By definition, the transition state is the transitory of molecular structure in which the molecule is no longer a substrate but not yet a product. All chemical reactions must go through the transition state to form a product from a substrate molecule. The transition state is the state corresponding to the highest energy along the reaction coordinate. It has more free energy in comparison to the substrate or product; thus, it is the least stable state. The specific form of the transition state depends on the mechanisms of the particular reaction.
In the equation S → X → P, X is the transition state, which is located at the peak of the curve on the Gibbs free energy graph.
Enzymes are usually proteins that act like catalysts. The enzyme's ability to make the reaction faster depends on the fact that it stabilizes the transition state. The transition state's energy or, in terms of a reaction, the activation energy is the minimum energy that is needed to break certain bonds of the reactants so as to turn them into products. Enzymes decreases activation energy by shaping its active site such that it fits the transition state even better than the substrate. When the substrate binds, the enzyme may stretch or distort a key bond and weaken it so that less activation energy is needed to break the bond at the start of the reaction. In many cases, the transition state of a reaction has a different geometry at the key atom (for instance, tetrahedral instead of trigonal planar). By optimizing binding of a tetrahedral atom, the substrate is helped on its way to the transition state and therefore lowers the activation energy, allowing more molecules to be able to turn into products in a given period of time. The enzyme stabilizes the transition state through various ways. Some ways an enzyme stabilizes is to have an environment that is the opposite charge of the transition state, providing a different pathway,and making it easier for the reactants to be in the right orientation for reaction.
Consider the peptide hydrolysis by chrymotypsin as an example.
In a normal peptide hydrolysis reaction without the help of a catalyst, water acts as a nucleophile to attack the electrophilic carbonyl carbon. The carbon atom being attacked goes from its initial sp2 state(trigonal planar) to a new sp3 state(tetrahedral) in its transition state.
In the presence of chymotypsin, however, a better nucleophile is used in the form of the catalytic triad - Asp 102, His 57, Ser 195 side chains. Moreover, the oxyanion hole, which consists of the backbone -NH- groups of Gly 193 and Ser 195 of the enzyme, have the N-H groups positioned in such a way that they will donate strong hydrogen bonds to the substrate's C=O oxygen, given that the carbon atom is tetrahedral as found in the transition state. This strains the bonds of the trigonal planar C=O of the original substrate, helping the reaction to proceed to the transition state. The hydrogen bonds also stabilize the formal negative charge on the oxygen atoms. In this way, the activation energy of the reaction is lowered and the rate of reaction thus increases.
In 1948, Linus Pauling proposed that transition state analogs should be effective inhibitors of enzymes. These molecules are mimics of transition states of the substrate of a particular enzyme reaction. Because they are so similar to the transition states of the substrate, they can bind to the enzyme, oftentimes much more tightly than the substrate can. The fact that these transition state analogs bind so tightly to enzymes makes it an effective enzyme inhibitor.