, lack mitochondria and can only use lacticoxyacid 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 ed until the emergency (oxygen deficiency) has ed. 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 islactic a normal, occurrence harm fatigue excessive acid daily associates w/ that paindoes andnot muscle muscle tissue or the individual. Excessive lactic acid producGlycogenesis and Glycogenolysis tion by muscles, however, is associated with pain and muscle Liver, muscles,ofand heart storeiscarbohydrates in form of glycogen, abundance of glucose fatigue.skeletal (The metabolism skeletal muscles discussed in molecules would 12.4.) exertInancontrast osmotic pressure and the would draw dangerous amount of water into cells chapter 12, section 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 it’s isomer, glucose may be present. 1-phosphate. Glycogen synthase removes phosphate group to polymerize glucose into glycogen Glycolysis conversion into 2 molecules of pyruvic acid C L I N I C- A L A P P Lof I Cglucose 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 aglucose 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(ortriglycerides (fat), in adipose tissue severe pain in the chest and left sometimes, right) armprimarily area. This pain is associated with increased blood levels of lactic acid Lipolysis - hydrolysis (breakdown) of triglycerides, primarily in adipose tissue which are produced by the of ischemic muscle. If the Ketogenesis - formation ketoneheart 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.

12

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.

Fructose 6-phosphate

GLYCOLYSIS

The liver contain enzyme, glucose 6-phosphatase, able to remove phosphate groups and produce free glucose able tobebe transported through plasma membrane Glucose 6-phosphate in liver and cells can then used as an 111 | C H blood E CCellKRespiration P O I NandTMetabolism intermediate for secrete glycogen synthesis, or into it can blood, be converted Liver can glucose andtothereby supply glucose for use by other organs

Chapter 5

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. PThe 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

5.2 AEROBIC RESPIRATION

H

Cori Cycle

1. Define the term glycolysis in 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

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

NAD

NADH + H+

H H C H H C H n the aerobic respiration of glucose, pyruvic acid is Skeletal muscles Liver in liver cells can then be used as an C O | + CSH ECoA C O + CO2 ormed by glycolysisGlucose and 6-phosphate then converted into acetyl CKPOINT Glycogen intermediateGlycogen for glycogen synthesis, or it can be converted to oenzyme A. Thisfree begins cyclic metabolic pathway Cori cycle. During C 1. Define the term glycolysisFigure CoA SThe glucose athat is secreted into the blood. The conversion in of5.6 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. As1 a result9 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. GlucoseNAD 6-phosphate Glucose 6-phosphate Glucose The arge amount of an reduced and FADcalled (NADH and extremely important process gluconeogenesis. Coenzyme Acetyl coenzyme Pyruvic acid lactic and acid pathway (steps 2. What are the initialAsubstrates final products of 1Athrough 3). 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 discussed2together with amino acid metabolism (section 5.3). Figure6 3.5.7 The formation(step of acetyl coenzyme A in 4) to the Describe the physiological functions ofliver, lacticwhere acid it is converted exercise, of thethe lacticformation acid produced by skelide electrons for a During process thatsome drives aerobic respiration. Notice that NADtois reduced to NADH (steps in back 6-phosphate 5 and Pyruvic acid Pyruvic acid fermentation. In which tissue(s) isglucose anaerobic etal muscles may be transformed through gluconeogenesis in this process.metabolism normal? In which 6). This is next f ATP. tissue is itconverted abnormal?into free glucose the liver to blood glucose. This new glucose can serve as an

5 3 (step 7), glucose which can beglycogen carried by the blood 4. Describe the pathways by which and 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 thisglycogen. glucose can be used to secrete from itsrest, stored 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. eachthepyruvic genesis in the liver allows depleted skeletal muscle glycogen processSince replenishes glycogenacid storesmolecule of skeletal is conAfter studying this section, should be able to: Intohumans and mammals, lactic acids produced anaerobic metabolism eliminated by aerobic be restoredyou within 48 hours. following exercise. verted into in 1muscles molecule of acetyl CoA and is 1 CO , 2 molecules 2

of lacticofacid 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

glucose. to These acetyl+ CoA acid to pyruvic acid and NAD is reduced NADH H. molecules serve as substrates for mitochondrial enzymes in the(lactic aerobicacid, pathway, whileacids, the car-glycerol) - conversion amino 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 mayacid, beThe transformed through cycle. During is derived fromFigure pyruvic5.6 notCori 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 skeletalThis muscle restore in 48hrs lactic acidglycogen is carried by theto blood Krebs Cycle 6 2 (step 4) to the liver, where it is converted 5.2: Aerobic Respiration backformed, to glucose the 6-phosphate and acidCoA has been Pyruvic acid Once Pyruvic acetyl acetic (steps acid 5subunit The aerobic respiration of glucose (C6H12 O6) is given Glucose used to formed pyruvic acidinby 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

C6H12O6 + O2 → 6 acid CO2 + 6 H2O Lactic

Blood

(step 8) back to the skeletal muscles.

acid only as a transporter zyme Lactic A acts acetic from During rest, thisof 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 (38-40%) released is captured in high-energy bonds Energy is released istosmall, and ainportion NAD). The formation of citric acid begins a cyclic metabolic f its final products (CO2respiration and H2O) and ofbegins the totalw/ glycolysis Aerobic ofinglucose 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 2carboxylic pyruvic acid acid, 2 ATP, 2 citric acid has three 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 25/06/10 9:10 eleased isfox78119_ch05_105-127.indd captured in the111high-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

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.

N

H

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

ble to:

H

C

H

H

C

O

+ S

NAD CoA

C HO

NADH + H+

H H

C

H

C

O + CO 2

S

CoA

O

Pyruvic acid

Coenzyme A

Acetyl coenzyme A

Figure 5.7 The 1 formation acetyl coenzyme A in Glycolysis converts glucoseofinto 2 pyruvic acid aerobic respiration. Notice that NAD is reduced to NADH each pyruvic acid is converted into 1 acetly CoA inand 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 con-

cose through

d oxidative ygen in this

m glycogen d how the liver

O6) is given in

ustion in 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

the cell cytomitochondria. rbon dioxide is n-long pyruvic

their 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 transportfor chain. The first molecule of the electron-transport chain turn becomes reduced when it accepts the electron mitochondrial enzymes in the aerobic pathway, while theincarC3 Pyruvic acid fromtoNADH. When the cytochromes receive a pair of bon dioxide is a waste product that is carried by thepair blood CYTOPLASM electrons, 2 ferric ions (Fe3+) become reduced to 2 ferrous the lungs for elimination. It is important to note thations the(Fe oxy2+ ). gas. gen in CO2 is derived from pyruvic acid, not from oxygen The electron-transport chain thus acts as an oxidizing Glycolysis

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(from subunit Fe2+ to Fe3+). This is an exergonic process, and the derived is used to phosphorylate ADP to ATP. The (2 carbons long) combines with oxaloacetic acid (4energy 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 +cyclic H+ NAD). The formation a metabolic Krebs cycleof citric acid begins released by electron transport (the “oxidative” part of oxidaCitric acid C6 1 FADH2 tive(for phosphorylation) and the energy incorporated into the pathway known as the citric acid cycle,1 ATP or TCA cycle trichemical bonds of ATP (the “phosphorylation” part of the C5 carboxylic acid; citric acid has three carboxylic acid groups). α-Ketoglutaric acid term). This difference in energy escapes the body as heat. Most commonly, however, this cyclic pathway is called theheat production is needed to maintain our internal Metabolic Krebs cycle, after its principal discoverer, Sir Hansbody Krebs. A temperature. NAD

Krebs Cycle

CO

simplified illustration 2of this pathway is shown in figure 5.8. FigureThrough 5.8 ACoA simplified of theacetic Krebs acid a series offormed, reactions involving thesubunit elimination Once acetyl hasdiagram 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 in contrast Only the numbers of carbon atoms in the Krebs cycle formation of citric acid begins cyclic metabolic pathways knownwith asunpaired citric electrons, acid cycle or TCA cycle to molecules oxaloacetic acid, the which completes theand cyclic metabolic path- that are not free radicals because they have two intermediates are shown; numbers of hydrogens oxygens (tricarboxylic acid) aka Krebs cycle areway not ed simplified scheme. (fig. 5.9for ). inInthis this process, these events occur: electrons per orbital. A superoxide radical is an oxygen molecule with 4 anoxygens extra, unpaired be generated in Reactions involve elimination of 2 carbons and (aselectron. CO2)These andcan removal of hydrogens,

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

through the leakage of electrons from the

system. Superoxide radicals have some Electron Transport anda phosphate group toelectron-transport 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

Three molecules of NAD areinner reduced to NADH (steps 4, 5, of bacteria. However, the production of free radicals destruction Built2. into the foldings, or cristae, of the mitochondrial and other molecules classified as reactive oxygen species membrane are8aof series molecules that serve as an electronand fig.of5.9 ). the superoxide, hydroxyl, and nitric oxide free transport system during aerobic respiration. This electron3. One molecule of FAD is reduced to FADH (step(including 6). radicals) have been implicated in many disease processes, transport chain of molecules consists of a protein containing2 atherosclerosis (hardening of the arteries—chapter 13, flavin mononucleotide (abbreviated FMNand andFADH derived by fromeach including The production of NADH “turn” of 2 ironsection 13.7). Accordingly, reactive oxygen species have been the vitamin riboflavin), coenzyme Q, and a group of

HO

H

H2O

COOH

Acetyl CoA (C2)

H

C O H

1

2

C H

H

C COOH COOH

H

O

COOH

CoA +

C C S

H2O

HH C OH

COOH

Acetyl H CoA (C2H)

C

H

COOH

CoA

HO

H2O

H NAD

1

C H

H

C H C COOH

COOH

C H COOH

CCOOH OH

NADH + H+

NADH + H+

H

H

FADH2

2H

7

Fumaric acid (C4) 6

C H

COOH

Fumaric acid (C4)

H

C6 H

H

C H

COOH

H H

Succinic acid (C4)

H

C OH

C H

H

C COOH

H

C OH

4

2H

NAD

4

2H

NAD

CO2 COOH

FADH2

ADP

2H

FAD

2H

ATP

GTP ADP

GDP

COOH C H C H

C COOH

ATP

C HOOC

H

FAD

COOH

H

COOH Isocitric acid (C6)

NAD

COOH C Malic acid (C4)

COOH

3

cis-Aconitic acid (C6)

2H

C H

H2O

NADH + H+

8

HC C H

H2O

2

C H

H

COOH Isocitric acid (C6)

COOH

Citric acid (C6)

COOH

COOH

HOOC

H2O

C COOH

Oxaloacetic acid (C4)

7 HH

H C H + H+ NADH

2H

C O

COOH Malic acid (C4)

H2O

HS

COOH

3

cis-Aconitic acid (C6)

citric acid is converted to oxaloacetic acid 8 H

H2O

C H

Citric acid (C6)

Oxaloacetic acid (C4)

Chapter 5

C H

COOH

C H COOH

114

COOH

C COOH

NADH + H+

2H GTP

GDP

NAD

COOH

Succinic acid (C4)

5

CO2

CO NADH 2

NADH H

+ H+

COOH C H CO2 C H C O

H

C H

H

C H C O COOH

α-Ketoglutaric acid (C5)

COOH α-Ketoglutaric acid (C5)

5 H2O

H2O

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 2

into the space between the inner and outer mito-

The respiratoryis assemblies consist ofwhich a group ofdonates proteins Step 5: 1 GTP (guanosine triphosphate) produced, a phosphate group to

system mitothat form a “stem”The 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 produced one grouped intoADP three to complexes that serve as ATP proton a channel through the inner mitochondrial membrane that chondrialis 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 age of protons (H ). The globular subunit, Steps 4, 5, and three NAD are is grouped into three complexes serve as proton a channel through thean inner mitochondrial membrane that Q  reductase complex) transports 4 that H+ 8: from the matrix which reduced protrudes into to the NADH matrix, contains ATP synthase to the intermembrane space for every pair ofreduced electrons toenzyme that permits catalyzes the reaction ADP +of Pi → ATP when(H it +). The globular subunit, Step 6: pump one FAD isNADH-coenzyme FADH2 pumps (fig. 5.11 ).  The first (the the age protons moved along the electron-transport system. The second is activated by the diffusion of protons through the respira+ Q  reductase transports H from theFADH2 matrix which protrudes into the matrix, contains an ATP synthase production of4complex) NADH and by each Krebs cycle is way, more significant in of pump complex) (the cytochrome c reductase also transtory assemblies andturn into theof matrix (fig. 5.11 ). In this ports 4 protons intospace the intermembrane space, and the phosphorylation (the addition of phosphate the to ADP) is cou- ADP + P → ATP when it to the intermembrane 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 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 backa series 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 flavin 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. + riboflavin), 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, favoringa3 thedonates diffusionelectrons of H+ back to oxygen in final reaction) out into the matrix. The inner mitochondrial membrane, the last cytochrome remainedand in atransport reduced state, it would Electron-transport system pick up electronsIffrom NADH and FADH2 them in difinite + however, doessequence not permitand diffusion of H , except through be unable to accept more electrons. Electron transport 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

78119_ch05_105-127.indd 114

25/06/10 9:10

Cell Respiration and Metabolism

NADH

FMN

NAD

FMNH2

Electron energy

2 H+

115

2 e–

FADH2

Oxidized

Fe2+

CoQ

Cytochrome b

FAD

Reduced

Fe3+ 2 e–

Fe2+ Cytochrome c1 and c 3+ Fe

Fe3+ Cytochrome a Fe2+ –

2e

Fe2+

H2O

Cytochrome a3 3+

2e

Fe

–

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 processof would continue until all of the elements of the ATP Balance Sheet system 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 ofoxidized electron-transport chain substrate-level becomes )reduced when accepts electron pair from FADH could not become by donating their electrons phosphorylation thatitoccurs 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 andaonly 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 acceptorand FAD ETC acts as oxidizing agent for NAD Cyanide is a fast-acting lethal poison that produces such of the electron-transport chain. This oxidizes cytochrome a , symptomspair as rapid rate, cytochrome tiredness, seizures, and One reduced cytochrome transfers its electron toheart next inheadache. ETC, functioning as a allowing electron transport and oxidative phosphorylation to 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 process and energy derived isone used to phosphorylate ADP to ATP reduced ed to the chainexergonic 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 (O ),w/ thisphosphorylation last reaction can be shownof 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

2

2

fox78119_ch05_105-127.indd 115

–

+

2

25/06/10 9:10 PM

116

Chapter 5

Outer mitochondrial membrane

Inner mitochondrial membrane

2

H+ Intermembrane space

Third pump

Second pump

H+

H+

1

2 H+

First pump 4 H+

e– 1

4 H+ NADH

H2O 3

2 H + 1/2 O2

ATP synthase

ADP + Pi

H+

ATP

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: Theelectron-transport theoretical ATP yield is 36 to 38 ATP inermembrane for every pair of and electrons moved along the system. different kindspump of cells. For many years, it was believed glucose. The yield, allowingspace for the costs Second (cytochrome c reductase complex)pertransports 4Hactual 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 diffusioning of H, except through respiratory Detailed 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 formstransport “stem” system and globular plasm of the cell.assemblies consist of group of proteins to that the electron at the firstsubunit. proton pump (see Stem3 permits age of protons (H). Roughly protons must through the respiratory fig. 5.11). The electrons are then ed to the second and assemblies and activate ATP synthase to produce 1 ATP. Howthirdthat proton pumps, activating themby in turn until the Globular subunit contain ATP synthase enzyme catalyzes ADP + each P toofATP diffusion ever, theofnewly formed ATP is in the mitochondrial matrix 2 electrons are ultimately ed to oxygen. The first and 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 + in reduced state,forunable to accept electrons. Electron transport and IfH last are cytochrome transported intoremain the cytoplasm in exchange 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 a fast-acting lethal poison that produces such cycle enzymes, no more NADH and FADH2 couldis be 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 final 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 bycytochrome the 2 electrons were electron transport and oxidative phosphorylation to This oxidizes a3,that allowing deadly is that it has one very specific action: it blocks the transfer . This reduced ed to the chain from NADH and FADH continue. 2 of electrons from cytochrome a3 to oxygen. The effects are thus oxygen binds 2 protons, andofa aerobic molecule respiration, of water is formed. Last step oxygen become reduced by 2if oxygen electrons were removed— ed to the same as would occur 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 ing Each NADH formed in mitochondrion donates 2 electrons to ETC at first proton pump. Electrons are then ed to second and third proton pumps, activating each until 2 electrons are ed 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 ed 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. Cell Respiration and Metabolism Adding 2 ATP from direct (substrate-level) phosphorylation in glycolysis and 2 ATP directly by117 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

ATP Made Directly

Reduced Coenzymes

Glucose to pyruvate (in cytoplasm)

2 ATP (net gain)

Pyruvate to acetyl CoA (× 2)

ATP Made by Oxidative Phosphorylation Theoretical Yield

Actual Yield

2 NADH, but usually goes into mitochondria as 2 FADH2

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

If from FADH2: 1.5 ATP (× 2) = 3 ATP or if stays NADH: 2.5 ATP (× 2) = 5 ATP

None

1 NADH (× 2) = 2 NADH

3 ATP (× 2) = 6 ATP

2.5 ATP (× 2) = 5 ATP

Krebs cycle (× 2)

1 ATP (× 2) = 2 ATP

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

3 ATP (× 6) = 18 ATP 2 ATP (× 2) = 4 ATP

2.5 ATP (× 6) = 15 ATP 1.5 ATP (× 2) = 3 ATP

Total ATP

4 ATP

32 (or 34) ATP

26 (or 28) ATP

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 extraisenergy 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 ATPcycle, production is inhibited and glucose is converted into glycogen and fat a grand total of 30 ATP (or, less 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 converted into acetyl CoA Multiplying by 2.5 ATPand per NADH givesacid 20 ATP. Some glycoltic intermediates (phosphoglyceraldehyde and dihydroxyacetone phosphate) do Electrons from FADH are donated later in the electron2 | Cdoes HEC KP O I NKrebs T transport system than those donated by NADH; consenot complete conversion to pyruvic acid and acetyle CoA not enter 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 byed, the cell respiration. bile saltsed and from steroid ketone ofbodies, and fatty acids electrons FADHhormones), result in the pumping only 2 Draw chain. a simplified Krebs cycle and indicate the high6 protonsacid (4 bysubunits the secondare pump and 2 by the third pump). Acetic ed together to from fatty7. acid energy products. Because 1 ATP isCoA produced every 4 protons six acetyl will for produce a fattypumped, 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 meal we get two Krebs cycles from 1 glucose, so thereaare 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. thattriglycerides glycolysis, which occurs in the cytoplasm, also produces 2 NADH. These as energy source 5.3 METABOLISM OF LIPIDS cytoplasmic NADH cannot the mitochondrion, glycerol released intodirectly bloodenter is mostly taken up by AND PROTEINS liver which converts into glucose through 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 provided by lipolysis are free fatty acids is that significant a molecule ofenergy NADH incarriers 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 Tissue2 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 sufficient 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 sufficient 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/ sufficient 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

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

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

Essential Amino Acids

Nonessential Amino Acids

Lysine

Aspartic acid

Tryptophan

Glutamic acid

Phenylalanine

Proline

Threonine

Glycine

Valine

Serine

Methionine

Alanine

Leucine

Cysteine

Isoleucine

Arginine

Histidine (in children)

Asparagine Glutamine Tyrosine

Oxidative Deamination As shown in figure 5.16, glutamic acid can be formed through transamination by the combination of an amine group with α-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 Different Energy gen, fat, and Uses protein.ofThese simplified metabolicSources pathways show how glycogen, Blood contains variety energy e most reactions are reversible, the reaction fromof pyruvic acid sources to acetyl CoA is not. ly plants, in a phase ofglucose photosynthesis the dark reaction, can use CO2 fatty to andcalled 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

one dies

nger after

Organ

Glucose

Fatty Acids

Ketone Bodies

Lactic Acid

se

Brain

+++

–

+

–

help outs?

Skeletal muscles + (resting)

+++

+

–

Liver

+

+++

++

+

Heart

+

++

+

+

pathway dicate only e steps of

d explain, ergy.

d explain

ain, in of energy.

25/06/10 9:10 PM