Enzyme Mechanisms

Enzymes can act in several ways, all of which lower ΔG‡

- Lowering the activation energy by creating an environment in which the transition state is stabilized (e.g. straining the shape of a substrate - by binding the transition-state conformation of the substrate/product molecules, the enzyme distorts the bound substrate(s) into their transition state form, thereby reducing the amount of energy required to complete the transition).
- Lowering the energy of the transition state, but without distorting the substrate, by creating an environment with the opposite charge distribution to that of the transition state.
- Providing an alternative pathway. For example, temporarily reacting with the substrate to form an intermediate ES complex, which would be impossible in the absence of the enzyme.
- Reducing the reaction entropy change by bringing substrates together in the correct orientation to react. Considering ΔH‡ alone overlooks this effect.
Interestingly, this entropic effect involves destabilization of the ground state, and its contribution to catalysis is relatively small.

Transition State Stabilization
The understanding of the origin of the reduction of ΔG‡ requires one to find out how the enzymes can stabilize its transition state more than the transition state of the uncatalyzed reaction. Apparently, the most effective way for reaching large stabilization is the use of electrostatic effects, in particular, by having a relatively fixed polar environment that is oriented toward the charge distribution of the transition state. Such an environment does not exist in the uncatalyzed reaction in water.


Dynamics and function
Recent investigations have provided new insights into the connection between internal dynamics of enzymes and their mechanism of catalysis. An enzyme's internal dynamics are described as the movement of internal parts (e.g. amino acids, a group of amino acids, a loop region, an alpha helix, neighboring beta-sheets or even entire domain) of these biomolecules, which can occur at various time-scales ranging from femtoseconds to seconds. Networks of protein residues throughout an enzyme's structure can contribute to catalysis through dynamic motions. Protein motions are vital to many enzymes, but whether small and fast vibrations or larger and slower conformational movements are more important depends on the type of reaction involved. These new insights also have implications in understanding allosteric effects and developing new drugs.

It should be clarified, however, that the dynamical time-dependent processes are not likely to help to accelerate enzymatic reactions, since such motions randomize and the rate constant is determined by the probability (P) of reaching the transition state, (P = exp {ΔG‡/RT}). Furthermore, the reduction of ΔG‡ requires having relatively smaller motions (in relation to the corresponding motions in solution reactions) for the transition between the reactant and the product states. Thus, it is not clear that motional or dynamical effects contribute to the catalysis of the chemical step.

Allosteric modulation
Allosteric enzymes change their structure in response to binding of effectors. Modulation can be direct, where the effector binds directly to binding sites in the enzyme, or indirect, where the effector binds to other proteins or protein subunits that interact with the allosteric enzyme and thus influence catalytic activity.