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Learning Objectives Associated with 2020_Spring_Bis2a_Facciotti_Lecture_08
- Understand how to use the equation ΔG = ΔH - TΔS and explain what each term represents.
- Interpret reaction coordinate diagrams and associate changes in Gibbs enthalpy and activation energy with relative rates of reactions, equilibrium conditions, and whether a reaction is endergonic or exergonic.
- Interpret reaction coordinate diagrams showing either or both catalyzed and
uncatalyzedreaction coordinates and identify respective activation energy barriers and relate these to the forward and reverse rates of reaction.
- Describe the relationship between free energy and chemical equilibrium using the equation ∆G° = -RTlnKeq, explicitly invoking appropriate “initial” and “final” states (as is done in an Energy Story).
- Interpret a biochemical transformation and predict
whether or notthe reaction is spontaneous by using a Gibbs enthalpy (energy) reaction coordinate diagram.
- Describe the concept of equilibrium in
the context ofreaction coordinate diagrams.
- Describe mechanisms used by enzymes to lower the activation energy and increase rates of reaction.
- Draw a rough sketch of an enzyme including its active site and other sites in the enzyme that might impact its function, such as an inhibitor binding site.
- Hypothesize how binding of small molecules to one or more binding pockets can lead to changes in protein function (i.e. competitive inhibition and/or allostery).
- Describe in general terms the functional link between cofactors, coenzymes, and their associated proteins.
Endergonic and exergonic reactions
Any system of molecules that undergoes a physical transformation/reorganization (
If, for the sake of simplicity we begin by considering only the contribution of the molecular transformations in the system on ∆G, we conclude that reactions with ∆G < 0, the products of the reaction have less Gibbs energy than the reactants. Since ∆G is the difference between the enthalpy and temperature-scaled entropy changes in a reaction, a net negative ∆G can arise in through changes largely of enthalpy, entropy or most often both. The left panel of Figure 1 below shows a common graphical representation of an exergonic reaction. This graph
It is important to note that the term "spontaneous"—in thermodynamics—implies nothing about how fast the reaction proceeds. The change in free energy only describes the difference between beginning and end states, NOT how fast that transition takes place. This is contrary to the everyday use of the
A chemical reaction with a positive ∆G means that the products of the reaction have a higher free energy than the reactants (see the right panel of Figure 1). These chemical reactions
Figure 1. Reaction coordinate diagrams of exergonic and endergonic reactions. Exergonic and endergonic reactions
The building of complex molecules, such as sugars, from simpler ones is an anabolic process and is endergonic.
An important concept in the study of metabolism and energy is that of chemical equilibrium. Most chemical reactions are reversible. They can proceed in both directions, often transferring energy into their environment in one direction and transferring energy in
If a reaction
Figure 2. At equilibrium, do not think of a static, unchanging system. Instead, picture molecules moving in equal amounts from one area to another. Here, at equilibrium, molecules are still moving from left to right and right to left. The net movement, however, is equal. There will still be about 15 molecules in each side of this flask once it reaches equilibrium. Source: https://courses.candelalearning.com/..
For a chemical reaction to happen, the reactants must first find one another in space. Chemicals in solution don't "plan" these collisions; they happen at random. In fact, most times, it's even more complicated. Not only do the reactants need to run into one another, but they also need to come into contact in a specific orientation. If reactants are very dilute, the rate of the reaction will be slow—collisions will happen infrequently. Increasing the concentrations will increase the rate of productive collisions. Another way to change the rate of reaction is to increase the rate of collisions by increasing the rate at which the reactants explore the reaction space—by increasing the velocity of the molecules or their kinetic energy. This can
A catalyst is something that helps increase the rate of a chemical reaction undergoing no change itself. You can think of a catalyst as a chemical change agent.
The most important catalysts in biology
Figure 1. Enzymes and other catalysts decrease the activation energy required to start a given chemical reaction. Without an enzyme (left), the energy input needed for a reaction to begin is high. With the help of an enzyme (right), la reaction needs less energy
In the figure above, What do you think the units are on the x-axis? Time would be one guess. However, if you compare the figures, it appears that the products are formed at the same time whether the activation energy barrier is high or low. Wasn't the point of this figure to illustrate that reactions with high activation energy barriers are slower than those with low activation energy barriers? What's going on?
Enzymes Section Overview
Enzymes are biological catalysts that speed up chemical reactions by lowering the activation energy. Enzymes are proteins comprising one or more polypeptide chains. Enzymes have an active site that provides a unique chemical environment made up of certain amino acid R groups (residues).
to convert particular chemical reactants for that enzyme, called substrates, into unstable intermediates, called transition states.
to bind with an induced fit
enzymes and substrates undergo slight conformational adjustments upon substrate contact, leading to binding. Enzymes bind to substrates and catalyze reactions in four different ways: bringing substrates together in an optimal orientation, compromising the
structures of substrates so that bonds can
, providing optimal environmental conditions for a reaction to occur, or taking part directly in their chemical reaction by forming transient covalent bonds with the substrates.
Enzyme action must
so that, in a
cell at a
time, the desired reactions are being catalyzed and the undesired reactions are not. Enzymes
by cellular conditions, such as temperature and pH.
through their location within a cell, sometimes being compartmentalized so
they can only catalyze reactions under certain circumstances. Inhibition and activation of enzymes via other molecules are other important ways that enzymes
. Inhibitors can act competitively, noncompetitively, or allosterically; noncompetitive inhibitors are usually allosteric. Activators can also enhance the function of enzymes allosterically. The most common method by which cells regulate the enzymes in metabolic pathways is through feedback inhibition. During feedback inhibition, the products of a metabolic pathway serve as inhibitors (usually allosteric) of one or more of the enzymes (usually the first committed enzyme of the pathway) involved in the pathway that produces them.
A substance that helps a chemical reaction to occur is a catalyst, and the special molecules that
Figure 1. Enzymes lower the activation energy of the reaction but do not change the free energy of the reaction. Here, the solid line in the graph shows the energy required for reactants to turn into products without a catalyst. The dotted line shows the energy required using a catalyst. This figure should say Gibbs Free Energy on the Y-axis and instead of noting deltaH should have deltaG. Attribution:
Enzyme active site and substrate specificity
The chemical reactants to which an enzyme binds are the enzyme’s substrates. There may be one or more substrates, depending on the particular chemical reaction. In some reactions, a
Figure 2. This is an enzyme with two different substrates bound in the active site.
At this point in the class, you should be familiar with all the
Possible NB Discussion Point: How your body breaks down caffeine
When you drink coffee or other caffeinated beverages like some sodas, you are consuming a molecule called caffeine! Caffeine over time gets metabolized (broken down) via a set of very related "CYP (Cytochrome P450)" enzymes to yield the three products shown in the figure below (Source: Wikipedia). To simplify slightly, you can interpret one arrow to represent a reaction catalyzed by one of the related CYP enzymes to yield paraxanthine, theobromine, or theophylline... all of which themselves get recognized by other enzymes that will further break them down and so on and so forth. Take a moment to examine the four structures below; the general structure should look vaguely familiar to you. Compare the reactant and the three products -- what are the noteworthy functional groups and properties of these molecules? What do you predict to be the key features of the active sites for the enzymes that break down these four molecules? If you were to design an enzyme that would break down caffeine AND theophylline only, how would you design your active site?
Look to see which atoms in Figure 2 (
in the hydrogen bonds between the amino acid R groups and the substrate. You will need to
identify these on your own; hydrogen bonds may not
in for you on the test.
If you changed the pH of the solution that
in, would the enzyme still be able to form hydrogen bonds with the substrate?
Which substrate (the left or right one) do you think is more stable in the active site? Why? How?
Figure 3. This is a depiction of an enzyme active site.
Source: created by
First, identify the
A new way of visualizing diseases in the body.
Structural instability of enzymes
Figure 4. Enzymes have an optimal pH. The pH at which the enzyme is most active will be the pH where the active site R groups are protonated/deprotonated such that the substrate can enter the active site and the initial step in the reaction can begin. Some enzymes require a very low pH (acidic) to be
The process where enzymes denature usually starts with the unwinding of the tertiary structure through destabilization of the bonds holding the tertiary structure together.
Figure 5. Enzymes have an optimal temperature. The temperature at which the enzyme is most active will usually be the temperature where the structure of the enzyme is stable or uncompromised. Some enzymes require a specific temperature to remain active and not denature. Source: http://academic.brooklyn.cuny.edu/bi..
Induced fit and enzyme function
For many years, scientists thought
When an enzyme binds its substrate, an enzyme-substrate complex
The activation energy required for many reactions includes the energy involved in slightly contorting chemical bonds so
Figure 6. According to the induced-fit model, both enzyme and substrate undergo dynamic conformational changes upon binding. The enzyme contorts the substrate into its transition state,
Creating an energy story for the reaction above
Using Figure 6, answer the questions posed in the energy story.
1. What are the reactants? What are the products?
2. What work
3. What state is the energy in initially? What state is the energy transformed into in the final state? This one might be tricky still, but try to identify where the energy is in the initial state and the final state.
Why regulate enzymes?
Cellular needs and conditions vary from cell to cell and change within individual cells
Regulation of enzymes by molecules
Figure 7. Competitive and noncompetitive inhibition affect the rate of reaction differently. Competitive inhibitors affect the initial rate but do not affect the maximal rate, whereas noncompetitive inhibitors affect the maximal rate.
Some inhibitor molecules bind to enzymes in a location where their binding induces a conformational change that reduces the affinity of the enzyme for its substrate. This
Figure 8. Allosteric inhibitors
Check out this short (one-minute) video on competitive vs. noncompetitive enzymatic inhibition. Also,
Many enzymes don’t work optimally, or even at all, unless bound to other specific non-protein
In eukaryotic cells, molecules such as enzymes
Possible NB Discussion Point: Reversing the Effects of Caffeine
Previously, we discussed caffeine and its metabolism. Let’s now think about caffeine’s pharmacology (mode of action). Were you able to identify, compare, and contrast the molecule that caffeine had a similar structure to? Because of caffeine's structural similarity to the molecule adenosine, it is actually able to bind to the adenosine-specific receptor protein in the brain. However, because the exact lock-and-key-fit is unsatisfied, caffeine will not "activate" the adenosine receptors upon binding as adenosine would. Normally, when adenosine binds to and thereby activates its specific receptor protein in the brain, the physiological effect is increased drowsiness and muscle relaxation. It makes sense that we get tired at night because we accumulate adenosine over the day -- that's a lot of receptor activation! But back to caffeine -- when caffeine is present, it can bind to the adenosine receptor protein, thereby blocking adenosine from binding/activating the receptor. The lack of adenosine action is what leads to suppressed sleepiness and increased alertness. The inhibition seen with this receptor protein and caffeine is similar to some of the inhibition we see with enzymes. What type of inhibition would you classify this as? Follow up question: If you were hired by a company to design a solution to reverse the effect of caffeine post-ingestion, what strategies would you try to test? Explain!
The following links will take you to a series of videos on kinetics. The first link contains four videos on reaction rates, and the second link contains nine videos related to the relationship between reaction rates and concentration. These videos are supplemental and
- Introduction to enzyme kinetics
- Reaction mechanism