General orrganic and biological chemistry structures off liffe 5th CH 23 citric acid cycle 5th ed

General, Organic, and Biological Chemistry: Structures of Life, 5/eKaren C.. General, Organic, and Biological Chemistry: Structures of Life, 5/eKaren C.. General, Organic, and Biological

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General, Organic, and Biological Chemistry: Structures of Life, 5/e

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Chapter 23 Metabolism and Energy Production

Exercise physiologists work with

athletes as well as patients who

have been diagnosed with

diabetes, heart disease,

pulmonary disease, or other

chronic disabilities or diseases

Often these patients have been

prescribed exercise as a form of

treatment, and they have been

referred to an exercise

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Karen C Timberlake

Chapter 23 Readiness

Core Chemistry Skills

• Writing Equations for Hydrogenation, Hydration,

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23.1 The Citric Acid Cycle

The citric acid cycle is

a series of reactions

that connects the

intermediate acetyl CoA

from the catabolic

pathways in stage 2

with electron transport

and the synthesis of

ATP in stage 3

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Karen C Timberlake

23.1 The Citric Acid Cycle

The citric acid cycle (stage 3)

• operates under aerobic conditions

• oxidizes the two-carbon acetyl group in acetyl CoA to CO2

• produces reduced coenzymes NADH and FADH2

• is named for the six-carbon citrate ion from citric acid

(C6H8O7), a tricarboxylic acid, formed in the first reaction

• is also known as the tricarboxylic acid (TCA) cycle or the

Krebs cycle

Core Chemistry Skill Describing the Reactions in the Citric Acid Cycle

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Citric Acid Cycle Overview

In the citric acid cycle,

• six carbons move through the citric acid cycle,

producing oxaloacetate and 2CO2.

• each turn contains four oxidation reactions

producing the reduced coenzymes NADH and

FADH2.

• one GTP (converted to ATP in the cell) is

produced during the citric acid cycle.

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Karen C Timberlake

Citric Acid Cycle Overview

• In the citric acid cycle, eight

reactions oxidize acetyl CoA

from pyruvate or fatty acids,

producing CO2 and the

high-energy compounds FADH2,

NADH, and GTP.

• Reactions involved in the

citric acid cycle include

condensation, dehydration,

hydration, oxidation,

reduction, and hydrolysis.

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Stages of Catabolism

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Karen C Timberlake

Reaction 1: Formation of Citrate

In the first reaction of the citric acid cycle,

• citrate synthase catalyzes the condensation of an acetyl

group (2C) from acetyl CoA with oxaloacetate (4C) to yield citrate (6C) and coenzyme A

• the energy to form citrate is provided by the hydrolysis of

the high-energy thioester bond in acetyl CoA

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Reaction 2: Isomerization

In reaction 2 of the citric acid cycle,

• citrate rearranges to isocitrate, a secondary alcohol

• aconitase catalyzes the dehydration of citrate (tertiary

alcohol) to yield cis-aconitate, followed by a hydration that

forms isocitrate (secondary alcohol)

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Karen C Timberlake

Reaction 3: Oxidation, Decarboxylation

In reaction 3, isocitrate undergoes decarboxylation by

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Reaction 4: Decarboxylation, Oxidation

In reaction 4, catalyzed by α-ketoglutarate dehydrogenase,

• α-ketoglutarate (5C) undergoes decarboxylation to yield

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Karen C Timberlake

Reaction 5: Hydrolysis

In reaction 5, catalyzed by succinyl CoA synthetase,

• hydrolysis of the thioester bond in succinyl CoA yields

succinate and HS — CoA

• energy from hydrolysis is transferred to the condensation of phosphate and GDP forming GTP, a high-energy

compound similar to ATP

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Reaction 6: Hydrolysis

In reaction 6, catalyzed by succinate dehydrogenase,

• succinate is oxidized to fumarate, a compound with a

C = C bond

• 2H lost from succinate are used to reduce the coenzyme

FAD to FADH2

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Karen C Timberlake

Reaction 7: Hydration

In reaction 7, catalyzed by fumarase, water is added

to the double bond of fumarate to yield malate, a

secondary alcohol.

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Reaction 8: Oxidation

In reaction 8, catalyzed by malate dehydrogenase,

• the hydroxyl group in malate is oxidized to a carbonyl group, yielding oxaloacetate

• oxidation provides hydrogen ions and electrons for the

reduction of NAD+ to NADH and H+

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Karen C Timberlake

Summary, Citric Acid Cycle

In the citric acid cycle,

• an acetyl group bonds with oxaloacetate to form citrate.

• two decarboxylations remove two carbons as two CO2.

• four oxidations provide hydrogen for three NADH and one FADH2.

• a direct phosphorylation forms GTP (ATP).

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Regulation of the Citric Acid Cycle

The reaction rate for the

citric acid cycle

• increases when low

levels of ATP or NAD+

activate isocitrate

dehydrogenase.

• decreases when high

levels of ATP or NADH

inhibit citrate synthetase

(first step in cycle).

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Karen C Timberlake

Study Check

How many of each of the following are produced in

one turn of the citric acid cycle?

A _ CO2

B _ NADH

C _ FADH2

D _ GTP

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How many of each of the following are produced in

one turn of the citric acid cycle?

A 2 CO2

B 3 NADH

C 1 FADH2

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Karen C Timberlake

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23.2 Electron Transport and ATP

The enzymes and

electron carriers for

electron transport are

located along the

inner membrane of

the mitochondria

Learning Goal Describe the transfer of hydrogen ions and

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Karen C Timberlake

Electron Transport

The reduced coenzymes NADH and FADH2 produced from

glycolysis, oxidation of pyruvate, and the citric acid cycle are oxidized to provide the energy for the synthesis of ATP

In electron transport or the respiratory chain,

• hydrogen ions and electrons from NADH and FADH2 are

passed from one electron acceptor or carrier to the next

until they combine with oxygen to form H2O

• energy released during electron transport is used to

synthesize ATP from ADP and Pi during oxidative

phosphorylation

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Glycolysis, Citric Acid Cycle Results

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Karen C Timberlake

Electron Transport System

In the electron transport system,

• there are five protein

complexes, which are numbered

I, II, III, IV, and V

• two electron carriers, coenzyme

Q and cytochrome c, attached

to the inner membrane of the

mitochondrion, carry electrons

between these protein

complexes bound to the inner

membrane

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Electron Transport Chain

In electron transport, the oxidation of NADH and FADH2

provides hydrogen ions and electrons that eventually

react with oxygen to form water.

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Karen C Timberlake

Complex I

In complex I,

• electron transport begins when hydrogen ions and

electrons are transferred from NADH to complex I.

• loss of hydrogen from NADH regenerates NAD+ to

oxidize more substrates in oxidative pathways such

as the citric acid cycle.

• hydrogen ions and electrons are transferred to the

mobile electron carrier CoQ, forming CoQH2.

• CoQH2 carries electrons from complexes I and II to

complex III.

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Complex I, Electron Transfer

During electron transfer,

• H+ ions are pumped through complex I into the

intermembrane space, producing a reservoir of H+

(hydrogen ion gradient).

• for every two electrons that pass from NADH to CoQ, 4H+ are pumped across the mitochondrial membrane, producing a charge separation on opposite sides of

the membrane.

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Karen C Timberlake

Complex II

Complex II consists of the enzyme succinate

dehydrogenase from the citric acid cycle.

In complex II,

• CoQ obtains hydrogen and electrons directly from

FADH2 This produces CoQH2 and regenerates the

oxidized coenzyme FAD, which becomes available to oxidize more substrates.

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Complex III

Complex II consists of the enzyme succinate

dehydrogenase from the citric acid cycle.

In complex II,

• CoQ obtains hydrogen and electrons directly from

FADH2 and becomes CoQH2.

• two electrons are transferred from the mobile carrier

CoQH2 to a series of iron-containing proteins called

cytochromes.

• electrons are then transferred to two cytochrome c,

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Karen C Timberlake

Complex III, Cytochrome c

Cytochrome c

• contains Fe3+/Fe2+, which is

reduced to Fe2+ and oxidized

to Fe3+.

• generates energy from electron

transfer to pump 4H+ from the

matrix into the intermembrane

space, increasing the hydrogen

ion gradient.

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Complex IV

At complex IV,

• four electrons from four cytochrome c are passed to

other electron carriers.

• electrons combine with hydrogen ions and oxygen

(O2) to form two molecules of water.

• energy is used to pump H+ from the mitochondrial

matrix into the intermembrane space, further

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Karen C Timberlake

Oxidative Phosphorylation

Energy is coupled with the production of ATP in a process

called oxidative phosphorylation In 1978, Peter

Mitchell theorized about a chemiosmotic model, which

• links the energy from electron transport to a hydrogen ion gradient that drives the synthesis of ATP.

• allows complexes I, III, and IV to act as hydrogen ion

pumps, producing a hydrogen ion gradient.

• equalizes pH and electrical charge between the matrix and intermembrane space that occurs when H+ must

return to the matrix.

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Oxidative Phosphorylation, ATP

In the chemiosmotic model,

• H + cannot move through the inner membrane but returns to the matrix by passing through a fifth protein complex in the inner

membrane called ATP synthase (also called complex V).

• the flow of H + from the intermembrane space through the ATP

synthase generates energy that is used to synthesize ATP

from ADP and Pi.

This process of oxidative phosphorylation couples the energy

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Karen C Timberlake

Electron Transport and ATP Synthesis

• When NADH enters electron transport at complex I, the

energy transferred can be used to synthesize 2.5 ATP

• When FADH2 enters electron transport at complex II, it

provides energy for the synthesis of 1.5 ATP

• Current research indicates that the oxidation of one

NADH yields 2.5 ATP and one FADH2 yields 1.5 ATP

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Regulation of Electron Transport and

When a cell is active and ATP is consumed rapidly, the

elevated levels of ADP will activate the synthesis of ATP

The activity of electron transport is strongly dependent on

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A a mobile carrier between complexes II and III

B carries electrons from complexes I and II to

complex III

C accepts H and electrons from FADH2

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Match each with its function:

CoQ cyt c

A a mobile carrier between complexes II and III Cyt C

B carries electrons from complexes I and II to

C accepts H and electrons from FADH2 CoQ

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Classify each as a product of the

1 CO2 A citric acid cycle

2 FADH2 A citric acid cycle

3 NAD+ B electron transport chain

5 H2O B electron transport chain

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Karen C Timberlake

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23.3 ATP Energy from Glucose

The malate–aspartate

shuttle transfers the

energy stored in NADH

to transporters that

move from the cytosol

into the mitochondrial

matrix, where NADH is

regenerated for use in

electron transport

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Karen C Timberlake

ATP from Glycolysis

The total ATP from complete oxidation of glucose is

calculated by combining the ATP produced from

• glycolysis (glucose produces 7 ATP):

five ATP from two NADH (malate–aspartate shuttle)

and two ATP from direct phosphate transfer.

• the oxidation of pyruvate.

• the citric acid cycle.

• electron transport.

In glycolysis, the oxidation of glucose stores energy in

two NADH molecules and two ATP molecules from direct phosphate transfer

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Malate–Aspartate Shuttle

Because glycolysis occurs in the cytosol,

• the NADH produced cannot pass through the

mitochondrial inner membrane

• the hydrogen ions and electrons from NADH can be

moved in and out of the mitochondria by a transporter, the

malate–aspartate shuttle.

• malate dehydrogenase catalyzes the reaction of

oxaloacetate and NADH to yield malate and NAD+

• a transporter binds the malate and carries it across the

membrane into the matrix, where malate dehydrogenase

oxidizes malate back to oxaloacetate

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Karen C Timberlake

Malate–Aspartate Shuttle, ATP

The oxidation to oxaloacetate provides hydrogen ions and

electrons that are used to reduce NAD+ to NADH, which can

now enter electron transport to synthesize ATP

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Malate–Aspartate Shuttle, ATP

Because the oxaloacetate produced in the matrix

cannot cross the mitochondrial membrane, it

• is converted back to aspartate;

• moves out of the matrix back into the cytosol; and

• undergoes transamination, which converts it to

oxaloacetate.

The resulting NAD+ can participate again in

glycolysis in the cytosol.

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Karen C Timberlake

ATP from Oxidation of Pyruvate

Under aerobic conditions, pyruvate

• enters the mitochondria.

• is oxidized to give acetyl CoA, CO2, and NADH.

Because glucose yields two pyruvate,

• two NADH enter electron transport.

• their oxidation leads to the production of five ATP.

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ATP from Citric Acid Cycle

The two acetyl CoA produced from two pyruvate

enter the citric acid cycle Two acetyl CoA from one

glucose produce a total of

• six NADH;

• two FADH2; and

• two ATP.

In electron transport, six NADH produce 15 ATP,

and two FADH2 produce 3 ATP

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Karen C Timberlake

ATP from Citric Acid Cycle

In two turns of the citric acid cycle, a total of 20 ATP are produced.

6 NADH × 2.5 ATP/NADH = 15 ATP

2 FADH2 × 1.5 ATP/FADH2 = 3 ATP

2 GTP × 1 ATP/GTP = 2 ATP

Total two turns = 20 ATP

The overall equation for the reaction of two acetyl CoA is

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