Chapter 8Chapter 8Chapter 8Chapter 8

An Introduction to An Introduction to MetabolismMetabolism

• Concept 8.1: An organismConcept 8.1: An organism’’s metabolism transforms matter s metabolism transforms matter and energy, subject to the laws of thermodynamicsand energy, subject to the laws of thermodynamics

• MetabolismMetabolism– Is the totality of an organismIs the totality of an organism’’s chemical s chemical

reactionsreactions

– manages the material and energy resources of manages the material and energy resources of the cell.the cell.

• A metabolic pathway has many stepsA metabolic pathway has many steps– begin with a begin with a specific moleculespecific molecule and end with a and end with a productproduct

– are each catalyzed by a specific are each catalyzed by a specific enzymeenzyme

Enzyme 1 Enzyme 2 Enzyme 3

A B C DReaction 1 Reaction 2 Reaction 3

Startingmolecule

Product

• Catabolic pathways (breakdown pathways)Catabolic pathways (breakdown pathways)– Break down complex molecules into simpler Break down complex molecules into simpler

compoundscompounds

– Release energyRelease energy

• Anabolic pathways (biosynthetic Anabolic pathways (biosynthetic

pathways)pathways)– Build complicated molecules from simpler onesBuild complicated molecules from simpler ones

– Consume energyConsume energy

- ex. cellular respiration, ex. cellular respiration,

(the (the sugar glucose and other organic fuelssugar glucose and other organic fuels are broken are broken

down down

in the presence of in the presence of oxygenoxygen to to carbon dioxide and carbon dioxide and

waterwater))

- ex. synthesis of a protein from amino acids.ex. synthesis of a protein from amino acids.

Forms of EnergyForms of Energy

• EnergyEnergy

– Is the capacity to cause Is the capacity to cause changechange..

– Exists in various forms, of which some can Exists in various forms, of which some can

perform workperform work..

The work of life depends on the ability of The work of life depends on the ability of

cells to cells to transform energy from one type into transform energy from one type into

anotheranother..

• Kinetic energyKinetic energy– Is the energy associated with motionIs the energy associated with motion

** heat, or thermal energy, is kinetic energy heat, or thermal energy, is kinetic energy

associated with the random movement of associated with the random movement of

atoms or moleculesatoms or molecules

• Potential energyPotential energy– Is stored in the location or structure of Is stored in the location or structure of

mattermatter

– Includes Includes chemical energychemical energy stored in stored in

molecular structure.molecular structure.is a term used by biologists to refer is a term used by biologists to refer to the potential energy available for to the potential energy available for

release in a chemical reactionrelease in a chemical reaction

• Energy can be converted Energy can be converted from one form to from one form to

anotheranother

--- organisms are energy transformers.--- organisms are energy transformers.On the platform, a diverhas more potential energy.

Diving converts potentialenergy to kinetic energy.

Climbing up converts kineticenergy of muscle movement to potential energy.

In the water, a diver has less potential energy.

Figure 8.2

The Laws of Energy TransformationThe Laws of Energy Transformation

• ThermodynamicsThermodynamics– Is the study of energy transformations.Is the study of energy transformations.

– Two laws of thermodynamics govern energy transformations in Two laws of thermodynamics govern energy transformations in organisms and all other collections of matter.organisms and all other collections of matter.

The First Law of ThermodynamicsThe First Law of Thermodynamics

• According to the first law of thermodynamicsAccording to the first law of thermodynamics

– The energy of universe is The energy of universe is constantconstant. .

(Energy can be transferred and transformed(Energy can be transferred and transformed

, but it cannot be created or destroyed), but it cannot be created or destroyed)

– The principle of The principle of conservation of energyconservation of energy..

• An example of energy conversion An example of energy conversion

Figure 8.3 

First law of thermodynamics: Energy can be transferred or transformed but Neither created nor destroyed. For example, the chemical (potential) energy in food will be converted to the kinetic energy of the cheetah’s movement in (b).

(a)

Chemicalenergy

The Second Law of ThermodynamicsThe Second Law of Thermodynamics

Figure 8.3 

Second law of thermodynamics: Every energy transfer or transformation increases the disorder (entropy) of the universe. For example, disorder is added to the cheetah’s surroundings in the form of heat and the small molecules that are the by-products of metabolism.

(b)

Heatco2

H2O+

During every energy transfer or transformation, some During every energy transfer or transformation, some energy becomes unusable energy, unavailable to do energy becomes unusable energy, unavailable to do work.work.

““Heat”Heat” (the energy associated with the (the energy associated with the randomrandom motion of atoms or molecules)motion of atoms or molecules)* * entropy: as a measure of disorder, or randomness.entropy: as a measure of disorder, or randomness.

““熵熵””

Second law of thermodynamics:Second law of thermodynamics:

~ Every energy transfer or transformation ~ Every energy transfer or transformation

increasesincreases

the disorder (entropy) of the universethe disorder (entropy) of the universe..

* * A process to occur on its own, without outside help (an A process to occur on its own, without outside help (an input ofinput of energy), it must increase the entropy of the universe.energy), it must increase the entropy of the universe.

SpontaneousSpontaneous NonspontaneousNonspontaneous

Another way to state the second law is:Another way to state the second law is:

For a process to occur spontaneously, it must For a process to occur spontaneously, it must

increase the entropy of the universe.increase the entropy of the universe.

• Concept 8.2: The free-energy change of a Concept 8.2: The free-energy change of a reaction tells us whether the reaction occurs reaction tells us whether the reaction occurs spontaneouslyspontaneouslyFree-Energy Change, Free-Energy Change,

GG

• A living system’s free energy

– Is energy that can do work under cellular conditions

• The change in free energy, ∆G, during a biological process

– is related directly to the enthalpy change (∆H) and the change in entropy

∆G = ∆H – T∆S

∆G = G final state – G initial state

焓焓

Free Energy, Stability, and EquilibriumFree Energy, Stability, and Equilibrium

• Organisms live at the expense of free energy• During a spontaneous change

– Free energy decreases and the stability of a system increases

• At maximum stabilityAt maximum stability– The system is at The system is at equilibriumequilibrium

** Only processes with a ** Only processes with a negative negative GG are are

spontaneousspontaneous

~ which means that every spontaneous process ~ which means that every spontaneous process

decreases the system’s free energy.decreases the system’s free energy.

• A process is spontaneous and can perform work only when it is moving toward equilibrium.

Chemical reaction. In a cell, a sugar molecule is broken down into simpler molecules.

Diffusion. Molecules

in a drop of dye diffuse until they are randomly dispersed.

Gravitational motion. Objects move spontaneously from ahigher altitude to a lower one.

• More free energy (higher More free energy (higher GG))• Less stableLess stable• Greater work capacityGreater work capacity

• Less free energy (lower Less free energy (lower GG))• More stableMore stable• Less work capacityLess work capacity

In a spontaneously change • The free energy of the system decreases (∆G<0) • The system becomes more stable• The released free energy can be harnessed to do work

(a) (b) (c)

Figure 8.5 

Free Energy and MetabolismFree Energy and Metabolism

Exergonic and Endergonic Reactions in Metabolism

• An exergonic reaction ( 釋能 )– Proceeds with a net release of free energy and

is spontaneous

Figure 8.6

Reactants

Products

Energy

Progress of the reaction

Amount ofAmount ofenergyenergyreleased released (∆(∆GG <0) <0)

Fre

e e

ne

rgy

(a) Exergonic reaction: energy released

• An An endergonic reactionendergonic reaction ( 吸能 )– Is one that absorbs free energy from its Is one that absorbs free energy from its

surroundings and is nonspontaneoussurroundings and is nonspontaneous

Figure 8.6

Energy

Products

Amount ofAmount ofenergyenergyreleased released (∆(∆GG>0)>0)

Reactants

Progress of the reaction

Fre

e e

ne

rgy

(b) Endergonic reaction: energy required

Equilibrium and MetabolismEquilibrium and Metabolism

• Reactions in a closed systemReactions in a closed system– Eventually reach Eventually reach equilibriumequilibrium

Figure 8.7 AFigure 8.7 A

(a) A closed hydroelectric system. Water flowing downhill turns a turbine that drives a generator providing electricity to a light bulb, but only until the system reaches equilibrium.

∆G < 0 ∆G = 0

• Cells in our body– Experience a constant flow of materials in and

out, preventing metabolic pathways from reaching equilibrium

Figure 8.7

(b) An open hydroelectric

system. Flowing water

keeps driving the generator

because intake and outflow

of water keep the system

from reaching equlibrium.

∆G < 0

• An analogy for cellular respirationAn analogy for cellular respiration

Figure 8.7

(c) A multistep open hydroelectric system. Cellular respiration is analogous to this system: Glucoce is brocken down in a series of exergonic reactions that power the work of the cell. The product of each reaction becomes the reactant for the next, so no reaction reaches equilibrium.

∆G < 0

∆G < 0

∆G < 0

• Concept 8.3: ATP powers cellular work by coupling Concept 8.3: ATP powers cellular work by coupling exergonic reactions to endergonic reactionsexergonic reactions to endergonic reactions

• A cell does three main kinds of workA cell does three main kinds of work– MechanicalMechanical– TransportTransport– ChemicalChemical

A key feature in the way cells manage their A key feature in the way cells manage their energy resources to do this workenergy resources to do this work

Energy coupling (the use of an exergonic Energy coupling (the use of an exergonic process to drive an endergonic one; require process to drive an endergonic one; require ATP)ATP)

The Structure and Hydrolysis of ATPThe Structure and Hydrolysis of ATP

• ATP (adenosine triphosphate)– Is the cell’s energy shuttle– Provides energy for cellular functions

Figure 8.8

O O O O CH2

H

OH OH

H

N

H H

O

NC

HC

N CC

N

NH2Adenine

RibosePhosphate groups

O

O O

O

O

O

-- - -

CH

pp pp pp

• Energy is released from ATPEnergy is released from ATP

– When the terminal phosphate bond is When the terminal phosphate bond is brokenbroken

Figure 8.9

P

Adenosine triphosphate (ATP)

H2O

+ EnergyEnergy

Inorganic phosphate Adenosine diphosphate (ADP)

PP

P PP i

““exergonic”exergonic”

• ATP hydrolysisATP hydrolysis

– Can be coupled to other reactionsCan be coupled to other reactions

Endergonic reaction: ∆G is positive, reaction is not spontaneous

∆G = +3.4 kcal/molGlu Glu

∆G = - 7.3 kcal/molATP H2O+

+ NH3

ADP +

NH2

Glutamic acid Ammonia Glutamine

Exergonic reaction: ∆ G is negative, reaction is spontaneous

P

Coupled reactions:Coupled reactions: Overall ∆G is negative; together, Overall ∆G is negative; together, reactions are reactions are spontaneousspontaneous

∆G = –3.9 kcal/mol

Figure 8.10

How ATP Performs Work ?How ATP Performs Work ?

• ATP drives endergonic reactionsATP drives endergonic reactions– By phosphorylation, transferring a phosphate to By phosphorylation, transferring a phosphate to

other moleculesother molecules

• The three types The three types

of cellular workof cellular work

– Are powered Are powered

by the by the

hydrolysis of hydrolysis of

ATPATP

(c) Chemical work: ATP phosphorylates key reactants

P

Membraneprotein

Motor protein

P i

Protein moved(a) Mechanical work: ATP phosphorylates motor proteins

ATP

(b) Transport work: ATP phosphorylates transport proteins

Solute

P P i

transportedSolute

GluGlu

NH3

NH2

P i

P i

+ +

Reactants: Glutamic acid and ammonia

Product (glutamine)made

ADP+

P

Figure 8.11

The Regeneration of ATPThe Regeneration of ATP

ATP synthesis from ADP + P i requires energy

ATP

ADP + P i

Energy for cellular work(endergonic, energy-consuming processes)

Energy from catabolism(exergonic, energy yieldingprocesses)

ATP hydrolysis to ADP + P i yields energy

Figure 8.12

* * ATP is a renewable resource that can be ATP is a renewable resource that can be

regenerated regenerated

by the addition of phosphate to ADPby the addition of phosphate to ADP

* ATP cycle: * ATP cycle:

• Concept 8.4: Enzymes speed up metabolic reactions by lowering energy barriers

• A catalyst– Is a chemical agent that speeds up a reaction

without being consumed by the reaction

• An enzyme– Is a catalytic protein

The Activation Energy Barrier

• The initial investment of energy for starting a reaction – the energy required to contort the reactant molecules so the bonds can change.

• The hydrolysis of sucrose– Is an example of a chemical reaction

Figure 8.13

H2O

H

H

H

H

HO

OH

OH

OH

O

O OO OHH H H

H

H

H

CH2OH CH2OH

OHCH2OH

SucraseSucrase

HOHO

OH OHCH2OH

H

CH2OH

H

CH2OH

H

O

Sucrose Glucose Fructose

C12H22O11 C6H12O6 C6H12O6

+HOH H

• The activation energy, EThe activation energy, EAA

– Is the initial amount of energy needed to start a chemical reaction

– Is often supplied in the form of heat from the surroundings in a system

• The energy profile for an exergonic reaction

Fre

e en

ergy

Progress of the reaction

∆∆G G < O< O

EA

Figure 8.14

A B

C D

Reactants

A

C D

B

Transition state

A B

C D

Products

How Enzymes Lower the EHow Enzymes Lower the EAA Barrier Barrier

• An enzyme catalyzes reactions

– By lowering the EA barrier

• The effect of enzymes on reaction rate

Progress of the reaction

Products

Course of reaction without enzyme

Reactants

Course of reaction with enzyme

EA

withoutenzyme EEA A with with

enzymeenzymeis loweris lower

∆G is unaffected by enzyme

Fre

e en

ergy

Figure 8.15

Substrate Specificity of EnzymesSubstrate Specificity of Enzymes

• The substrate

– Is the reactant an enzyme acts on

• The enzyme

– Binds to its substrate, forming an enzyme-substrate complex

Catalysis in the EnzymeCatalysis in the Enzyme’’s Active Sites Active Site

• In an enzymatic reaction– The substrate binds to the active site

• The active siteactive site– Is the region on the

enzyme where the substrate binds

Figure 8.16

Substate

Active site

Enzyme(a)

Figure 8.16

(b)

Enzyme- substratecomplex

• Induced fit of a substrateInduced fit of a substrate– Brings chemical groups of

the active site into positions that enhance their ability to catalyze the chemical reaction

• The catalytic cycle of an enzymeThe catalytic cycle of an enzyme

Substrates

Products

Enzyme

Enzyme-substratecomplex

1 Substrates enter active site; enzymechanges shape so its active siteembraces the substrates (induced fit).

2 Substrates held inactive site by weakinteractions, such ashydrogen bonds andionic bonds.

3 Active site (and R groups ofits amino acids) can lower EA

and speed up a reaction by• acting as a template for substrate orientation,• stressing the substrates and stabilizing the transition state,• providing a favorable microenvironment,• participating directly in the catalytic reaction.

4 Substrates are Converted intoProducts.

5 Products areReleased.

6 Active siteIs available fortwo new substrateMole.

Figure 8.17

• The active site can lower an EA barrier by

– Orienting substrates correctly

– Straining substrate bonds

– Providing a favorable microenvironment

– Covalently bonding to the substrate

Effects of Local Conditions on Enzyme ActivityEffects of Local Conditions on Enzyme Activity

• The activity of an enzyme– Is affected by general environmental factors

Effects of Temperature and pH

• Each enzyme– Has an optimal temperature in which it can

function

Figure 8.18

Optimal temperature for enzyme of thermophilic

Rat

e o

f re

actio

n

0 20 40 80 100Temperature (Cº)

(a) Optimal temperature for two enzymes

Optimal temperature fortypical human enzyme

(heat-tolerant) bacteria

– Has an optimal pH in which it can function

Figure 8.18

Rat

e o

f re

actio

n

(b) Optimal pH for two enzymes

Optimal pH for pepsin (stomach enzyme)

Optimal pHfor trypsin(intestinalenzyme)

10 2 3 4 5 6 7 8 9

CofactorsCofactors• Cofactors

– Are nonprotein enzyme helpers

– Bind tightly to the enzyme as permanent residents, or they may bind loosely and reversibly along with the substrate.

– Ex. inorganic metal atoms.

• Coenzymes– Are organic cofactors ex. vitamins

Enzyme InhibitorsEnzyme Inhibitors

* * ReversibleReversible inhibition inhibition

--- inhibitor binds to the enzyme by --- inhibitor binds to the enzyme by weak bondweak bond. .

1. 1. competitive inhibitorcompetitive inhibitor

(inhibitors resemble the normal substrate molecule and

compete for

binding to active site)

2. 2. non competitive inhibitornon competitive inhibitor (do not directly compete with the substrate to bind to the enzyme at the active site) change the shape of active site

* Irreversible* Irreversible inhibition inhibition

--- inhibitor attaches to the enzyme by covalent bonds.--- inhibitor attaches to the enzyme by covalent bonds.Ex. Toxins and poisons.Ex. Toxins and poisons.

(the small molecule from(the small molecule from a nerve gas, sarin, binds covalently to a nerve gas, sarin, binds covalently to the R group on the amino acid serine which is found in the the R group on the amino acid serine which is found in the active site of acetylcholinesterase, and enzyme important in active site of acetylcholinesterase, and enzyme important in the nervous system)the nervous system)

Enzyme InhibitorsEnzyme Inhibitors

• Competitive inhibitors– Bind to the active site of an enzyme,

competing with the substrate

Figure 8.19 (b) Competitive inhibition

A competitiveinhibitor mimics the

substrate, competingfor the active site.

Competitiveinhibitor

A substrate canbind normally to the

active site of anenzyme.

Substrate

Active site

Enzyme

(a) Normal binding

• Noncompetitive inhibitors– Bind to another part of an enzyme,

changing the function

Figure 8.19

A noncompetitiveinhibitor binds to the

enzyme away fromthe active site, altering

the conformation ofthe enzyme so that its

active site no longerfunctions.

Noncompetitive inhibitor

(c) Noncompetitive inhibition

• Concept 8.5: Regulation of enzyme activity Concept 8.5: Regulation of enzyme activity helps control metabolismhelps control metabolism

• A cellA cell’’s metabolic pathwayss metabolic pathways

--- Must be tightly regulated--- Must be tightly regulated

--- by controlling when and where its various--- by controlling when and where its various

enzymes are active.enzymes are active.

** The molecular that naturally regulate enzyme activity The molecular that naturally regulate enzyme activity

in a cell behave like reversiblein a cell behave like reversible noncompetitive noncompetitive

inhibitors.inhibitors.

* * Allosteric regulationAllosteric regulation

--- Is the term used to describe any case in which a

protein’s function at one site is affected by binding

of a regulatory molecule at another site.

Allosteric Activation and InhibitionAllosteric Activation and Inhibition

• Many enzymes are allosterically regulated

Stabilized inactiveform

Allosteric activaterstabilizes active fromAllosteric enyzme

with four subunitsActive site

(one of four)

Regulatorysite (oneof four)

Active formActivator

Stabilized active form

Allosteric activaterstabilizes active form

InhibitorInactive formNon-functionalactivesite

(a) Allosteric activators and inhibitors. In the cell, activators and inhibitors dissociate when at low concentrations. The enzyme can then oscillate again.

Oscillation

Figure 8.20

* * Constructed from two or Constructed from two or more polypeptide chains, or more polypeptide chains, or subunits.subunits.

* The entire complex * The entire complex oscillate between oscillate between catalytically active and catalytically active and inactive state.inactive state.

* A single activator or * A single activator or inhibitor molecule that inhibitor molecule that binds to one regulatory site binds to one regulatory site will affect the active sites of will affect the active sites of all subunits.all subunits.

allosteric siteallosteric site

• CooperativityCooperativity– Is a form of allosteric regulation that can amplify Is a form of allosteric regulation that can amplify

enzyme activityenzyme activity

Figure 8.20

Binding of one substrate molecule toactive site of one subunit locks all subunits in active conformation.

Substrate

Inactive form Stabilized active form

(b) Cooperativity: another type of allosteric activation. Note that the inactive form shown on the left oscillates back and forth with the active form when the active form is not stabilized by substrate.

Feedback InhibitionFeedback Inhibition

• In feedback inhibition

– The end product of a metabolic pathway shuts down the pathway

Active siteavailable

Isoleucineused up bycell

Feedbackinhibition

Isoleucine binds to allosteric site

Active site of enzyme 1 no longer binds threonine;pathway is switched off

Initial substrate(threonine)

Threoninein active site

Enzyme 1(threoninedeaminase)

Intermediate A

Intermediate B

Intermediate C

Intermediate D

Enzyme 2

Enzyme 3

Enzyme 4

Enzyme 5

End product(isoleucine)

Figure 8.21

Specific Localization of Enzymes Within the Specific Localization of Enzymes Within the CellCell

• Within the cell, enzymes may be– Grouped into complexes– Incorporated into membranes

– Contained inside organelles

1 µm

Mitochondria,sites of cellular respiraion

Figure 8.22