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How do enzymes lower the free energy of activation?

  1. Sep 3, 2004 #1
    Hey guys;

    I've a question. How do enzymes lower the free energy of activation?

    My thinking is that the enzyme binds, and when it binds it alters the shape of whatever it binds to, and the altered shape is energetically favored to the unaltered shape for the reaction. This is purely speculation on my part.

    Does anyone know this?

    Thank you
  2. jcsd
  3. Sep 3, 2004 #2


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    You're right, it facilitates a transition state. Also: it brings two molecules in close proximity so they can react together. After the reaction has occured the enzyme will release the compound so it can bind new molecules.
  4. Sep 3, 2004 #3
    Hi Monique, thank you for the reply.

    So when the enzyme binds the substrate, it changes the shape of the substrate, and this new shape makes it energetically favored to reach the transition state?

    I think I'm not understanding how the enzyme can make things more energetically favored.

    May I ask how the enzyme brings the two molecules closer together? Also, do you know what triggers the release of the enzyme after the reaction has occured?
  5. Sep 4, 2004 #4


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    I don't know if you've ever seen free energy (G) diagrams of chemical reactions? http://www.ilpi.com/organomet/gifs/microscopic1.gif

    In the diagram you see there is a barrier of energy that has to be overcome in order for the reaction to proceed: the barrier has a value of 20 kcal/mol in that particular case. With that amount of energy, the reactants can go into a transition state: the re-arrangement of bonding energy. When the bonds are re-arranged, it is easy for the molecule to go either back to its original state or proceed to a novel state. If the reaction proceeds, 30 kcal/mol of free energy is released: a net energy release of 10 kcal/mol.

    What a catalyst does is lower the energy barrier of the reaction, thereby increasing the faction of molecules that can reach the transition state. Important to note is that at the point of transition, the reaction can still go in either direction: the point of equilibrium maintains unchanged.

    The catalyst can reduce the energy requirement, by forcing the reactant into an intermediate state that resembles the transition state but is of lower energy (because of favorable energetics of binding to the catalyst).

    The dominant model for enzymatic catalysis is that of the induced fit hypothesis, which is an elaboration of the lock-and-key hypothesis. Basically the enzyme has pockets to which the substrate fits (like a lock in a key), but when it binds it is distorted into the transition state.

    The reacted molecules are released simply because they don't fit anymore after the reaction.
  6. Sep 4, 2004 #5
    Some things to consider:

    -desolvation. The same reactant(s) and product(s) that occur in aqueous solution can occur in an enzyme, although in a far less hydrated environment. There are typically thermodynamic penalties for desolvating stable reactants - however, in a hydrophobic enzyme binding site, no such penalties need to be factored in, which can then lower the free energy.

    -Electrostatics. As a reactant proceeds through its transition state, charge may build up on certain parts of the reactant (for example, an oxygen becomes a little more negatively charged, a carbocation might form at a certain carbon position). It is not unusual to see that an enzyme active site is arranged to accomodate this - one might imagine a lysine positioned just right to balance out that negatively charged oxygen or an aspartic acid which sidles right up to that carbocation.

    -hydrogen bonding. It may be that as the reactant proceeds through its transformation, hydrogen bonding increases either through the strength of the already-existing hydrogen bonds, more hydrogen bonds are formed, or some combination thereof, all of which enables the enzyme to better bind the transition state.

    -the enzyme itself. It could very well be the case that the enzyme is more energetically stable when bound to a transition state species than to the original reactant(s), which can reduce the activation free energy. Also, conformational changes in the enzyme can play a role - for example, binding of the substrate can cause conformational changes in other parts of the protein which might contribute to the catalysis.

    If you're really interested in the topic, there's a pretty good recent paper that came out which covers most of this stuff in far more detail (and with references!):

    Mireia Garcia-Viloca, Jiali Cao, Martin Karplus, Donald G. Truhlar. "How Enzymes Work: Analysis by Modern Rate Theory and Computer Simulations." Science. 303:186 - 195 (9 January 2004).

    They also talk about the so-called "transmission coefficient" which includes such aspects as tunneling effects.
  7. Sep 4, 2004 #6
    Hey guys!

    You have given me a lot to think about! This really is interesting stuff, and I want to thank you for the answers. It's amazing that all this stuff works like it does, its just freaking fascinating.
  8. Sep 4, 2004 #7
    You may be interested in the following sites:

    Stroud Lab @ UCSF. There are some pretty cool movies here based upon crystal structures of enzymes, which may help with the visualization of enzyme function. (And they're pretty cool no matter what - although it usually takes a couple of viewings to get an idea of everything that's going on in the movie.) You can find a few more neat movies at the Kraut webpage (UCSD) http://chem-faculty.ucsd.edu/kraut/dhfr.html [Broken].

    Bruice Group @ UCSB Some papers from Tom Bruice's lab under "Enzyme Mechanisms" may be illuminating - he's done some interesting work in what's known as "near attack conformers" - that is, the geometrical arrangement of substrates in the ground state is similar to the geometry of the transition state, and is something else that is implicated in enzyme function and efficiency.

    A few other things to keep in mind (because, hey, I'm a biophysicist and I can never get too tired of babbling about the physical underpinnings of interesting biology):

    -these different components can all contribute to an enzyme's efficiency, even though it may be that one or two are the ones that really lower the activation free energy.

    -it's always important to remember that enzymes can catalyze the same reactant to product pathway that occurs in solution but through a totally different mechanism (for example, electrolysis of water can cause the evolution of oxygen by passing an electrical current through a solution, but nature accomplishes the same reaction by light induced electron transfer in photosystem II from plants and cyanobacteria).

    There is vigorous debate in this field (see, for example, this C&EN article) about the details, but at least it's one of those areas where there's plenty of work being done and isn't stagnating due to lack of experimental results.
    Last edited by a moderator: May 1, 2017
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