Frederick A. BettelheimWilliam H. BrownMary K. CampbellShawn O. Farrellwww.cengage.com/chemistry/bettelheim

William H. Brown • Beloit College

Chapter 27 Bioenergetics; How the Body

Converts Food to Energy

27-2

MetabolismMetabolism:Metabolism: The sum of all chemical reactions involved in maintaining the dynamic state of a cell or organism.• Pathway:Pathway: A series of biochemical reactions.• Catabolism:Catabolism: The process of breaking down large

nutrient molecules into smaller molecules with the concurrent production of energy.

• Anabolism:Anabolism: The process of synthesizing larger molecules from smaller ones.

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MetabolismMetabolism is the sum of catabolism and anabolism.

oxidation and the release of energy

Triglycerides Proteins

Fatty acidsand glycerol

Amino Acids

Small molecules

Anabolismof proteins

beakdown of larger molecules to smaller ones

Some nutrients and products of catabolism

Products of anabolism, including proteins and

nucleic acids

Catabolism Excretion

energy andreducing agents

Monosac-charides

Polysac-charides

ExcretionAnabolism

Catabolism Anabolism

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Cells and MitochondriaAnimal cells have many components, each with specific functions; some components along with one or more of their functions are:• Nucleus:Nucleus: Where replication of DNA takes place.• Lysosomes:Lysosomes: Remove damaged cellular components and some

unwanted foreign materials.• Golgi bodies:Golgi bodies: Package and process proteins for secretion and

delivery to other cellular components.• Mitochondria:Mitochondria: Organelles in which the common catabolic pathway

takes place in higher organisms; the purpose of this catabolic pathway is to convert the energy stored in food molecules into energy stored in molecules of ATP.

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A Rat Liver Cell• Figure 27.2

Diagram of a rat liver cell, a typical higher animal cell.

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A Mitochondrion• Figure 27.3 Schematic of a mitochondrion cut to reveal

the internal organization.

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The Common Metabolic Pathway• The two parts to the common catabolic pathway:

• TheThe citric acid cycle citric acid cycle, also called the tricarboxylic acid (TCA) or Krebs cycle.

• Electron transport chain Electron transport chain and phosphorylation phosphorylation, together called oxidative phosphorylationoxidative phosphorylation.

• Four principal compounds participating in the common catabolic pathway are:• AMP, ADP, and ATP: agents for the storage and transfer of

phosphate groups.• NAD+/NADH: agents for the transfer of electrons in

biological oxidation-reduction reactions• FAD/FADH2: agents for the transfer of electrons in biological

oxidation-reduction reactions • Coenzyme A; abbreviated CoA or CoA-SH: An agent for the

transfer of acetyl groups.

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Adenosine Triphosphate (ATP)ATPATP is the most important compound involved in the transfer of phosphate groups.• ATP contains two phosphoric anhydride bonds and

one phosphoric ester bond.

-N-glycosidic bondHH

HO

-O-P-O-P-O-P-O-CH2

HO OH

N

N

N

N

NH2

phosphoric anhydrides

phosphoricester

-D-ribofuranose

adenine

O-O- O-

H

O O O

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Adenosine Triphosphate (ATP)• Hydrolysis of the terminal phosphate (anhydride) of

ATP gives ADP, phosphate ion, and energy.

• Hydrolysis of a phosphoric anhydride liberates more energy than hydrolysis of a phosphoric ester.

• We say that ATP and ADP each contain high-energy phosphoric anhydride bonds.

• ATP is a universal carrier of phosphate groups.• ATP is also a common currency for the storage and

transfer of energy.

-O-P-O-P-O-AMPO

O--O

OH2O

ATP ADP

-O-P-O-AMP-O

OH2PO4

-+ + + 7.3 kcal/mol

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NAD+/NADH• Nicotinamide adenine dinucleotide (NADNicotinamide adenine dinucleotide (NAD++)) is a biological

oxidizing agent.

HH

H

O

HO OH

N

CNH2

-O-P-O-CH2

O

O

AMP H

O

a -N-glycosidic bond

+

The plus sign on NAD+

represents the positivecharge on this nitrogen

Nicotinamide;derivedfrom niacin

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NAD+/NADH• NAD+ is a two-electron oxidizing agent, and is reduced to

NADH.• NADH is a two-electron reducing agent, and is oxidized to

NAD+. The structures shown here are the nicotinamide portions of NAD+ and NADH.

• NADH is an electron and hydrogen ion transporting molecule.

NAd

CNH2

OH

H+ 2e-

NAd

CNH2

OH H

+ +

NAD+

(oxidized form)NADH

(reduced form)

:

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FAD/FADH2

• Flavin adenine dinucleotide (FAD)Flavin adenine dinucleotide (FAD) is also a biological oxidizing agent.

O=P-O-AMP

O-

CH2

C

O

C

C

CH2

N

H OH

OHH

H

N

N

NH3C

H3C O

HO

OH Ribitol

Flavin

Riboflavin

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FAD/FADH2

• FAD is a two-electron oxidizing agent, and is reduced to FADH2.

• FADH2 is a two-electron reducing agent, and is oxidized to FAD.

• Only the flavin moiety is shown in the structures below.

AdN

N

N

NHH3C

H3C O

O

+ 2H+ + 2e-H3C

H3C O

OH

HAdN

N

N

NH

FAD FADH2

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Coenzyme A• Coenzyme A (CoA)Coenzyme A (CoA) is an acetyl-carrying group.• Like NAD+ and FAD, coenzyme A contains a unit of

ADP• CoA is often written CoA-SHCoA-SH to emphasize the fact that

it contains a sulfhydryl group.• The vitamin part of coenzyme A is pantothenic acid.• The acetyl group of acetyl CoA is bound as a high-

energy thioester.

CH3-C-S-CoAO

Acetyl coenzyme A(An acyl CoA)

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Coenzyme A• Figure 27.7 The structure of coenzyme A.

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Citric Acid Cycle• Overview: the two-carbon acetyl group of acetyl CoA is

fed into the cycle and two CO2 are given off.• There are four oxidation steps in the cycle.

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

CoA

+ H+

+ H+

H+ +

CoA

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Citric Acid CycleStep 1: The condensation of acetyl CoA with oxaloacetate:• The high-energy thioester of acetyl CoA is hydrolyzed.• This hydrolysis provides the energy to drive Step 1.

• Citrate synthase, an allosteric enzyme, is inhibited by NADH, ATP, and succinyl-CoA.

CH3C-SCoAO

+

C-COO-

CH2-COO-O

C-COO-HO

CH2-COO-

CH2-COO-

+ CoA-SHAcetyl-CoA

Oxaloacetate

Coenzyme A

citratesynthase

Citrate

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Citric Acid CycleStep 2: Dehydration and rehydration, catalyzed by

aconitase, gives isocitrate.

• Citrate and aconitate are achiral; neither has a stereocenter.

• Isocitrate is chiral; it has 2 stereocenters and 4 stereoisomers are possible.

• Only one of the 4 possible stereoisomers is formed in the cycle.

C-COO-HO

CH2-COO-

CH2-COO-

Citrate

C-COO-

CH2-COO-

C-COO-H

CH-COO-

CH2-COO-

Aconitate

HO

Isocitrate

CH-COO-Aconitase

-H2O H2O

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Citric Acid CycleStep 3: Oxidation of isocitrate to oxalosuccinate followed by decarboxylation gives -ketoglutarate.

• Isocitrate dehydrogenase is an allosteric enzyme; it is inhibited by ATP and NADH, and activated by ADP and NAD+.

C-COO-H

CH-COO-

CH2-COO-

HOIsocitrate

C-COO-H

C-COO-

CH2-COO-

C-HH

C-COO-

CH2-COO-

NADH + H+NAD+

-Ketoglutarate

CO2

isocitratedehydrogenase

O O

Oxalosuccinate

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Citric Acid CycleStep 4: Oxidative decarboxylation of -ketoglutarate to succinyl-CoA.

• The two carbons of the acetyl group of acetyl CoA are still present in succinyl CoA.

• This multienzyme complex is inhibited by ATP, NADH, and succinyl CoA. It is activated by ADP and NAD+.

CH2

C-COO-

CH2-COO-

-Ketoglutarate

O

CoA-SH

NADHNAD+

-ketoglutaratedehydrogenase

complex

CH2

C

CH2-COO-

SCoAOSuccinyl-CoA

+ CO2

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Citric Acid Cycle• Step 5: Formation of succinate.

• The two CH2-COO- groups of succinate are now equivalent.

• This is the first, and only, energy-yielding step of the cycle. A molecule of GTP is produced.

CH2

C

CH2-COO-

SCoAO

+ GDP + PiCH2-COO-

CH2-COO-

+ GTP + CoA-SH

Succinyl-CoA Succinate

succinyl-CoAsynthetase

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Citric Acid Cycle• Step 6: Oxidation of succinate to fumarate.

• Step 7: Hydration of fumarate to L-malate.

• Malate is chiral and can exist as a pair of enantiomers; It is produced in the cycle as a single stereoisomer.

FAD FADH2

CH2-COO-

CH2-COO-

Succinate

succinatedehydrogenase

C

CH

H

COO-

-OOC

Fumarate

CC

H

H

COO-

-OOCFumarate

H2O CH-COO-HO

CH2-COO-

L-Malate

fumarase

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Citric Acid Cycle• Step 8: Oxidation of malate.

• Oxaloacetate now can react with acetyl CoA to start another round of the cycle by repeating Step 1.

• The overall reaction of the cycle is:

C-COO-

CH2-COO-

Oxaloacetate

NAD+ NADH

malatedehydrogenase

CH-COO-HO

CH2-COO-

L-Malate

O

CH3C-SCoAO

+ GDP +Pi + 3NAD++ FAD + 2H2O

2CO2 + GTPCoA + 3NADH + FADH2 + 3H++

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Citric Acid CycleControl of the cycle:• Controlled by three feedback mechanisms.• Citrate synthase:Citrate synthase: inhibited by ATP, NADH, and succinyl

CoA; also product inhibition by citrate.• Isocitrate dehydrogenaseIsocitrate dehydrogenase:: activated by ADP and NAD+,

inhibited by ATP and NADH.• -Ketoglutarate dehydrogenase complex-Ketoglutarate dehydrogenase complex:: inhibited by

ATP, NADH, and succinyl CoA; activated by ADP and NAD+.

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TCA Cycle in CatabolismThe catabolism of proteins, carbohydrates, and fatty acids all feed into the citric acid cycle at one or more points:

Pyruvate

-KetoglutarateSuccinyl-CoA

Fumarate

Oxaloacetate

Fatty AcidsProteins

Acetyl-CoA

Carbohydrates

Malate

intermediatesof the citric acid cycle

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Oxidative PhosphorylationCarried out by four closely related multisubunit membrane-bound complexes and two electron carriers, coenzyme Q and cytochrome c.• In a series of oxidation-reduction reactions, electrons

from FADH2 and NADH are transferred from one complex to the next until they reach O2.

• O2 is reduced to H2O.

• As a result of electron transport, protons are pumped across the inner membrane to the intermembrane space.

O2 + 4H+ + 4e- 2H2O + energy

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Oxidative Phosphorylation• Figure 27.10 Schematic diagram of the electron and H+

transport chain and subsequent phosphorylation.

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Complex IThe sequence starts with Complex I.• This large complex contains some 40 subunits, among

them are a flavoprotein, several iron-sulfur (FeS) clusters, and coenzyme Q (CoQ, ubiquinone).

• Complex I oxidizes NADH to NAD+.

• The oxidizing agent is CoQ, which is reduced to CoQH2.

• Some of the energy released in the oxidation of NAD+ is used to move 2H+ from the matrix into the intermembrane space.

NADH +H+ + CoQ NAD+ + CoQH2 + energy

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Complex II• Complex II oxidizes FADH2 to FAD.

• The oxidizing agent is CoQ, which is reduced to CoQH2.

• The energy released in this reaction is not sufficient to pump protons across the membrane.

FADH2 + CoQ FAD + CoQH2 + energy

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Complex III• Complex III delivers electrons from CoQH2 to

cytochrome c (Cyt c).

• This integral membrane complex contains 11 subunits, including cytochrome b, cytochrome c1, and FeS clusters.

• Complex III has two channels through which the two H+ from each CoQH2 oxidized are pumped from the matrix into the intermembrane space.

CoQH2 +

CoQ +2H+ +

2Cyt c (reduced)

2Cyt c (oxidized)

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Complex IV• Complex IV is also known as cytochrome oxidase.

• It contains 13 subunits, one of which is cytochrome a3

• Electrons flow from Cyt c (oxidized) in Complex III to Cyt a3 in Complex IV.

• From Cyt a3 electrons are transferred to O2.

• During this redox reaction, H+ are pumped from the matrix into the intermembrane space.

Summing the reactions of Complexes I - IV, six H+ are pumped out per NADH and four H+ per FADH2.

O2 + 4H+ + 4e- 2H2O + energy

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Chemiosmotic PumpTo explain how electron and H+ transport produce the chemical energy of ATP, Peter Mitchell proposed the chemiosmoticchemiosmotic theorytheory that electron transport is that electron transport is accompanied by an accumulation of protons in the accompanied by an accumulation of protons in the intermembrane space of the mitochondrion, which in turn intermembrane space of the mitochondrion, which in turn creates osmotic pressure; the protons driven back to the creates osmotic pressure; the protons driven back to the mitochondrion under this pressure generate ATP.mitochondrion under this pressure generate ATP. • The energy-releasing oxidations give rise to proton

pumping and a pH gradientgradient is created across the inner mitochondrial membrane.

• There is a higher concentration of H+ in the intermembrane space than inside the mitochondria.

• This proton gradient provides the driving force to propel protons back into the mitochondrion through the enzyme complex called proton translocating proton translocating ATPase.ATPase.

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Chemiosmotic Pump• Protons flow back into the matrix through channels in

the F0 unit of ATP synthase.

• The flow of protons is accompanied by formation of ATP in the F1 unit of ATP synthase.

The functions of oxygen are:

• To oxidize NADH to NAD+ and FADH2 to FAD so that these molecules can return to participate in the citric acid cycle.

• Provide energy for the conversion of ADP to ATP.

ADP + Pi ATP + H2O

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Chemiosmotic Pump• The overall reactions of oxidative phosphorylation are:

• Oxidation of each NADH gives 3ATP.

• Oxidation of each FADH2 gives 2 ATP.

NADH + 3ADP + O2 + 3Pi + H+ NAD+ + 3ATP + H2O12

FADH2 + 2ADP + O2 + 2Pi FAD + 2ATP + H2O12

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Energy YieldA portion of the energy released during electron transport is now built into ATP.• For each two-carbon acetyl unit entering the citric acid

cycle, we get three NADH and one FADH2.

• For each NADH oxidized to NAD+, we get three ATP.

• For each FADH2 oxidized to FAD, we get two ATP.

• Thus, the yield of ATP per two-carbon acetyl group oxidized to CO2 is:

3 NADH3 ATP

NADH= 9 ATP

1 FADH22 ATP

FADH2

= 2 ATP

1 GTP = 1 ATP= 12 ATP

x

x

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Other Forms of EnergyThe chemical energy of ATP is converted by the body to several other forms of energy:

Electrical energyElectrical energy• The body maintains a K+ concentration gradient across

cell membranes; higher inside and lower outside.• It also maintains a Na+ concentration gradient across

cell membranes; lower inside, higher outside.• This pumping requires energy, which is supplied by the

hydrolysis of ATP to ADP.• Thus, the chemical energy of ATP is transformed into

electrical energy, which operates in neurotransmission.

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Other Forms of EnergyMechanical energyMechanical energy• ATP drives the alternating association and dissociation

of actin and myosin and, consequently, the contraction and relaxation of muscle tissue.

Heat energyHeat energy• Hydrolysis of ATP to ADP yields 7.3 kcal/mol.• Some of this energy is released as heat to maintain

body temperature.

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Chapter 27 Bioenergetics

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

CoA

+ H+

+ H+

H+ +

CoA

End End Chapter 27Chapter 27