Download An Introduction to Metabolism

Chapter 8
An Introduction to Metabolism
AP Biology
Overview: The Energy of Life
•
Cells are like mini chemical factories where 1000s of reactions occur
–
Ex) Sugars are converted to amino acids that are then used to form proteins
–
Ex) Proteins are broken down into amino acids that
can be converted to sugars during digestion
•
Cellular respiration extracts energy stored in sugars
–
This energy is then used to perform work (in this case,
the transport of solutes across the plasma membrane)
•
In a more exotic example, cells of some fungi convert energy to light, called
BIOLUMINESCENCE
– Glowing attracts insects that disperse the fungal spores
Concept 8.1:
An organism’s metabolism
transforms matter and energy,
subject to the laws of
thermodynamics
Metabolism
• Metabolism is all the chemical reactions that
take place inside an organism
– Metabolism is an emergent property of life
that can occur only as a result of interactions
between molecules within the cell
Organization of the Chemistry of Life into Metabolic Pathways
•
Cellular metabolism can be through of as a roadmap of 1000s of different chemical
reactions arranged as intersecting metabolic pathways
–
A metabolic pathway begins with a specific molecule that is changed in a
series of defined steps, resulting in a certain product
• Each step is catalyzed by a specific enzyme
Enzyme 1
A
Reaction 1
Starting
molecule
Enzyme 2
B
Reaction 2
Enzyme 3
C
Reaction 3
D
Product
Catabolic Pathways
• Some metabolic pathways release energy by breaking down complex
molecules into simpler compounds
• This type of metabolic pathways is called a CATABOLIC
PATHWAY
– A major pathway of catabolism is CELLULAR RESPIRATION
• Glucose is broken down in the presence of O2 into CO2 and
water
• The energy stored in glucose can then be used to do cellular
work
Anabolic Pathways
•
Anabolic pathways use energy to build more complex molecules from simpler ones
–
These are sometimes called biosynthetic pathways
• Ex) Building a protein from amino acids
–
***Energy released from the “downhill” reactions of catabolic pathways is
stored and then used to drive the “uphill” reactions of anabolic pathways***
•
A basic knowledge of energy is necessary to understand how cellular metabolism
works
–
Bioenergetics is the study of how energy flows through living organisms
Forms of Energy
• Energy is the capacity to cause change
– Energy exists in various forms, some of which can
perform work
• Kinetic energy
• Potential energy
– Life depends on the ability of cells to change
energy from one form to another
Forms of Energy
•
Forms of energy include:
–
Kinetic energy: energy associated with motion
• Heat (thermal energy): kinetic energy associated with the random
movement of atoms or molecules
–
Potential energy: energy that matter possesses because of its location
or structure
• Chemical energy: potential energy available for release in a
chemical reaction
•
Energy can be converted from one form to another
Animation: Energy Concepts
Fig. 8-2
A diver has more potential
energy on the platform
than in the water.
Climbing up converts the kinetic
energy of muscle movement
to potential energy.
Diving converts
potential energy to
kinetic energy.
A diver has less potential
energy in the water
than on the platform.
The Laws of Energy Transformation
•
Thermodynamics is the study of energy transformations that occur in a collection of matter
–
The term “system” is used to denote the matter under study
•
–
Everything outside the system is called the “surroundings”
ISOLATED SYSTEMS are unable to exchange energy or matter with their
surroundings
•
–
Ex) Liquid in a thermos
OPEN SYSTEMS allow transfer of energy and matter between the systems and their
surroundings
•
Ex) Organisms are open system (they absorb energy in light or in the chemical
form of organic molecules and release heat and metabolic waste products like CO2
to the surroundings
The First Law of Thermodynamics
•
There are 2 laws of thermodynamics that govern energy transformations
–
The 1st law of thermodynamics states that the energy of the universe is constant
•
Energy can be transferred or transformed, but it cannot be created or destroyed
–
This law is also known as the principle of conservation of energy
The Second Law of Thermodynamics
•
During every energy transfer or transformation, some energy becomes unusable
•
–
A logical consequence of the loss of usable energy is that each such event makes the
universe more disordered
•
–
This energy is often lost as heat to the surroundings
A quantity called ENTROPY is used to measure disorder (or randomness)
The 2nd Law of Thermodynamics states that every energy transfer or transformation
increases the entropy of the universe (increases disorder or randomness)
Spontaneous vs. Nonspontaneous Processes
• For a process to occur on its own, without the input of energy, it must
increase the entropy of the universe
–
This is known as a SPONTANEOUS process
• Spontaneous does not imply that the process occurs quickly
– Ex) Rust forms on an old car over time
• A process that cannot occur on its own is a NONSPONTANEOUS process
–
A nonspontaneous process will happen only if energy is added to the
system
Biological Order and Disorder
• Cells create ordered structures from less organized starting materials
• Ex) Amino acids are ordered into specific sequence of a
polypeptide chains
– Organisms also replace ordered forms of matter and energy with
less ordered forms
• Ex) Digestion
– On a larger scale, energy flows into an ecosystem in the form of
light and exits in the form of heat
Evolution and Entropy
•
During Earth’s history, complex organisms evolved from simpler ancestors
• This increased order, however, does not violate the 2nd law of
thermodynamics
–
The entropy of a system may decrease as long as the total entropy of the
universe increases
Concept Check 8.1
• 1) How does the 2nd law of thermodynamics help explain the
diffusion of a substance across a membrane?
• 2) Describe the forms of energy found in an apple as it grows
on a tree, then falls and is digested by someone who eats it.
• 3) If you place a teaspoon of sugar in the bottom of a glass of
water, it will dissolve completely over time. Left longer,
eventually the water will disappear and the sugar crystals will
reappear. Explain these observations in terms of entropy.
Concept 8.2:
The free-energy change of a reaction
tells us whether or not the reaction
occurs spontaneously
• Biologists want to know which reactions occur
spontaneously and which require input of
energy
– To do so, they need to determine energy
and entropy changes that occur in chemical
reactions
Free-Energy Change, G
•
The free energy of a system (without considering its surroundings) is symbolized with the
letter “G”
•
Free energy is the portion of a system’s energy that can perform work when
temperature and pressure are uniform in a system (like in a living cell)
–
To determine the free energy change that occurs when a system changes (like during a
chemical reaction):
∆G = ∆H – T∆S
•
ΔH: change in system’s enthaply (equivalent to total energy in system)
•
ΔS: change in system’s entropy
•
T: absolute temperature in Kelvins (K = oC +273)
Predicting Spontaneity of Reactions From ΔG
•
Knowing the value for ΔG allows us to predict if a process will be
spontaneous:
–
Negative values are spontaneous For a process to occur
spontaneously, the system must either (Keep in mind: ∆G = ∆H – T∆S):
– 1) Give up enthalpy (energy) – H must decrease
– 2) Give up order (increase TS)
– 3) Or both
–
•
Positive values are nonspontaneous
Energy released from spontaneous processes can then be harnessed to
perform work
Free Energy, Stability, and Equilibrium
•
We can think of free energy as a measure of a system’s instability or its tendency to change to
a more stable state
–
–
Unstable systems (higher free energy G) want to become more stable (lower free
energy G)
•
Ex) A diver on a diving board is less stable (more likely to fall) than when he is in
the water
•
Ex) A sugar molecule is less stable (more likely to break down) than the simpler
molecules into which it can be split
Another term that describes the state of maximum stability is equilibrium
•
As a chemical reaction proceeds toward equilibrium, the free energy of the mix of
products and reactants DECREASES
–
•
For a system at equilibrium (most stable), G is at its lowest possible value in
that system
A system at equilibrium cannot spontaneously change - it can do no work
–
A process can only be spontaneous and perform work when it is moving
toward equilibrium
•
The top row of pictures represent unstable systems that are thus rich in free energy
–
These systems have the tendency to change spontaneously to a more stable state
(bottom pictures)
•
It is possible to harness this “downhill” change to perform work
•
a) Gravitational motion – objects can move spontaneously from higher altitudes to lower ones
•
b) Diffusion – molecules in a drop of dye diffuse until they are randomly dispersed (increased
disorder)
•
c) Chemical reaction – in a cell, sugar molecules are broken down into simpler molecules
Free Energy and Metabolism
• The concept of free energy can be applied more
specifically to the chemistry of life’s processes
– Based on their free energy changes, chemical
reactions can be classified as either exergonic or
endergonic
Exergonic vs. Endergonic Reactions
•
1) Exergonic reactions have a net release of free energy
–
Because G decreases, ΔG is negative
for all exergonic reactions (spontaneous)
•
2) Endergonic reactions absorb free energy
from their surroundings
–
Because G increases, ΔG is positive
(not spontaneous)
–
Its value gives the amount of energy
needed to drive a chemical reaction
Equilibrium and Metabolism
•
Reactions in closed systems eventually reach equilibrium and can do no work
–
•
Living cells are NOT at equilibrium;
•
The constant flow of materials in and out of a cell keeps metabolic pathways from
ever reaching equilibrium
•
Cells can therefore continue to do work
Catabolic pathways release free energy in a series of reactions:
–
Ex) Cell respiration
•
•
Some of the reversible reactions of cell respiration are constantly pulled in one
direction (kept out of equilibrium) by making sure the product of a reaction
doesn’t accumulate
–
This product instead becomes a reactant in the next step
–
At the end, waste products are expelled from the cell
***As long as our cells have a steady supply of glucose and oxygen and are able
to expel waste products to the surroundings, their metabolic pathways never reach
equilibrium and can continue to do work of life***
Equilibrium and Metabolism
•
We can use closed and open hydroelectric system as analogies
–
A) Isolated hydroelectric system: water flowing downhill turns on a turbine that drives
a generator, providing electricity to a light bulb
•
The light bulb will only turn on (work can
only be performed)until the system reaches
equilibrium
–
B) An open hydroelectric system: flowing water
keeps the generator going because intake and
outflow of water keep the system from reaching
equilibrium
–
C) A multistep open hydroelectric system: cell
respiration is analogous to this system
•
Glucose is broken down in a series of
exergonic reactions that powers the work
of cells
•
The product of each reaction becomes the
reactant for next, so no reaction reaches
equilibrium
Concept Check 8.2
•
1) Cellular respiration uses glucose and oxygen, which have high levels of free
energy, and release CO2 and water, which have low levels of free energy. Is
respiration spontaneous or not? Is it exergonic or endergonic? What happens to the
energy released from glucose?
•
2) A key process in metabolism is the transport of H+ ions across a membrane to
create a concentration gradient. Other processes can result in an equal
concentration hydrogen ions on each side. Which arrangement of hydrogen ions
allows the H+ to perform work in this system?
•
3) At nighttime celebrations, revelers can sometimes be seen wearing glow-in-thedark necklaces. The necklaces start glowing once they are “activated,” which usually
involves snapping the necklace in a way that allows two chemicals to react and emit
light in the form of “chemiluminescence.” Is the chemical reaction exergonic or
endergonic? Explain your answer.
Concept 8.3:
ATP powers cellular work by
coupling exergonic reactions to
endergonic reactions
Types of Cellular Work
•
A cell does 3 main kinds of work:
–
1) Chemical work: the pushing of endergonic (nonspontaneous) reactions
•
–
Ex) The synthesis of polymers from monomers
2) Transport work: the pumping of substances across membranes against their
concentration gradients
•
–
Ex) The sodium-potassium pump
3) Mechanical work
•
Ex) Beating of cilia
•
Ex) Contraction of muscle cells
•
Ex) Movement of chromosomes during cellular reproduction
Types of Cellular Work
•
Cells manage their energy resources to perform these different types of work by the process
of ENERGY COUPLING
•
Energy coupling is the use of an exergonic (releases energy, spontaneous) process
to drive an endergonic one
–
–
ATP (adenosine triphosphate) mediates most energy coupling in cells
–
In most cases, ATP acts as immediate energy source to power cellular work
ATP is composed of 3 parts:
•
1)A sugar (ribose)
•
2)A nitrogenous base (adenine)
•
3)A chain of 3 phosphate groups
Hydrolysis of ATP
•
The bonds between the phosphate groups of ATP can be broken via hydrolysis
–
When the terminal phosphate bond is broken, a molecule of inorganic phosphate leaves
ATP, forming ADP
•
This reaction is EXERGONIC
–
It releases 7.3 kcal of energy per mole of ATP hydrolyzed (ΔG = -7.3
kcal/mol)
–
The release of energy during the
hydrolysis of ATP comes from
the chemical change to a state
of lower free energy (not from
phosphate bonds themselves)
Hydrolysis of ATP
•
Why does hydrolysis of ATP release so much energy relative to most other molecules?
–
All 3 phosphate groups are negatively charged
•
The mutual repulsion of like (negative) charges contributes to instability (potential
energy)of this region of ATP
•
The triphosphate tail is thus like a compressed spring
How ATP Performs Work
• The cell’s proteins harness the energy released by hydrolysis of ATP
to perform the 3 types of cellular work discussed (mechanical,
transport, and chemical)
– With the help of specific enzymes, cells can use the energy
released by hydrolysis of ATP to drive endergonic reactions
• If ΔG of endergonic reaction is LESS than the amount of
energy released by ATP hydrolysis, these 2 reactions can be
coupled so that, OVERALL, the reactions are exergonic
a) Endergonic reaction – Conversion of amino acids from one amino acid to another is
endergonic (requires energy)
• G = +3.4 kcal/mol
b) Coupled with ATP hydrolysis – an exergonic reaction
– Glutamine synthesis occurs in
2 steps in the cell:
• 1) ATP phosphorylates
glutamic acid, making the
AA less stable
• 2)Ammonia displaces the
phosphate group, forming
glutamine
c) Overall free-energy change
– Net G is negative
– Thus, the reaction occurs
spontaneously
Phosphorylation
• ATP drives endergonic reactions by phosphorylation
• Phosphorylation is the transfer of a phosphate
group from ATP to another molecule; often to the
reactant
– This forms a phosphorylated intermediate which is
more reactive (less stable) than the original
unphosphorylated molecule
Phosphorylation Examples
•
Transport and mechanical work are also nearly always powered by hydrolysis of ATP:
–
a) ATP hydrolysis leads to change in a protein’s shape
•
–
This change in shape affects its ability to bind another molecule
b) Noncovalent binding of ATP to a motor protein
•
ATP is then hydrolyzed, releasing ADP and inorganic phosphate
–
•
Another ATP can then bind
At each stage, the motor protein changes
its shape and ability to bind to the
cytoskeleton
– This results in the movement of
the protein along a cytoskeletal track
The Regeneration of ATP
•
ATP is a renewable resource that can be regenerated by adding phosphate to ADP
•
–
The process that regenerates ATP from ADP is called the ATP cycle
•
–
The energy required for phosphorylation of ADP comes from catabolic reactions
in the cell – mainly cell respiration
The ATP cycle couples the cell’s exergonic processes to the endergonic
phosphorylation of ADP
The ATP cycle moves at astonishing pace
•
Ex) A working muscle cell recycles all of its ATP in less than 1 minute
–
This represents a turnover rate of 10 million ATP molecules consumed and
regenerated per second per cell
Concept Check 8.3
• 1) In most cases, how does ATP transfer
energy from exergonic to endergonic reactions
in the cell?
• 2) Which of the following combinations has
more free energy: glutamic acid + ammonia +
ATP or glutamine + ADP + Pi? Explain your
answer.
Concept 8.4:
Enzymes speed up metabolic
reactions by lowering energy
barriers
Enzymes as Catalysts
• Enzymes are macromolecules that act as catalysts
– Catalysts are any chemical agents that speed up a reaction
without themselves being
consumed by the reaction
• Ex) The hydrolysis of
sucrose by the enzyme
sucrase is an example of
an enzyme-catalyzed
reaction
Sucrase
The Activation Energy Barrier
•
Chemical reactions between molecules involve the breakage and formation of bonds
•
Ex) The hydrolysis of sucrose involves breaking the bond between glucose and
fructose and one of the bonds of a water molecule and then formation of new
bonds
–
To reach a contorted state where bonds can change, reactant molecules must absorb
energy from their surroundings
•
When new bonds of product molecules
form, energy is released as heat
–
These product molecules are
returned to stable shapes with
lower energy than the contorted
state
The Activation Energy Barrier
•
The initial investment of energy for starting a reaction (the energy required to contort a
molecule so its bonds can break) is known as its free energy of activation, or activation
energy (EA)
–
Activation energy is often supplied in the
form of heat that reactant molecules
absorb from their surroundings
•
Absorption of thermal energy
increases the speed of the reactant
molecules, so they collide more
often and more forcefully
•
This thermal agitation of atoms within molecules makes their bonds more likely to
break
How Enzymes Lower the EA Barrier
•
Enzymes catalyze reactions by lowering the activation energy
•
This allows reactant molecules to absorb enough energy to reach their transition
state, even at moderate temperatures
–
Enzymes cannot change the free energy change (ΔG) for a reaction
•
In other words, they
cannot make endergonic
reactions exergonic
–
Enzymes can only make
reactions occur more quickly
Animation: How Enzymes Work
Substrate Specificity of Enzymes
•
Enzymes are very specific for the reactions they catalyze
•
–
The reactant that an enzyme acts on is referred to as the enzyme’s SUBSTRATE
An enzyme bonds to its substrate and forms an ENZYME-SUBSTRATE COMPLEX
•
While the enzyme and substrate are joined, the enzyme converts the substrate to
product
–
Only a restricted region of the enzyme, known as the ACTIVE SITE, actually binds to
the substrate
•
The active site is usually a pocket or groove on the surface of the enzyme
•
The active site is usually formed by only a few of the enzyme’s amino acids
Substrate Specificity of Enzymes
•
The specificity of enzymes results from the compatible fit between the shape of their active
site and the shape of their substrate
–
The shape of active site changes, however, when the substrate binds
•
Interactions between chemical groups of the substrate and side chains of the
enzyme’s amino acids cause the enzyme to change shape slightly
•
The active site then fits even more snugly around its substrate
– This is called INDUCED FIT
–
Induced fit brings the chemical groups of the active site into positions that enhance
their ability to catalyze the chemical reaction
Induced Fit: An Example
• The figure below shows the induced fit between an enzyme and its substrate
– A) The active site of the enzyme HEXOKINASE is shown as a groove on its surface
• Its substrate (glucose) is shown in red
–
B) When the substrate enters the active site, it changes the shape of the enzyme
• This change allows more weak bonds to form
• This, in turn, causes
the active site to
enfold the substrate
and hold it in place
Catalysis in the Enzyme’s Active Site
•
Once an enzyme binds its substrate in the active site, it can lower the activation energy in a variety
of ways:
–
1) Orienting substrates correctly:
•
–
2) Straining substrate bonds
•
–
In reactions involving 2+ reactant, the active site provides a template on which
substrates can come together in their proper orientation for a reaction to occur between
then
As an enzyme clutches the bound substrate, it may stretch the substrate toward its
transition state form (stress and bend critical chemical bonds that must be broken)
3) Provide a favorable microenvironment
•
The active site may provide a microenvironment that is more conducive to a particular
type of reaction
–
–
Ex) Acidic amino acids create a pocket of low pH in an otherwise neutral cell
4) Covalently bonding to the substrate
•
There may be direct participation of the active site in a chemical reaction, including
brief covalent bonding between the substrate and the R group of an enzyme’s amino
acid
The Catalytic Cycle of an Enzyme
•
1) The substrate enters the active site
– The active site enfolds the substrate(s); INDUCED FIT
•
2) The substrates are held in the active site by weak interactions (ex: H-bonds, ionic bonds)
•
3) The active site lowers the activation energy and speeds up a reaction by:
– Acting as 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 to products
•
5)Products are released
•
6) The active site is now available for new
substrate molecules
Effects of Local Conditions on Enzyme Activity
• Enzyme activity is affected by general environmental
factors, including:
• Temperature
• pH
– It can also be affected by chemicals that specifically
influence the enzyme
Effects of Temperature
•
Enzymes work better under some conditions, called OPTIMAL CONDITIONS, than others
•
–
Optimal conditions favor the active shape of the enzyme
Optimal conditions and temperature:
•
The rate of enzymatic reaction
increases with increasing
temperature, to a certain point
–
•
Higher temperatures cause
substrate molecules to move
faster and thus collide more
frequently with the active site
of an enzyme
Above a certain temperature, however, the reaction rate drops sharply
–
Thermal agitation of the enzyme molecule disrupts H-bonds, ionic bonds, and
other weak interactions that stabilize the active shape of the enzyme
•
•
This eventually causes the protein enzyme to denature
Optimal temperature is the temperature at which the most molecular collisions
occur without denaturation (usually 35-40 oC in humans)
Effects of pH
• Optimal conditions and pH:
– Optimal pH values for most enzymes are between 6 and 8
• Exceptions include pepsin, a digestive enzyme of the
stomach, which works best at a pH of 2
Cofactors
•
Many enzymes need nonprotein enzyme helpers, which are called COFACTORS
–
–
Cofactors may be:
•
1) Bound tightly to enzyme (permanently)
•
2) Bound loosely and reversibly
Cofactors can be:
•
1) Inorganic
–
•
Ex) Ionic forms of Cu, Fe, Zn
2) Organic
•
–
Ex) Vitmains
Organic cofactors are called COENZYMES
Enzyme Inhibitors
• Certain chemical selectively inhibits enzyme function
– If an inhibitor attaches to an enzyme with covalent bonds,
inhibition is usually irreversible
• Ex) Toxins, poisons, pesticides (DDT), and antibiotics
(penicillin)
– If an inhibitor binds by weak interactions (ex: H-bonds),
inhibition is reversible
Competitive vs. Noncompetitive Inhibition
•
Reversible inhibitors include:
–
–
1)Competitive inhibitors – resemble the normal substrate molecule and compete for the
active site
•
This reduces the productivity of an enzyme by blocking substrates from entering
the active site
•
This type of inhibition can usually be overcome by increasing substrate
concentration, so that there is more substrate than inhibitor
2) Noncompetitive inhibitors – bind to other parts of enzyme (not the active site)
•
This bonding causes the enzyme to change shape
•
As a result, the active site becomes less effective at catalyzing the reaction
Concept Check 8.4
• 1) Many spontaneous reactions occur very slowly.
Why don’t all spontaneous reactions occur instantly?
• 2) Why do enzymes act only on very specific
substrates?
• 3) Malonate is an inhibitor of the enzyme succinate
dehydrogenase. How would you determine whether
malonate is a competitive or noncompetitive inhibitor?
Concept 8.5:
Regulation of enzyme activity helps
control metabolism
Regulation of Enzyme Activity
• Cells must be able to regulate their metabolic pathways by
controlling when and where various enzymes are active
– They do so by either:
• Switching genes encoding these enzymes off or on
• Regulating the activity of enzymes once they are
made
Allosteric Regulation of Enzymes
• Molecules exist that naturally regulate enzyme activity in the cell
– These molecules behave something like noncompetitive
inhibitors
• They change an enzyme’s shape and thus the functioning of
its active site by noncovalently binding to a site elsewhere on
the enzyme
– This is called ALLOSTERIC REGULATION
– Allosteric regulation can either inhibit OR stimulate enzyme
activity
Allosteric Activation and Inhibition
•
Most allosterically-regulated enzymes are made of 2+ polypeptide subunits
•
–
–
Each subunit has its own active site
The entire enzyme complex alternates between 2 shapes: one active and one inactive
•
The binding of an ACTIVATOR to this enzyme complex stabilizes the shape of its
active form
•
The binding of an INHIBITOR to the
enzyme complex, in contrast, stabilizes the
inactive form of the enzyme
Subunits of the enzyme fit together so that a
shape change in one subunit is transmitted to all
other subunits
•
Thus, a single activator or inhibitor binding
to only one regulatory site will affect the
active sites of all the subunits on the
enzyme complex
Allosteric Regulation: Cooperativity
•
Another form of allosteric regulation is COOPERATIVITY
–
In this type of regulation, a substrate molecule binds to the active site of one subunit on
a multisubunit enzyme
•
Binding triggers the same favorable shape change in all active sites
–
–
This stimulates the catalytic powers of the enzyme, priming the enzyme to
accept additional substrate molecules
Ex) Hemoglobin is the vertebrate oxygen transport protein (not an enzyme but shows
how cooperative binding works)
•
This protein has 4 subunits, each with an oxygen-binding site
– The binding of oxygen to each site increases the affinity of the remaining
binding sites for oxygen
–
In oxygen-depleted tissues, on
the other hand, hemoglobin is
less likely to bind oxygen and
will thus release it where needed
Identification of Allosteric Regulators
•
Allosteric regulators are attractive drug candidates for enzyme regulation
–
Enzymes called caspases play an active role in inflammation and cell death in
the body
• Caspases are known to exist in both active and inactive forms
–
The goal is to find a compound that will stabilize caspases in their inactive
form
• By specifically regulating these enzymes, we can better manage
inappropriate inflammatory responses seen in vascular and
neurodegenerative diseases
•
•
•
Are there allosteric inhibitors of caspase enzymes?
–
Close to 8,000 compounds were tested for their ability to bind allosterically in caspase
1 and thereby inhibit this enzyme’s activity
–
Each compound forms a disulfide bond with a cysteine near the site, stabilizing the
inactive form of the enzyme
Experiment:
–
X-ray diffraction analysis was used to determine
the structure of caspase 1 when bound to
each of these compounds
–
These structures where then compared to the
active and inactive form of caspase 1 to determine
which compounds worked to inhibit the caspase
Results:
–
14 compounds were found to induce the
inactive form and block enzymatic activity
Feedback Inhibition
•
Allosteric inhibition of enzymes can result in FEEDBACK INHIBITION
• Feedback inhibition is a common method of metabolic control
–
A metabolic pathway is switched off by the inhibitory binding of its end
product to an enzyme that acts early in the pathway
• This prevents the cell from wasting chemical resources by making more
product than is needed
– Ex) Feeback inhibition of isoleucine synthesis (next slide)
Feedback Inhibition in Isoleucine Synthesis
•
Feedback inhibition in isoleucine synthesis:
–
Isoleucine is made in a 5-step
pathway from threonine, another
amino acid
–
As isoleucine accumulates, it slows
down its own synthesis by allosterically
inhibiting the enzyme for the 1st
step in the pathway
Specific Localization of Enzymes Within the Cell
•
Cells have compartments and other structures that help bring order to metabolic pathways
•
Ex) If a team of enzymes is required to complete a metabolic pathway, they are
sometimes assembled into a multi-enzyme complex (so all enzymes are in the
same location)
–
Some enzymes and enzyme complexes have fixed locations in the cell and can act as
structural components of membranes
–
Others are found in the solution of specific membrane-bound organelles, each with its
own internal chemical environment
•
Ex) The enzymes for cellular respiration are
found in specific locations in the mitochondria
–
The mitochondrial matrix contains enzymes
in solution that are involved in stage 1 of
cell respiration
– Enzymes for another stage of cellular
respiration are embedded in the inner
membrane of cristae
Concept Check 8.5
• 1) How can an activator and an inhibitor have different
effects on an allosterically regulated enzyme?
• 2) Imagine you are a pharmacological researcher who
wants to design a drug that inhibits a particular
enzyme. Upon reading the scientific literature, you
find that the enzyme’s active site is similar to that of
several other enzymes. What might be the best
approach to developing your inhibitor drug?
You should now be able to:
1. Distinguish between the following pairs of
terms: catabolic and anabolic pathways;
kinetic and potential energy; open and closed
systems; exergonic and endergonic reactions
2. In your own words, explain the second law of
thermodynamics and explain why it is not
violated by living organisms
3. Explain in general terms how cells obtain the
energy to do cellular work
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4. Explain how ATP performs cellular work
5. Explain why an investment of activation
energy is necessary to initiate a spontaneous
reaction
6. Describe the mechanisms by which enzymes
lower activation energy
7. Describe how allosteric regulators may inhibit
or stimulate the activity of an enzyme
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings