Catalytic Modes of Enzymes
Enzyme molecules contain a special pocket called an active site, which contain amino acid from different parts of the polypeptide chains that create a three dimensional surface complementary to the substrate, just as a key fits into a lock. Substrates initially bind to the active site by non-covalent interactions, including hydrogen bonds, ionic bonds, and hydrophobic interactions, which could rapidly induce conformational changes in the enzyme, thus strengthening binding and resulting in an enzyme substrate complex. The most favored enzyme-substrate interaction belongs to an induced fit model. Once a substrate is bound to the active site of an enzyme, multiple mechanisms of catalysis could lower the energy of the reaction's transition state, by providing an alternative chemical pathway for the reaction to obtain an enzyme product complex that is subsequently dissociated to enzyme and product. Although the thousands of enzymes in cells catalyze numerous different types of chemical reactions, the basic principle applied to their operation is the same.
Figure 1. General mode of enzyme catalysis.
The exact mechanism of lowering the energy barrier is dependent on individual systems. The most important one of these mechanisms refers to initial binding of enzyme to the substrates in the correct orientation to react, being close to the catalytic groups on the active enzyme complex and any other substrates. In this manner, the binding energy is partially used to reduce the involvement of the excessive activation entropy caused by the loss of the reactants' and catalytic groups' translational and rotation al entropy, in the overall activation energy. The energies available for enzymes to bind with their substrates are primarily dependent on the complementarity of structures. These binding energies are able to be relatively large, while enzymes do not use this potential binding energy simply to bind with the substrates and form stable long-lasting complexes. Enzymes must employ binding energy to decrease the free energy of the transition state, which is generally achieved by increasing the binding to the transition state rather than the reactants, introducing an energetic strain into the system and allowing more favorable interactions between catalytic groups of enzymes and reactants.
Other contributing factors are the provision of an alternative reactive pathway, the desolvation of reacting and catalyzing ionic groups and the introduction of strain into the reactants, which allows more binding energy to be available for the transition state. The specificity is determined by the absence of unsolvated or unpaired charges, minimal steric repulsion, and the presence of sufficient hydrogen bonds.
Enzyme-substrate interactions could align the reactive chemical groups and make them close together in an optimal geometry, thus increasing the reaction rate. The entropy of the reactants is reduced, which makes addition or transfer reactions less unfavorable, since the integration of two reactants into a single product could decrease the reduction in the overall entropy. This effect of proximity and orientation is analogous to an effective increase in concentration of the reagents and endows the reaction an intramolecular character with a massive rate increase.
Bond strain is the principal effect of induced fit binding, where the affinity of enzyme to the transition state is greater than to the substrate itself. This leads to structural rearrangements that could strain bonds of substrate into a position closer to the conformation of the transition state, thus decreasing the energy difference between the substrate and transition state. It is beneficial to catalyze the reaction. However, the strain effect is actually a ground state destabilization effect, rather than transition state stabilization effect. Enzymes are very flexible so that they cannot use large strain effect. Apart from bond strain in the substrate, bond strain may also occur within the enzyme itself to stimulate residues in the active site.
Acid-base catalysis is a reaction transferring a proton to or from another molecule in order to stabilize developing charges in the transition state, which has the effect of activating nucleophile and electrophile groups, or stabilizing leaving groups. Histidine is often implicated in these acid-base reactions, since it has a pKa close to neutral pH and can therefore both accept and donate protons. pKa value can be altered by both the local environment of the residue and the surrounding environment. The reaction rate in this particular catalysis is determined by the concentration of the proton carrier, and in specific acid-base catalysis the reaction rate is free from the influence of catalyst concentration.
Covalent catalysis refers to the substrate forming a transient covalent bond with a cofactor or with residues in the enzyme active site, which brings an additional covalent intermediate to the reaction, and contributes to diminish the energy of later transition states of the reaction. At a later stage in the reaction, the covalent bond would be broken to release the enzyme. This kind of mechanism is applied by the catalytic triad of enzymes like chymotrypsin and trypsin, leaving an acyl-enzyme intermediate. An alternative mechanism can be observed in the enzyme aldolase during glycolysis, where schiff base is formed by using the free amine from a lysine residue.
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