An Introduction to Metabolism

An Introduction to Metabolism
Chapter 8 An Introduction to Metabolism

Overview 8.1 An organism′s metabolism transforms matter and energy, subject to the laws of thermodynamics 8.2 The free–energy change of a reaction tells us whether the reaction occurs spontaneously 8.3 ATP powers cellular work by coupling exergonic reactions to endergonic reactions 8.4 Enzymes speed up metabolic reactions by lowering energy barriers 8.5 Regulation of enzyme activity helps control metabolism

Overview: The Energy of Life
The living cell is a miniature chemical factory where thousands of reactions occur The cell extracts energy and applies energy to perform work Some organisms even convert energy to light, as in bioluminescence

Metabolism is the totality of an organism’s chemical reactions
Concept 8.1: An organism’s metabolism transforms matter and energy, subject to the laws of thermodynamics Metabolism is the totality of an organism’s chemical reactions Metabolism is an emergent property of life that arises from interactions between molecules within the cell

Organization of the Chemistry of Life into Metabolic Pathways
A metabolic pathway begins with a specific molecule and ends with a product Each step is catalyzed by a specific enzyme

LE 8-UN141 Enzyme 1 Enzyme 2 Enzyme 3 A B C D Reaction 1 Reaction 2 Reaction 3 Starting molecule Product

We can picture a cell′s metabolism as an elaborate road map of the thousands of chemical reactions that occur in a cell, arranged as intersecting metabolic pathways Analogous to the red, yellow, and green stoplights that control the flow of traffic, mechanisms that regulate enzymes balance metabolic supply and demand, averting deficits or surpluses of important cellular molecules

Metabolism as a whole manages the ________________ and ___________________ resources of the cell. Some metabolic pathways release energy by breaking down complex molecules to simpler compounds

Catabolic pathways release energy by breaking down complex molecules into simpler compounds
Anabolic pathways consume energy to build complex molecules from simpler ones Bioenergetics is the study of how organisms manage their energy resources

Energy released from the downhill reactions of catabolism can be stored and then used to drive the uphill reactions of the anabolic pathways

Forms of Energy Energy is the capacity to cause change
Energy exists in various forms, some of which can perform work

Animation: Energy Concepts
Kinetic energy is energy associated with motion ____________ (thermal energy) is kinetic energy associated with random movement of atoms or molecules ________________ energy is energy that matter possesses because of its location or structure ________________ energy is potential energy available for release in a chemical reaction Energy can be converted from one form to another Animation: Energy Concepts

LE 8-2 On the platform, the diver has more potential energy.
Diving converts potential energy to kinetic energy. Climbing up converts kinetic energy of muscle movement to potential energy. In the water, the diver has less potential energy.

Recall that catabolic pathways release energy by breaking down complex molecules. Complex molecules, such as glucose, are high in chemical energy. During a catabolic reaction, atoms are rearranged and energy is released, resulting in lower–energy breakdown products. This transformation also occurs, for example, in the engine of a car when the hydrocarbons of gasoline react explosively with oxygen, releasing the energy that pushes the pistons and producing exhaust. Although less explosive, a similar reaction of food molecules with oxygen provides chemical energy in biological systems, producing carbon dioxide and water as waste products. It is the structures and biochemical pathways of cells that enable them to release chemical energy from food molecules, powering life processes

Organisms are energy transformers.
The study of the energy transformations that occur in a collection of matter is called thermodynamics

The Laws of Energy Transformation
Two words…. Scientists use the word system to denote the matter under study; they refer to the rest of the universe—everything outside the system—as the surroundings. A closed system, such as liquid in a thermos bottle, is isolated from its surroundings. In an open system, energy (and often matter) can be transferred between the system and its surroundings. Organisms are __________ systems. They absorb energy—for instance, light energy or chemical energy in the form of organic molecules—and release heat and metabolic waste products, such as carbon dioxide, to the surroundings. Two laws of thermodynamics govern energy transformations in organisms and all other collections of matter

The First Law of Thermodynamics
According to the first law of thermodynamics, the energy of the universe is constant Energy can be transferred and transformed Energy cannot be created or destroyed The first law is also called the principle of conservation of energy

The electric company does not make energy, but merely converts it to a form that is convenient to use. By converting sunlight to chemical energy, a green plant acts as an energy transformer, not an energy producer.

LE 8-3 The cheetah will convert the chemical energy of the organic molecules in its food to kinetic and other forms of energy as it carries out biological processes. What happens to this energy after it has performed work? The second law helps to answer this question CO2 Chemical energy Heat H2O First law of thermodynamics Second law of thermodynamics

The Second Law of Thermodynamics
If energy cannot be destroyed, why can′t organisms simply recycle their energy over and over again? During every energy transfer or transformation, some energy is unusable, often lost as ___________ which is the energy associated with the random motion of atoms or molecules.

In most energy transformations, more usable forms of energy are at least partly converted to heat,
Only a small fraction of the chemical energy from the food is transformed into the motion of the cheetah; most is lost as heat, which dissipates rapidly through the surroundings

In the process of carrying out chemical reactions that perform various kinds of work, living cells unavoidably convert organized forms of energy to heat. Can a system put heat to work? only when there is a temperature difference that results in the heat flowing from a warmer location to a cooler one. If temperature is uniform, as it is in a living cell, then the only use for heat energy generated during a chemical reaction is to warm a body of matter, such as the organism.

Concept of Entropy The loss of usable energy during energy transfer or transformation makes the universe more disordered. Scientists use a quantity called entropy as a measure of disorder, or randomness. The more randomly arranged a collection of matter is, the greater its entropy

State the second law of Thermodynamics
The loss of usable energy during energy transfer or transformation makes the universe more disordered… We can now state the second law of thermodynamics as follows: Every energy transfer or transformation increases the entropy of the universe. Although order can increase locally, there is an unstoppable trend toward randomization of the universe as a whole.

In many cases, increased entropy is evident in the physical disintegration of a system′s organized structure. For example, you can observe increasing entropy in the gradual decay of an unmaintained building. Much of the increasing entropy of the universe is less apparent, however, because it appears as increasing amounts of heat and less ordered forms of matter. As the cheetah converts chemical energy to kinetic energy, it is also increasing the disorder of its surroundings by producing heat and the small molecules that are the breakdown products of food

Biological Order and Disorder
Living systems increase the entropy of their surroundings, as predicted by thermodynamic law. How do you explain…. Cells create ordered structures from less organized starting materials. For example, amino acids are ordered into the specific sequences of polypeptide chains. The extremely symmetrical anatomy of a plant′s root, formed by biological processes from simpler starting materials. How do you explain evolution… The entropy of a particular system, such as an organism, may actually decrease, so long as the total entropy of the universe—the system plus its surroundings—increases. Thus, organisms are islands of low entropy in an increasingly random universe. The evolution of biological order is perfectly consistent with the laws of thermodynamics

Biological Order and Disorder
Living systems increase the entropy of their surroundings, as predicted by thermodynamic law. Question you would ask is; that cells create ordered structures from less organized starting materials. For example, amino acids are ordered into the specific sequences of polypeptide chains.

An organism also takes in organized forms of matter and energy from the surroundings and replaces them with less ordered forms. For example, an animal obtains starch, proteins, and other complex molecules from the food it eats. As catabolic pathways break these molecules down, the animal releases carbon dioxide and water—small molecules that store less chemical energy than the food did. The depletion of chemical energy is accounted for by heat generated during metabolism. On a larger scale, energy flows into an ecosystem in the form of light and leaves in the form of heat

why certain processes occur?
The concept of entropy helps us understand why certain processes occur. It turns out that for a process to occur on its own (spontaneously), without outside help (an input of energy), it must ____________________ the entropy of the universe.

Spontaneous process… Let′s first agree to use the word spontaneous for a process that can occur without an input of energy. The word spontaneous does not imply that such a process would occur quickly. Some spontaneous processes may be virtually instantaneous, such as an explosion, while others may be much slower, such as the rusting of an old car over time.

Nonspontaneous process…
A process that cannot occur on its own is said to be nonspontaneous; it will happen only if energy is added to the system. We know from experience that certain events occur spontaneously and others do not. For instance, we know that water flows downhill spontaneously, but moves uphill only with an input of energy, for instance when a machine pumps the water against gravity. In fact, another way to state the second law is: For a process to occur spontaneously, it must increase the entropy of the universe.

Living cells unavoidably convert organized forms of energy to heat
Spontaneous processes occur without energy input; they can happen quickly or slowly For a process to occur without energy input, it must increase the entropy of the universe

Q1a) How does the second LAW OF THERMODYNAMICS explain the diffusion of a substance across a membrane?

Q2a) 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.

Q3a) How does the disease ‘Familial Hypercholesterolemia” cause high levels of cholesterol in the blood?

Q1. If a Paramecium were to swim from a HYPOTONIC environment to an ISOTONIC one, how would the activity of contractile vacuole be affected? Explain with the help of a diagrammatic representation.

Q2. Explain why the sodium potassium pump would not be considered a COTRANSPORTER.

LE 7-16 Cytoplasmic Na+ bonds to the sodium-potassium pump
EXTRACELLULAR FLUID [Na+] high [K+] low Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ [Na+] low [K+] high ATP P Na+ P CYTOPLASM ADP Cytoplasmic Na+ bonds to the sodium-potassium pump Na+ binding stimulates phosphorylation by ATP. Phosphorylation causes the protein to change its conformation, expelling Na+ to the outside. K+ K+ K+ K+ K+ P P K+ Extracellular K+ binds to the protein, triggering release of the phosphate group. Loss of the phosphate restores the protein’s original conformation. K+ is released and Na+ sites are receptive again; the cycle repeats.

– EXTRACELLULAR + FLUID ATP – + H+ H+ Proton pump H+ – + H+ H+ – +
LE 7-18 – EXTRACELLULAR FLUID + ATP – + H+ H+ Proton pump H+ – + H+ H+ – + CYTOPLASM H+ – +

Proton pump Diffusion of H+ Sucrose-H+ cotransporter Sucrose
LE 7-19 – + ATP H+ H+ – + Proton pump H+ H+ – + H+ – + H+ Diffusion of H+ Sucrose-H+ cotransporter H+ – + – + Sucrose

Q3. As a cell grows, its plasma membrane expands
Q3. As a cell grows, its plasma membrane expands. Which type of bulk transport process is involved. Explain.

cytoplasm nucleus cell membrane nuclear pore protein secreted rough ER
transport vesicle Golgi apparatus smooth ER rough ER nuclear pore nucleus ribosome cell membrane protein secreted cytoplasm

Concept 8.2: The free-energy change of a reaction tells us whether 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 changes that occur in chemical reactions

Free–Energy Change, ΔG In 1878, J. Willard Gibbs, a professor at Yale, defined a very useful function called the Gibbs free energy of a system (without considering its surroundings), symbolized by the letter G . Free energy measures the portion of a system′s energy that can perform work when temperature and pressure are uniform throughout the system, as in a living cell. Let′s consider how we determine the free energy change that occurs when a system changes—for example, during a chemical reaction

The change in free energy (∆G) during a process is related to the change in enthalpy, or change in total energy (∆H), and change in entropy (T∆S): ∆G = ∆H - T∆S Only processes with a negative ∆G are spontaneous Spontaneous processes can be harnessed to perform work

LE 8-5 Gravitational motion Diffusion Chemical reaction

Free Energy, Stability, and Equilibrium
when a process occurs spontaneously in a system, we can be sure that ΔG is negative. Another way to think of ΔG is to realize that it represents the difference between the free energy of the final state and the free energy of the initial state

Free Energy, Stability, and Equilibrium
A living system’s free energy is energy that can do work when temperature and pressure are uniform, as in a living cell Free energy is a measure of a system’s instability, its… tendency to change to a more stable state During a spontaneous change, free energy _______________ and the stability of a system increases

Thus, ΔG can only be negative when the process involves a __________of free energy during the change from initial state to final state. Because it has less free energy, the system in its final state is less likely to change and is therefore more stable than it was previously

The relationship of free energy to stability, work capacity, and spontaneous change.
_____________ systems are rich in free energy, or G. They have a tendency to change __________________ to a more stable state (bottom), and it is possible to harness this “downhill” change to perform _____________

Equilibrium is a state of ______________ stability
A process is spontaneous and can perform work only when it is moving toward equilibrium

Another term for a state of maximum stability is equilibrium
There is an important relationship between free energy and equilibrium, including chemical equilibrium. reversible ……there is no further net change in the relative concentration of products and reactants. As a reaction proceeds toward equilibrium, the free energy of the mixture of reactants and products ________________. Free energy increases when a reaction is somehow pushed away from equilibrium, perhaps by removing some of the products (and thus changing their concentration relative to that of the reactants). For a system at equilibrium, G is at its lowest possible value in that system.

Equilibrium state as an energy valley…
G lowest value…can it change spontaneously? Because a system at equilibrium cannot spontaneously change, it can do no work. A process is spontaneous and can perform work only when it is moving toward equilibrium

Free Energy and Metabolism
The concept of free energy can be applied to the chemistry of life’s processes

Exergonic and Endergonic Reactions in Metabolism
An exergonic reaction proceeds with a net release of free energy and is spontaneous An endergonic reaction absorbs free energy from its surroundings and is nonspontaneous

Progress of the reaction
LE 8-6a Reactants Amount of energy released (G < 0) Free energy Energy Products Progress of the reaction Exergonic reaction: energy released

LE 8-6b Products Amount of energy required (G > 0) Free energy Energy Reactants Progress of the reaction Endergonic reaction: energy required

Equilibrium and Metabolism
Reactions in a closed system eventually reach equilibrium and then do no work Is cell’s metabolism at equilibrium? Cells are not in equilibrium; they are open systems experiencing a constant flow of materials A catabolic pathway in a cell releases free energy in a series of reactions Closed and open hydroelectric systems can serve as analogies

LE 8-7a G < 0 G = 0 A closed hydroelectric system

LE 8-7b G < 0 A catabolic pathway in a cell releases free energy in a series of reactions An open hydroelectric system

G < 0 G < 0 G < 0 A multistep open hydroelectric system

Concept 8.3: ATP powers cellular work by coupling exergonic reactions to endergonic reactions
A cell does three main kinds of work: Mechanical Transport Chemical To do work, cells manage energy resources by energy coupling, the use of an exergonic process to drive an endergonic one

The Structure and Hydrolysis of ATP
ATP (adenosine triphosphate) is the cell’s energy shuttle ATP provides energy for cellular functions

LE 8-8 Adenine Phosphate groups Ribose

Energy is released from ATP when the terminal phosphate bond is broken
The bonds between the phosphate groups of ATP’s tail can be broken by hydrolysis Energy is released from ATP when the terminal phosphate bond is broken P P P Adenosine triphosphate (ATP) H2O P + P P + Energy i Inorganic phosphate Adenosine diphosphate (ADP)

This release of energy comes from the chemical change to a state of lower free energy, not from the phosphate bonds themselves P P P Adenosine triphosphate (ATP) H2O P + P P + Energy i Inorganic phosphate Adenosine diphosphate (ADP)

In the cell, the energy from the exergonic reaction of ATP hydrolysis can be used to drive an endergonic reaction Overall, the coupled reactions are exergonic

Glutamic acid Ammonia Glutamine ATP H2O ADP
LE 8-10 Endergonic reaction: DG is positive, reaction is not spontaneous NH2 + NH3 DG = +3.4 kcal/mol Glu Glu Glutamic acid Ammonia Glutamine Exergonic reaction: DG is negative, reaction is spontaneous ATP + H2O ADP P + DG = –7.3 kcal/mol i Coupled reactions: Overall DG is negative; together, reactions are spontaneous DG = –3.9 kcal/mol

How ATP Performs Work? ATP drives endergonic reactions by phosphorylation, transferring a phosphate group to some other molecule, such as a reactant The recipient molecule is now phosphorylated The three types of cellular work (mechanical, transport, and chemical) are powered by the hydrolysis of ATP

Reactants: Glutamic acid
LE 8-11 P i P Motor protein Protein moved Mechanical work: ATP phosphorylates motor proteins Membrane protein ADP ATP + P i P P i Solute Solute transported Transport work: ATP phosphorylates transport proteins P NH2 + NH3 Glu + P i Glu Reactants: Glutamic acid and ammonia Product (glutamine) made Chemical work: ATP phosphorylates key reactants

The Regeneration of ATP
ATP is a renewable resource that is regenerated by addition of a phosphate group to ADP The energy to phosphorylate ADP comes from catabolic reactions in the cell The chemical potential energy temporarily stored in ATP drives most cellular work

LE 8-12 Because both directions of a reversible process cannot go downhill, the regeneration of ATP from ADP and Pi is necessarily endergonic ATP Energy for cellular work (endergonic, energy- consuming processes) Energy from catabolism (energonic, energy- yielding processes) ADP P + i

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

LE 8-13 Hydrolysis of sucrose by the enzyme sucrase is an example of an enzyme-catalyzed reaction Sucrose C12H22O11 Glucose C6H12O6 Fructose C6H12O6

The Activation Energy Barrier
Every chemical reaction between molecules involves both bond breaking and bond forming. Changing one molecule into another generally involves contorting the starting molecule into a highly unstable state before the reaction can proceed. This contortion can be compared to a metal key ring when you bend it and pry it open to add a new key. The key ring is highly unstable in its opened form but returns to a stable state once the key is threaded all the way onto the ring.

To reach the contorted state where bonds can change, reactant molecules must absorb energy from their surroundings. When the new bonds of the product molecules form, energy is released as heat, and the molecules return to stable shapes with lower energy. The initial investment of energy for starting a reaction—the energy required to contort the reactant molecules so the bonds can change—is known as the free energy of activation, or activation energy, abbreviated EA.

We can think of activation energy as the amount of energy needed to push the reactants over an energy barrier, or hill, so that the “downhill” part of the reaction can begin. Figure 8.14 graphs the energy changes for a hypothetical reaction that swaps portions of two reactant molecules: 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 heat from the surroundings

Energy profile of an exergonic reaction
Energy profile of an exergonic reaction. Thermodynamically, this is an exergonic reaction, with a negative ΔG, and the reaction occurs spontaneously. However, the activation energy (EA) provides a barrier that determines the rate of the reaction

The energizing, or activation, of the reactants is represented by the uphill portion of the graph, with the free–energy content of the reactant molecules increasing.

At the summit, the reactants are in an unstable condition known as the transition state: They are activated, and the breaking and making of bonds can occur.

The bond–forming phase of the reaction corresponds to the downhill part of the curve, which shows the loss of free energy by the molecules

Activation energy is often supplied in the form of heat that the reactant molecules absorb from the surroundings. The bonds of the reactants break only when the molecules have absorbed enough energy to become unstable and are therefore more reactive The absorption of thermal energy increases the speed of the reactant molecules, so they collide more often and more forcefully.

Also, thermal agitation of the atoms in the molecules makes the bonds more likely to break.
As the molecules settle into their new, more stable bonding arrangements, energy is released to the surroundings. If the reaction is exergonic, EA will be repaid with dividends, as the formation of new bonds releases more energy than was invested in the breaking of old bonds.

The reactants must absorb enough energy to reach the top of the activation energy barrier before the reaction can occur. For some reactions, EA is modest enough that even at room temperature there is sufficient thermal energy for many of the reactants to reach the transition state in a short time. In most cases, however, EA is so high and the transition state is reached so rarely that the reaction will hardly proceed at all. In these cases, the reaction will occur at a noticeable rate only if the reactants are heated.

The spark plugs in an automobile engine energize the gasoline–oxygen mixture so that the molecules reach the transition state and react; only then can there be the explosive release of energy that pushes the pistons. Without a spark, a mixture of gasoline hydrocarbons and oxygen will not react because the EA barrier is too high.

Proteins, DNA, and other complex molecules of the cell are rich in free energy and have the potential to decompose spontaneously; that is, the laws of thermodynamics favor their breakdown. Why these molecules persist in cells? At the temperature of a cell, only few molecules can make it over the hump of activation energy. However, the barriers for selected reactions must occasionally be surmounted for cells to carry out the processes necessary for life.

One solution is… Heat speeds a reaction by allowing reactants to attain the transition state more often, but this solution would be inappropriate for biological systems. First, high temperature denatures proteins and kills cells. Second, heat would speed up all reactions, not just those that are necessary. Organisms therefore use an alternative: catalysis.

Animation: How Enzymes Work
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 Animation: How Enzymes Work

An enzyme catalyzes a reaction by lowering the EA barrier, enabling the reactant molecules to absorb enough energy to reach the transition state even at moderate temperatures.

An enzyme cannot change the ΔG for a reaction
It cannot make an endergonic reaction exergonic. Enzymes can only hasten reactions that would occur eventually anyway, But this function makes it possible for the cell to have a dynamic metabolism, routing chemical traffic smoothly through the cell. And because enzymes are very selective in the reactions they catalyze, they determine which chemical processes will be going on in the cell at any particular time.

LE 8-15 Course of reaction without enzyme EA without enzyme EA with enzyme is lower Reactants Free energy Course of reaction with enzyme DG is unaffected by enzyme Products Progress of the reaction

Substrate Specificity of Enzymes
The reactant that an enzyme acts on is called the enzyme’s substrate

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

Induced fit of a substrate brings chemical groups of the active site into positions that enhance their ability to catalyze the reaction

The reaction catalyzed by each enzyme is very specific; an enzyme can recognize its specific substrate even among closely related compounds, such as isomers. What accounts for this molecular recognition? Recall that enzymes are proteins, and proteins are macromolecules with unique three–dimensional conformations. The specificity of an enzyme results from its shape, which is a consequence of its amino acid sequence

LE 8-16 Substrate Active site Enzyme Enzyme-substrate complex

LE 8-17 Substrates enter active site; enzyme
changes shape so its active site embraces the substrates (induced fit). Substrates held in active site by weak interactions, such as hydrogen bonds and ionic bonds. Active site (and R groups of its 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. Substrates Enzyme-substrate complex Active site is available for two new substrate molecules. Enzyme Products are released. Substrates are converted into products. Products

Catalysis in the Enzyme’s Active Site
In an enzymatic reaction, the substrate binds to the active site Mechanism? The active site can lower an EA barrier by - Orienting substrates correctly Straining substrate bonds Providing a favorable microenvironment Covalently bonding to the substrate

The enzyme always catalyzes the reaction in the direction of equilibrium.

The rate at which a particular amount of enzyme converts substrate to product is partly a function of the initial concentration of the substrate: The more substrate molecules are available, the more frequently they access the active sites of the enzyme molecules. However, there is a limit to how fast the reaction can be pushed by adding more substrate to a fixed concentration of enzyme.

At some point, the concentration of substrate will be high enough that all enzyme molecules have their active sites engaged. At this substrate concentration, the enzyme is said to be saturated, and the rate of the reaction is determined by the speed at which the active site can convert substrate to product. When an enzyme population is saturated, the only way to increase the rate of product formation is to add more enzyme. As soon as the product exits an active site, another substrate molecule enters.

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

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

LE 8-18 Optimal temperature for typical human enzyme
enzyme of thermophilic (heat-tolerant bacteria) Rate of reaction 20 40 60 80 100 Temperature (°C) Optimal temperature for two enzymes Optimal pH for pepsin (stomach enzyme) Optimal pH for trypsin (intestinal enzyme) Rate of reaction 1 2 3 4 5 6 7 8 9 10 pH Optimal pH for two enzymes

Cofactors Cofactors are nonprotein enzyme helpers
Coenzymes are organic cofactors

Enzyme Inhibitors Competitive inhibitors bind to the active site of an enzyme, competing with the substrate Noncompetitive inhibitors bind to another part of an enzyme, causing the enzyme to change shape and making the active site less effective

LE 8-19 A substrate can Substrate bind normally to the
active site of an enzyme. Substrate Active site Enzyme Normal binding A competitive inhibitor mimics the substrate, competing for the active site. Competitive inhibitor Competitive inhibition A noncompetitive inhibitor binds to the enzyme away from the active site, altering the conformation of the enzyme so that its active site no longer functions. Noncompetitive inhibitor Noncompetitive inhibition

Toxins and poisons are often irreversible enzyme inhibitors.
An example is sarin, a nerve gas that caused the death of several people and injury to many others when it was released by terrorists in the Tokyo subway in 1995. This small molecule binds covalently to the R group on the amino acid serine, which is found in the active site of acetylcholinesterase, an enzyme important in the nervous system.

Other examples include the pesticides DDT and parathion, inhibitors of key enzymes in the nervous system. Finally, many antibiotics are inhibitors of specific enzymes in bacteria. For instance, penicillin blocks the active site of an enzyme that many bacteria use to make their cell walls.

Citing enzyme inhibitors that are metabolic poisons may give the impression that enzyme inhibition is generally abnormal and harmful. In fact, molecules naturally present in the cell often regulate enzyme activity by acting as inhibitors. Such regulation—selective inhibition—is essential to the control of cellular metabolism

Concept 8.5: Regulation of enzyme activity helps control metabolism
Chemical chaos would result if a cell’s metabolic pathways were not tightly regulated To regulate metabolic pathways, the cell switches on or off the genes that encode specific enzymes Or, by regulating the activity of enzymes once they are made Production Level (gene level) Activity Level…

Allosteric Regulation of Enzymes
Allosteric regulation is the term used to describe cases where a protein’s function at one site is affected by binding of a regulatory molecule at another site Allosteric regulation may either inhibit or stimulate an enzyme’s activity

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

LE 8-20a Allosteric activator stabilizes active form. Allosteric enzyme with four subunits Active site (one of four) Allosteric regulation is the term used to describe cases where a protein’s function at one site is affected by binding of a regulatory molecule at another site Regulatory site (one of four) Activator Active form Stabilized active form Oscillation Allosteric inhibitor stabilizes inactive form. Non- functional active site Inhibitor Inactive form Stabilized inactive form Allosteric activators and inhibitors

Fluctuating concentrations of regulators can cause a sophisticated pattern of response in the activity of cellular enzymes. The products of ATP hydrolysis (ADP and Pi), for example, play a major role in balancing the flow of traffic between anabolic and catabolic pathways How? By their effects on key enzymes.

For example, ATP binds to several catabolic enzymes allosterically, lowering their affinity for substrate and thus inhibiting their activity. ADP, however, functions as an activator of the same enzymes. This is logical because a major function of catabolism is to regenerate ATP. Glucose E ATP ADP

If ATP production lags behind its use, ADP accumulates and activates these key enzymes that speed up catabolism, producing more ATP. If the supply of ATP exceeds demand, then catabolism slows down as ATP molecules accumulate and bind these same enzymes, inhibiting them. ATP, ADP, and other related molecules also affect key enzymes in anabolic pathways

Cooperativity is a form of allosteric regulation that can amplify enzyme activity
In cooperativity, binding by a substrate to one active site stabilizes favorable conformational changes at all other subunits

Binding of one substrate molecule to
LE 8-20b Binding of one substrate molecule to active site of one subunit locks all subunits in active conformation. Substrate Inactive form Stabilized active form Cooperativity another type of allosteric activation

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

LE 8-21 Initial substrate (threonine) Active site available Threonine
in active site Enzyme 1 (threonine deaminase) Isoleucine used up by cell Intermediate A Feedback inhibition Enzyme 2 Active site of enzyme 1 can’t bind theonine pathway off Intermediate B Enzyme 3 Intermediate C Isoleucine binds to allosteric site Enzyme 4 Intermediate D Enzyme 5 End product (isoleucine)

Specific Localization of Enzymes Within the Cell
Structures within the cell help bring order to metabolic pathways Some enzymes act as structural components of membranes Some enzymes reside in specific organelles, such as enzymes for cellular respiration being located in mitochondria

LE 8-22 Mitochondria, sites of cellular respiration 1 µm

An Introduction to Metabolism

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