26 26-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e...

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26-1© 2003 Thomson Learning, Inc.All rights reserved

General, Organic, and General, Organic, and Biochemistry, 7eBiochemistry, 7e

Bettelheim,Bettelheim,

Brown, and MarchBrown, and March

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Chapter 26 BioenergeticsChapter 26 Bioenergetics

How the Body Converts Food to EnergyHow the Body Converts Food to Energy

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

Coenzyme A

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MetabolismMetabolism• Metabolism: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 biochemical pathways that are involved

in generating energy by breaking down large nutrient molecules into smaller molecules with the concurrent production of energy

• anabolism:anabolism: the pathways by which biomolecules are synthesized

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MetabolismMetabolism• metabolism is the sum of catabolism and anabolism

oxidation and the release of energy

Fats 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 MitochondriaCells and Mitochondria• Animal 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: responsible for generation of most of the

energy for cells• see also Figure 26.2, next screen

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A Rat Liver A Rat Liver CellCell

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A MitochondrionA Mitochondrion• Schematic of a mitochondrion cut to reveal its

inner organization

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Common Catabolic PthwyCommon Catabolic Pthwy• The two parts to the common catabolic pathway

• citric acid cyclecitric acid cycle, also called the tricarboxylic acid or Krebs cycle

• oxidative phosphorylationoxidative phosphorylation, also called the electron transport chain, or the respiratory chain

• The four principal compounds participating in the common catabolic pathway are:• AMP, ADP, and ATP• NAD+/NADH

• FAD/FADH2

• coenzyme A; abbreviated CoA or CoA-SH

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Adenosine TriphosphateAdenosine Triphosphate• 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 TriphosphateAdenosine Triphosphate• hydrolysis of the terminal phosphate 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 contain high-energy phosphoric anhydride bonds

• ATP is a universal carrier of phosphate groups• it 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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NADNAD++/NADH/NADH22• 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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NADNAD++/NADH/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+

• NAD+ and NADH are also hydrogen ion transporting molecules

NAd

CNH2

OH

H+ 2e-

NAd

CNH2

OH H

+ +

NAD+

(oxidized form)NADH

(reduced form)

:

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FAD/FADHFAD/FADH22• 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/FADHFAD/FADH22• FAD is a two-electron oxidizing agent, and is reduced

to FADH2

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

AdN

N

N

NHH3C

H3C O

O

+ 2H++ 2e-

H3C

H3C O

OH

HAdN

N

N

NHFAD

FADH2

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Coenzyme ACoenzyme 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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Citric Acid CycleCitric Acid Cycle• overview: the two carbon acetyl group of acetyl CoA is

fed into the cycle and oxidized to 2 CO2

• there are four oxidation steps in the cycle

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

Coenzyme A

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Citric Acid CycleCitric Acid Cycle• Step 1: 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 is an allosteric enzyme; it 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 CycleCitric Acid Cycle• Step 2: dehydration and rehydration, catalyzed by

aconitase, gives isocitrate

• citrate is achiral; it has no stereocenter• aconitate is also achiral• 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-

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Citric Acid CycleCitric Acid Cycle• Step 3: oxidation of isocitrate 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-

NADHNAD+

-Ketoglutarate

CO2

isocitratedehydrogenase

O O

Oxalosuccinate

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Citric Acid CycleCitric Acid Cycle• Step 4: oxidative decarboxylation of -

ketoglutarate to succinyl-CoA

• the two carbons of the acetyl group of acetyl CoA are still present in succinyl CoA and in succinate

• 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 CycleCitric Acid Cycle• Step 5: formation of succinate

• the two CH2-COO- groups of succinate are now equivalent

• this is the first 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 CycleCitric Acid Cycle• Step 6: oxidation of succinate to fumarate

• Step 7: hydration of fumarate to L-malate

• L-malate is chiral and can exist as a pair of enantiomers; it is produced in the citric acid 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 CycleCitric 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 + 3H2O

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

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Citric Acid CycleCitric Acid Cycle• Control 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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CA Cycle in CatabolismCA Cycle in Catabolism• The 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

Amino Acids

Acetyl-CoA

Carbohydrates

Malate

intermediatesof the citric acid cycle

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Oxidative PhosphorylationOxidative Phosphorylation• Carried 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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Complex IComplex I• The 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 this reaction is used to move 2H+ from the matrix into the intermembrane space

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

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Complex IIComplex 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 IIIComplex 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 CoQH2 are pumped from the matrix into the intermembrane space

CoQH2 +

CoQ +2H+ +

2Cyt c (reduced)

2Cyt c (oxidized)

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Complex IVComplex 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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Coupling of Ox and PhosCoupling of Ox and Phos• To explain how electron and H+ transport produce

the chemical energy of ATP, Peter Mitchell proposed the chemiosmotic theorychemiosmotic theory• the energy-releasing oxidations give rise to proton

pumping and a pH gradientgradient across the inner mitochondrial membrane

• there is a higher concentration of H+ in the intermembrane space than inside the mitochondrion

• this proton gradient provides the driving force to propel protons back into the mitochondrion through the enzyme complex called proton translocating proton translocating ATPaseATPase

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Coupling of Ox and PhosCoupling of Ox and Phos• 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

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Coupling of Ox and PhosCoupling of Ox and Phos• The overall reactions of oxidative

phosphorylation are:

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

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

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The Energy YieldThe Energy Yield• A 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 Energy FormsOther Energy Forms• The 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 EnergyOther Forms of Energy• Mechanical 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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End End Chapter 26Chapter 26

BioenergeticsBioenergetics

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

Coenzyme A

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