Structural Biochemistry/Enzyme/Specificity

Introduction
A key feature of nearly all enzymes is that they bind their substrates with a high affinity or high degree of specificity. For example, because hexokinase binds glucose very well, we say it has a high affinity for glucose. On the other hand, hexokinase has a low affinity for other sugars, such as fructose, and galactose, which have similar structures to glucose. The interactions between enzymes and their substrates have been studied by a German scientist, Emil Fischer, who proposed that the recognition of a substrate by an enzyme resembles the interaction between a lock and key: only the right-sized key (the substrate) will fit into the keyhole (active site) of the lock (the enzyme). Further studies revealed that the interaction between an enzyme and its substrates also involves movements or conformational in the enzyme itself. These conformational changes cause the substrates to bind more tightly to the enzyme, a phenomenon called induced fit. The enzyme catalyzes the conversion of reactants to products only after this conformational change takes place.

Enzyme
Enzymes are used to accelerate reactions. Most enzymes provide accelerated reaction mechanisms by reducing the energy required to obtain the transition state between reactants and products. For example, carbonic anhydrase, one of the fastest enzymes known, is capable of transforming carbon dioxide into carbonic acid at a rate of 1 million molecules per second. The reactants used in a reaction are also known as substrates. These substrates require enzymes to be specific so that enzymes act on the correct substrate or bond to catalyze the desired reaction. More precisely, the specificity of an enzyme is due to the precise interaction of the substrate with the enzyme. This precision is a result of the intricate three-dimensional structure of the enzyme protein.

Enzyme-ligand complex
Enzyme specificity results from the binding site features. In other words, the specificity of an enzyme and substrate could be analogous to a lock and a key. The key will not open a lock if the key does not have the compatible shape. The active site is often characterized by complementarity in which the shape matches the substrate to which it binds. It also contains a specialized microenvironment in which certain amino acid side chains contribute to its general properties such as hydrophobic preferences or polarity. This environment allows the active site to be more compatible with the substrate. The enzyme and substrate complex is held together by weak noncovalent interactions such as hydrogen bonding, ionic bonding, hydrophobic effect or Van der Waals interactions which makes the exact arrangement of atoms in the active site and on the substrate necessary for proper binding.



Inhibitors
The concept of specificity is what allows enzyme inhibitors to work. Many inhibitors make use of specificity by having structures that are very similar to the substrate. They are therefore able to bind to the enzymes and deactivate them by either modifying part of the active site, covalently binding to the active site, or causing the enzyme to begin catalysis, generating an intermediate that inactivates the enzyme.

Some highly potent inhibitors make use of specificity by the mimicking the transition state of a catalyzed reaction. An example of this is pyrrole 2-carboxylic acid. The α-carbon of pyrrole 2-carboxylic acid resembles the trigonal α-carbon of the transition state of the racemization of proline. Pyrrole 2-carboxylic acid is therefore known as a transition-state analog. Since proline has a tetrahedral α-carbon, the inhibitor more closely resembles the transition state of the reaction than the substrate. Because the enzyme's ultimate goal is the formation of the transition state, the enzyme has a greater specificity to the transition state-analog than the substrate.