Download Regulation of Gene Expression

LECTURE PRESENTATIONS
For CAMPBELL BIOLOGY, NINTH EDITION
Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson
Chapter 18
Regulation of Gene Expression
Lectures by
Erin Barley
Kathleen Fitzpatrick
© 2011 Pearson Education, Inc.
Overview: Conducting the Genetic
Orchestra
• Prokaryotes and eukaryotes alter gene
expression in response to their changing
environment
• In multicellular eukaryotes, gene expression
regulates development and is responsible for
cell differentiation
• RNA molecules play many roles in regulating
gene expression in eukaryotes
© 2011 Pearson Education, Inc.
Figure 18.1
Concept 18.1: Bacteria often respond to
environmental change by regulating
transcription
• Bacterial cells rely on regulating their gene
expression to conserve energy and resources.
• Prokaryotes arrange genes that are expressed
together and function as a unit in operons.
© 2011 Pearson Education, Inc.
Figure 18.2
Precursor
Feedback
inhibition
trpE gene
Enzyme 1
trpD gene
Enzyme 2
Regulation
of gene
expression
trpC gene
−
trpB gene
−
Enzyme 3
trpA gene
Tryptophan
(a) Regulation of enzyme
activity
(b) Regulation of enzyme
production
Operons: The Basic Concept
• A cluster of functionally related genes can be
under coordinated control by a single “on-off
switch”
• The regulatory “switch” is a segment of DNA
called an operator usually positioned within the
promoter
• An operon is the entire stretch of DNA that
includes the operator, the promoter, and the
genes that they control
© 2011 Pearson Education, Inc.
• The operon can be switched off by a protein
repressor
• The repressor prevents gene transcription by
binding to the operator and blocking RNA
polymerase
• The repressor is the product of a separate
regulatory gene
© 2011 Pearson Education, Inc.
• The repressor can be in an active or inactive
form, depending on the presence of other
molecules
• A corepressor is a molecule that cooperates with
a repressor protein to switch an operon off
• For example, E. coli can synthesize the amino
acid tryptophan
© 2011 Pearson Education, Inc.
• By default the trp operon is on and the genes for
tryptophan synthesis are transcribed
• When tryptophan is present, it binds to the trp
repressor protein, which turns the operon off
• The repressor is active only in the presence of its
corepressor tryptophan; thus the trp operon is
turned off (repressed) if tryptophan levels are
high
© 2011 Pearson Education, Inc.
Figure 18.3a
trp operon
Promoter
Promoter
Genes of operon
DNA
trpR
Regulatory
gene
mRNA
trpE
3′
Operator
RNA
Start codon
polymerase
mRNA 5′
trpD
trpC
trpB
trpA
C
B
A
Stop codon
5′
E
Protein
Inactive
repressor
D
Polypeptide subunits that make up
enzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
Figure 18.3b-1
DNA
mRNA
Protein
Active
repressor
Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
Figure 18.3b-2
DNA
No RNA
made
mRNA
Protein
Active
repressor
Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
Repressible and Inducible Operons: Two
Types of Negative Gene Regulation
• A repressible operon is one that is usually on;
binding of a repressor to the operator shuts off
transcription
• The trp operon is a repressible operon
• An inducible operon is one that is usually off; a
molecule called an inducer inactivates the
repressor and turns on transcription
© 2011 Pearson Education, Inc.
• The lac operon is an inducible operon and
contains genes that code for enzymes used in the
hydrolysis and metabolism of lactose
• By itself, the lac repressor is active and switches
the lac operon off
• A molecule called an inducer inactivates the
repressor to turn the lac operon on
© 2011 Pearson Education, Inc.
Figure 18.4a
Regulatory
gene
DNA
Promoter
Operator
lacI
lacZ
No
RNA
made
3′
mRNA
5′
Protein
RNA
polymerase
Active
repressor
(a) Lactose absent, repressor active, operon off
Figure 18.4b
lac operon
lacI
DNA
lacZ
lacY
lacA
Permease
Transacetylase
RNA polymerase
3′
mRNA
5′
mRNA 5′
β-Galactosidase
Protein
Allolactose
(inducer)
Inactive
repressor
(b) Lactose present, repressor inactive, operon on
• Inducible enzymes usually function in catabolic
pathways; their synthesis is induced by a chemical
signal
• Repressible enzymes usually function in
anabolic pathways; their synthesis is repressed
by high levels of the end product
• Regulation of the trp and lac operons involves
negative control of genes because operons are
switched off by the active form of the repressor
© 2011 Pearson Education, Inc.
Positive Gene Regulation
• Some operons are also subject to positive
control through a stimulatory protein, such as
catabolite activator protein (CAP), an activator of
transcription
• When glucose (a preferred food source of E. coli)
is scarce, CAP is activated by binding with
cyclic AMP (cAMP)
• Activated CAP attaches to the promoter of the lac
operon and increases the affinity of RNA
polymerase, thus accelerating transcription
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• When glucose levels increase, CAP detaches from
the lac operon, and transcription returns to a
normal rate
• CAP helps regulate other operons that encode
enzymes used in catabolic pathways
© 2011 Pearson Education, Inc.
Figure 18.5a
Promoter
DNA
lacI
lacZ
CAP-binding site
cAMP
Operator
RNA
polymerase
Active binds and
transcribes
CAP
Inactive
CAP
Allolactose
Inactive lac
repressor
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized
Figure 18.5b
Promoter
DNA
lacI
CAP-binding site
lacZ
Operator
RNA
polymerase less
likely to bind
Inactive
CAP
Inactive lac
repressor
(b) Lactose present, glucose present (cAMP level low):
little lac mRNA synthesized
Concept 18.2: Eukaryotic gene expression
is regulated at many stages
• All organisms must regulate which genes are
expressed at any given time
• In multicellular organisms regulation of gene
expression is essential for cell specialization
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Differential Gene Expression
• Almost all the cells in an organism are genetically
identical
• Differences between cell types result from
differential gene expression, the expression of
different genes by cells with the same genome
• Abnormalities in gene expression can lead to
diseases including cancer
• Gene expression is regulated at many stages
© 2011 Pearson Education, Inc.
Figure 18.6a
Signal
NUCLEUS
Chromatin
DNA
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethylation
Gene available
for transcription
Gene
Transcription
RNA
Exon
Primary transcript
Intron
RNA processing
Cap
Tail
mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
Figure 18.6b
CYTOPLASM
mRNA in cytoplasm
Degradation
of mRNA
Translation
Polypeptide
Protein processing, such
as cleavage and
chemical modification
Degradation
of protein
Active protein
Transport to cellular
destination
Cellular function (such
as enzymatic activity,
structural support)
Regulation of Chromatin Structure
• Genes within highly packed heterochromatin
are usually not expressed
• Chemical modifications to histones and DNA of
chromatin influence both chromatin structure and
gene expression
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Histone Modifications
• In histone acetylation, acetyl groups are
attached to histone tails
• This loosens chromatin structure, thereby
promoting the initiation of transcription
• The addition of methyl groups (methylation) can
condense chromatin; the addition of phosphate
groups (phosphorylation) next to a methylated
amino acid can loosen chromatin
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Animation: DNA Packing
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© 2011 Pearson Education, Inc.
Figure 18.7
Histone
tails
Amino acids
available
for chemical
modification
DNA
double
helix
Nucleosome
(end view)
(a) Histone tails protrude outward from a nucleosome
Acetylated histones
Unacetylated histones
(b) Acetylation of histone tails promotes loose chromatin
structure that permits transcription
DNA Methylation
• DNA methylation, the addition of methyl groups
to certain bases in DNA, is associated with
reduced transcription in some species
• DNA methylation can cause long-term
inactivation of genes in cellular differentiation
• In genomic imprinting, methylation regulates
expression of either the maternal or paternal
alleles of certain genes at the start of development
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Regulation of Transcription Initiation
• Chromatin-modifying enzymes provide initial
control of gene expression by making a region of
DNA either more or less able to bind the
transcription machinery
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Organization of a Typical Eukaryotic Gene
• Associated with most eukaryotic genes are
multiple control elements, segments of
noncoding DNA that serve as binding sites for
transcription factors that help regulate
transcription
© 2011 Pearson Education, Inc.
Figure 18.8-1
Enhancer
(distal control
elements)
DNA
Upstream
Proximal
control
elements
Transcription
start site
Exon
Promoter
Intron
Exon
Poly-A
signal Transcription
sequence termination
region
Intron Exon
Downstream
Figure 18.8-2
Enhancer
(distal control
elements)
DNA
Upstream
Proximal
control
elements
Transcription
start site
Exon
Intron
Promoter
Primary RNA
transcript
5′
(pre-mRNA)
Exon
Poly-A
signal Transcription
sequence termination
region
Intron Exon
Downstream
Poly-A
signal
Intron Exon
Cleaved
3′ end of
primary
transcript
Transcription
Exon
Intron
Exon
Figure 18.8-3
Enhancer
(distal control
elements)
Proximal
control
elements
Transcription
start site
Exon
DNA
Upstream
Intron
Exon
Intron
Downstream
Poly-A
signal
Intron Exon
Exon
Cleaved
3′ end of
primary
RNA processing
transcript
Promoter
Transcription
Exon
Primary RNA
transcript
5′
(pre-mRNA)
Poly-A
signal Transcription
sequence termination
region
Intron Exon
Intron RNA
Coding segment
mRNA
G
P
AAA ⋅⋅⋅ AAA
P P
5′ Cap
5′ UTR
Start
Stop
codon codon
3′ UTR Poly-A
tail
3′
The Roles of Transcription Factors
• To initiate transcription, eukaryotic RNA
polymerase requires the assistance of proteins
called transcription factors
• Proximal control elements are located close to
the promoter
• Distal control elements, groupings of which are
called enhancers, may be far away from a gene
or even located in an intron
© 2011 Pearson Education, Inc.
• An activator is a protein that binds to an
enhancer and stimulates transcription of a gene
• Activators have two domains, one that binds DNA
and a second that activates transcription
• Bound activators facilitate a sequence of proteinprotein interactions that result in transcription of
a given gene
© 2011 Pearson Education, Inc.
Animation: Initiation of Transcription
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Figure 18.9
Activation
domain
DNA-binding
domain
DNA
• Some transcription factors function as
repressors, inhibiting expression of a particular
gene by a variety of methods
• Some activators and repressors act indirectly by
influencing chromatin structure to promote or
silence transcription
© 2011 Pearson Education, Inc.
Figure 18.10-1
Activators
Promoter
DNA
Enhancer
Distal control
element
TATA box
Gene
Figure 18.10-2
Promoter
Activators
DNA
Enhancer
Distal control
element
Gene
TATA box
General
transcription
factors
DNAbending
protein
Group of mediator proteins
Figure 18.10-3
Promoter
Activators
DNA
Enhancer
Distal control
element
Gene
TATA box
General
transcription
factors
DNAbending
protein
Group of mediator proteins
RNA
polymerase II
RNA
polymerase II
Transcription
initiation complex
RNA synthesis
Figure 18.11a
Enhancer
Control
elements
Promoter
LIVER CELL
NUCLEUS
Albumin gene
Crystallin
gene
Available
activators
Albumin gene
expressed
Crystallin gene
not expressed
(a) Liver cell
Figure 18.11b
Enhancer
Control
elements
Promoter
LENS CELL
NUCLEUS
Albumin gene
Crystallin
gene
Available
activators
Albumin gene
not expressed
Crystallin gene
expressed
(b) Lens cell
Coordinately Controlled Genes in Eukaryotes
• Unlike the genes of a prokaryotic operon, each of
the co-expressed eukaryotic genes has a
promoter and control elements
• These genes can be scattered over different
chromosomes, but each has the same
combination of control elements
• Copies of the activators recognize specific control
elements and promote simultaneous
transcription of the genes
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RNA Processing
• In alternative RNA splicing, different mRNA
molecules are produced from the same primary
transcript, depending on which RNA segments are
treated as exons and which as introns
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Animation: RNA Processing
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Figure 18.13
Exons
DNA
1
3
2
4
5
Troponin T gene
Primary
RNA
transcript
3
2
1
5
4
RNA splicing
mRNA
1
2
3
5
or
1
2
4
5
mRNA Degradation
• The life span of mRNA molecules in the
cytoplasm is a key to determining protein
synthesis
• Eukaryotic mRNA is more long lived than
prokaryotic mRNA
• Nucleotide sequences that influence the
lifespan of mRNA in eukaryotes reside in the
untranslated region (UTR) at the 3′ end of the
molecule
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Animation: mRNA Degradation
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Animation: Blocking Translation
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Protein Processing and Degradation
• After translation, various types of protein
processing, including cleavage and the addition
of chemical groups, are subject to control
• Proteasomes are giant protein complexes that
bind protein molecules and degrade them
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Animation: Protein Processing
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Animation: Protein Degradation
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Figure 18.14
Ubiquitin
Proteasome
Protein to
be degraded
Ubiquitinated
protein
Proteasome
and ubiquitin
to be recycled
Protein entering
a proteasome
Protein
fragments
(peptides)
Concept 18.3: Noncoding RNAs play
multiple roles in controlling gene expression
• Only a small fraction of DNA codes for proteins,
and a very small fraction of the non-protein-coding
DNA consists of genes for RNA such as rRNA and
tRNA
• Noncoding RNAs regulate gene expression at two
points: mRNA translation and chromatin
configuration
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Effects on mRNAs by MicroRNAs and
Small Interfering RNAs
• MicroRNAs (miRNAs) are small single-stranded
RNA molecules that can bind to mRNA
• These can degrade mRNA or block its
translation
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Figure 18.15
Hairpin
Hydrogen
bond
miRNA
Dicer
5′ 3′
(a) Primary miRNA transcript
miRNA
miRNAprotein
complex
mRNA degraded Translation blocked
(b) Generation and function of miRNAs
• The phenomenon of inhibition of gene expression
by RNA molecules is called RNA interference
(RNAi)
• RNAi is caused by small interfering RNAs
(siRNAs)
• In some yeasts siRNAs play a role in
heterochromatin formation and can block large
regions of the chromosome
© 2011 Pearson Education, Inc.
Concept 18.4: A program of differential
gene expression leads to the different cell
types in a multicellular organism
• During embryonic development, a fertilized egg
gives rise to many different cell types
• Cell types are organized successively into tissues,
organs, organ systems, and the whole organism
• Gene expression orchestrates development.
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Figure 18.16
1 mm
(a) Fertilized eggs of a frog
2 mm
(b) Newly hatched tadpole
• Cell differentiation is the process by which cells
become specialized in structure and function
• The physical processes that give an organism its
shape constitute morphogenesis
• Differential gene expression results from genes
being regulated differently in each cell type
• Materials in the egg can set up gene regulation
that is carried out as cells divide
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• The other important source of developmental
information is the environment around the cell,
especially signals from nearby embryonic cells
• In the process called induction, signal molecules
from embryonic cells cause transcriptional
changes in nearby target cells
• Thus, interactions between cells induce
differentiation of specialized cell types
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Animation: Cell Signaling
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Figure 18.17b
(b) Induction by nearby cells
Early embryo
(32 cells)
NUCLEUS
Signal
transduction
pathway
Signal
receptor
Signaling
molecule
(inducer)
Sequential Regulation of Gene Expression
During Cellular Differentiation
• Determination commits a cell to its final fate
• Determination precedes differentiation
• Cell differentiation is marked by the production of
tissue-specific proteins
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Figure 18.18-3
Nucleus
Embryonic
precursor cell
Master regulatory
gene myoD
Other muscle-specific genes
DNA
Myoblast
(determined)
OFF
OFF
mRNA
OFF
MyoD protein
(transcription
factor)
mRNA
MyoD
Part of a muscle fiber
(fully differentiated cell)
mRNA
Another
transcription
factor
mRNA
mRNA
Myosin, other
muscle proteins,
and cell cycle–
blocking proteins
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
• Hydrolysis of sucrose by the enzyme sucrase
is an example of an enzyme-catalyzed
reaction
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Figure 8.UN02
Sucrase
Sucrose
(C12H22O11)
Glucose
(C6H12O6)
Fructose
(C6H12O6)
The Activation Energy Barrier
• Every chemical reaction between molecules
involves bond breaking and bond forming
• The initial energy needed to start a chemical
reaction is called the free energy of activation,
or activation energy (EA)
• Activation energy is often supplied in the form
of thermal energy that the reactant molecules
absorb from their surroundings
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Figure 8.12
A
B
C
D
Free energy
Transition state
A
B
C
D
EA
Reactants
A
B
∆G < O
C
D
Products
Progress of the reaction
How Enzymes Lower the EA Barrier
• Enzymes catalyze reactions by lowering the
EA barrier
• Enzymes do not affect the change in free
energy (∆G); instead, they hasten reactions
that would occur eventually
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Animation: How Enzymes Work
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Figure 8.13
Free energy
Course of
reaction
without
enzyme
EA
without
enzyme
EA with
enzyme
is lower
Reactants
∆G is unaffected
by enzyme
Course of
reaction
with enzyme
Products
Progress of the reaction
Substrate Specificity of Enzymes
• The reactant that an enzyme acts on is called the
enzyme’s substrate
• The enzyme binds to its substrate, forming an
enzyme-substrate complex
• The active site is the region on the enzyme
where the substrate binds
• Induced fit of a substrate brings chemical
groups of the active site into positions that
enhance their ability to catalyze the reaction
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Figure 8.14
Substrate
Active site
Enzyme
(a)
Enzyme-substrate
complex
(b)
Catalysis in the Enzyme’s Active Site
• In an enzymatic reaction, the substrate binds to
the active site of the enzyme
• The active site can lower an EA barrier by
–
–
–
–
Orienting substrates correctly
Straining substrate bonds
Providing a favorable microenvironment
Covalently bonding to the substrate
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Figure 8.15-1
1 Substrates enter active site.
2 Substrates are held
in active site by weak
interactions.
Substrates
Enzyme-substrate
complex
Active
site
Enzyme
Figure 8.15-2
1 Substrates enter active site.
2 Substrates are held
in active site by weak
interactions.
Substrates
Enzyme-substrate
complex
3 Active site can
lower EA and speed
up a reaction.
Active
site
Enzyme
4 Substrates are
converted to
products.
Figure 8.15-3
1 Substrates enter active site.
2 Substrates are held
in active site by weak
interactions.
Substrates
Enzyme-substrate
complex
3 Active site can
lower EA and speed
up a reaction.
6 Active
site is
available
for two new
substrate
molecules.
Enzyme
5 Products are
released.
4 Substrates are
converted to
products.
Products
Effects of Local Conditions on Enzyme
Activity
• An enzyme’s activity can be affected by
– General environmental factors, such as
temperature and pH
– Chemicals that specifically influence the
enzyme
• Enzymes are environment specific- some
function well in high temperatures and/or
extreme pH.
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Effects of Temperature and pH
• Each enzyme has an optimal temperature in
which it can function
• Each enzyme has an optimal pH in which it can
function
• Optimal conditions favor the most active shape
for the enzyme molecule
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Figure 8.16
Rate of reaction
Optimal temperature for
Optimal temperature for
typical human enzyme (37°C) enzyme of thermophilic
(heat-tolerant)
bacteria (77°C)
60
80
Temperature (°C)
(a) Optimal temperature for two enzymes
0
20
40
Rate of reaction
Optimal pH for pepsin
(stomach
enzyme)
0
5
pH
(b) Optimal pH for two enzymes
1
2
3
4
120
100
Optimal pH for trypsin
(intestinal
enzyme)
6
7
8
9
10
Figure 8.16a
Rate of reaction
Optimal temperature for
Optimal temperature for
typical human enzyme (37°C) enzyme of thermophilic
(heat-tolerant)
bacteria (77°C)
60
80
Temperature (°C)
(a) Optimal temperature for two enzymes
0
20
40
100
120
Rate of reaction
Figure 8.16b
Optimal pH for pepsin
(stomach
enzyme)
0
5
pH
(b) Optimal pH for two enzymes
1
2
3
4
Optimal pH for trypsin
(intestinal
enzyme)
6
7
8
9
10
Cofactors
• Cofactors are nonprotein enzyme helpers
• Cofactors may be inorganic (such as a metal in
ionic form) or organic
• An organic cofactor is called a coenzyme
• Coenzymes include vitamins
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Enzyme Inhibitors
• Competitive inhibitors bind to the active site
of an enzyme, competing with the substrate
• Noncompetitive (allosteric) inhibitors bind to
another part of an enzyme, causing the enzyme
to change shape and making the active site
less effective
• Examples of inhibitors include toxins, poisons,
pesticides, and antibiotics
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Figure 8.17
(a) Normal binding
(b) Competitive inhibition
(c) Noncompetitive
inhibition
Substrate
Active
site
Competitive
inhibitor
Enzyme
Noncompetitive
inhibitor
The Evolution of Enzymes
• Enzymes are proteins encoded by genes
• Changes (mutations) in genes lead to changes
in amino acid composition of an enzyme
• Altered amino acids in enzymes may alter
their substrate specificity
• Under new environmental conditions a novel
form of an enzyme might be favored
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Concept 8.5: Regulation of enzyme activity
helps control metabolism
• Chemical chaos would result if a cell’s
metabolic pathways were not tightly regulated
• A cell does this by switching on or off the
genes that encode specific enzymes or by
regulating the activity of enzymes
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Allosteric Regulation of Enzymes
• Allosteric regulation may either inhibit or
stimulate an enzyme’s activity
• Allosteric regulation occurs when a regulatory
molecule binds to a protein at one site and
affects the protein’s function at another site
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Allosteric Activation and Inhibition
• Most allosterically regulated enzymes are
made from polypeptide subunits
• Each enzyme has active and inactive forms
• The binding of an activator stabilizes the
active form of the enzyme
• The binding of an inhibitor stabilizes the
inactive form of the enzyme
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Figure 8.19
(b) Cooperativity: another type of allosteric activation
(a) Allosteric activators and inhibitors
Allosteric enzyme
with four subunits
Active site
(one of four)
Regulatory
site (one
of four)
Substrate
Activator
Inactive form
Stabilized active form
Active form
Oscillation
Nonfunctional
active site
Inactive form
Inhibitor
Stabilized inactive
form
Stabilized active
form
Figure 8.19a
(a) Allosteric activators and inhibitors
Allosteric enzyme
with four subunits
Active site
(one of four)
Regulatory site
(one of four)
Activator
Active form
Stabilized active form
Oscillation
Nonfunctional
active site
Inactive form
Inhibitor
Stabilized inactive form
Figure 8.19b
(b) Cooperativity: another type of allosteric activation
Substrate
Inactive form
Stabilized active
form
• Cooperativity is a form of allosteric regulation
that can amplify enzyme activity
• One substrate molecule primes an enzyme to
act on additional substrate molecules more
readily
• Cooperativity is allosteric because binding by a
substrate to one active site affects catalysis in
a different active site
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Feedback Inhibition
• In feedback inhibition, the end product of a
metabolic pathway shuts down the pathway
• Feedback inhibition prevents a cell from
wasting chemical resources by synthesizing
more product than is needed
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Figure 8.21
Active site
available
Isoleucine
used up by
cell
Active site of
Feedback
enzyme 1 is
inhibition
no longer able
to catalyze the
conversion
of threonine to
intermediate A;
pathway is
switched off. Isoleucine
binds to
allosteric
site.
Initial
substrate
(threonine)
Threonine
in active site
Enzyme 1
(threonine
deaminase)
Intermediate A
Enzyme 2
Intermediate B
Enzyme 3
Intermediate C
Enzyme 4
Intermediate D
Enzyme 5
End product
(isoleucine)