Enzymes/Terminology

[victorias]

I just want to clarify a few points.

Since the enzyme structure is slightly altered as it makes partial bonds with the substrate (of course the enzyme is changed back to its normal state at the end of the reaction), can we really say that enzymes also have a "transition state"?

And when measuring the degree of affinity, should we be looking at it between the transition state of substrate + transition state of the enzyme?

If a molecule has a greater affinity for the enzyme, does that mean that a greater amount of binding energy is released. Yet, the reaction would not necessarily go faster? (eg. drugs that are antagonists and have greater affinity for enzymes but the reaction doesn't happen between the antagonist and enzyme.) What happens to the binding energy in this case - does it get used for some other process instead of lowering the activation energy?

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[aldol16]

Since the enzyme structure is slightly altered as it makes partial bonds with the substrate (of course the enzyme is changed back to its normal state at the end of the reaction), can we really say that enzymes also have a "transition state"?

Transition state refers to the potential energy maximum of a reaction where the substrate has both the energy and orientation to go on to product. So it wouldn't make sense to say an enzyme has a transition state because it neither goes to product nor is a substrate. However, it can change conformation to alter a reaction pathway.

And when measuring the degree of affinity, should we be looking at it between the transition state of substrate + transition state of the enzyme?

No transition state of the enzyme. Just look at the "transition state" of the substrate and how it binds to the enzyme at that point in time.

If a molecule has a greater affinity for the enzyme, does that mean that a greater amount of binding energy is released. Yet, the reaction would not necessarily go faster? (eg. drugs that are antagonists and have greater affinity for enzymes but the reaction doesn't happen between the antagonist and enzyme.) What happens to the binding energy in this case - does it get used for some other process instead of lowering the activation energy?

Thermodynamics does not govern kinetics. If you have a molecule with a huge binding energy, it's possible the enzyme-transition state complex is sitting in a potential energy well that is lower in energy than either substrate or product (and thus would be an enzyme-intermediate) and thus would not go on to form product. It's also possible that the molecule has greater affinity for the active site but once it gets there, it's stuck and does not go on (see how HIV protease or sarin works).

 

[victorias]

I came across a question on Khan Academy passages which seems to imply the enzymes have a transition state

 

[aldol16]

Khan Academy is not the best for accurate scientific questions - good to test if you understand concepts, but is scientifically fallacious in many cases.

In this case, it's a minor problem - just a matter of terminology. It's referring to the structure of the enzyme during the transition state. As I noted above, an enzyme can change conformation (textbook example: hexokinase) upon substrate binding to better stabilize the transition state (which again refers to the potential energy maximum along the substrate to product reaction coordinate). So it's referring to the enzyme conformation at that point, relative to "resting state." And "resting state" is usually used to refer to coenzymes, e.g. cytochromes, but again, in this case, they are using it to refer to the enzyme when it is not bound to the transition state structure.

 

[NextStepTutor_2]

I came across a question on Khan Academy passages which seems to imply the enzymes have a transition state

View attachment 200296

This might be beyond the requirements of the MCAT, but when we speak of enzyme-substrate reactions, it is not quite the same "transition-state" as when we talk about common chemical reactions. One of the most important ways that an enzyme catalyzes any given reaction is through entropy reduction: by bringing order to a disordered situation. For example the methylation of adenosine in DNA.

In order for this reaction to occur, the two substrates must come into contact in precisely the right way. If they are both floating around free in solution, the likelihood of this occurring is very small – the entropy of the system is simply too high. In other words, this reaction takes place very slowly without the help of a catalyst.

The enzyme's pocket is lined with various functional groups from the amino acid main and side chains, and has a very specific three-dimensional architecture that has evolved to bind to both of the substrates. If the SAM molecule, for example, diffuses into the active site, it can replace its (favorable) interactions with the surrounding water molecules with (even more favorable) new interactions with the functional groups lining the active site.

Now we have both substrates bound in the active site. But they are not just bound in any random orientation – they are specifically positioned relative to one another so that the nucleophilic nitrogen is held very close to the electrophilic carbon, with a free path of attack. What used to be a very disordered situation – two reactants diffusing freely in solution – is now a very highly ordered situation, with everything set up for the reaction to proceed. This is what is meant by entropy reduction: the entropic component of the energy barrier has been lowered.

However it's not really the noncovalent interaction between enzyme and substrate that are responsible for catalysis. Remember: all catalysts, enzymes included, accelerate reactions by lowering the energy of the transition state. With this in mind, it should make sense that the primary job of an enzyme is to maximize favorable interactions with the transition state, not with the starting substrates. This does not imply that enzyme-substrate interactions are not strong, rather that enzyme-TS interactions are far stronger, often by several orders of magnitude.

Think about it this way: if an enzyme were to bind to (and stabilize) its substrate(s) more tightly than it bound to (and stabilized) the transition state, it would actually slow down the reaction, because it would be increasing the energy difference between starting state and transition state. The enzyme has evolved to maximize favorable non-covalent interactions to the transition state: in the above example, this is the state in which the nucleophilic nitrogen is already beginning to attack the electrophilic carbon, and the carbon-sulfur bond has already begun to break.


More detailed explanation can be found HERE.

Hope this helps, good luck!

 

[NextStepTutor_2]

Khan Academy is not the best for accurate scientific questions - good to test if you understand concepts, but is scientifically fallacious in many cases.

In this case, it's a minor problem - just a matter of terminology. It's referring to the structure of the enzyme during the transition state. As I noted above, an enzyme can change conformation (textbook example: hexokinase) upon substrate binding to better stabilize the transition state (which again refers to the potential energy maximum along the substrate to product reaction coordinate). So it's referring to the enzyme conformation at that point, relative to "resting state." And "resting state" is usually used to refer to coenzymes, e.g. cytochromes, but again, in this case, they are using it to refer to the enzyme when it is not bound to the transition state structure.

+1, Khan academy MCAT passages and Qs can be very iffy when it comes to proper explanations and scientific accuracy. Still, free practice is a good deal!