Relenza is a neuraminidase inhibitor used to treat influenza. Here, neuraminidase is a viral enzyme which cleaves docking proteins of the host. The inhibition of the activity of this enzyme by the drug prevents the cleavage of the enzyme, preventing the spreading of the virus. Noncompetitive inhibition is a type of reversible inhibition in which the inhibitor molecules bind to the enzyme-substrate complex at an allosteric site, a site other than the active site.
Here, the binding of the inhibitor molecules to the allosteric site results in the conformational change in the active site of the enzyme. It alters the specificity of the active site to the corresponding substrate, making the active site unavailable for the binding to the substrate. However, since noncompetitive inhibitors do not directly compete with the substrate, they do not change the substrate concentration.
Figure 2: Noncompetitive Inhibition. Moreover, cyanide is a poison which binds to an allosteric site of cytochrome oxidase, a carrier protein in the electron transport chain. It prevents the ATP production through aerobic respiration , leading to death eventually. Competitive inhibition refers to the blockage of the action of an enzyme on its substrate by replacing the substrate with a similar but inactive compound, which can combine with the active site of the enzyme but is not acted upon or split by the enzyme.
In contrast, noncompetitive inhibition refers to the enzyme inhibition in which the inhibiting compound does not compete with the natural substrate for the active site on the enzyme but inhibits reaction by combining with the enzyme-substrate complex after forming the complex.
Thus, this is the main difference between competitive and noncompetitive inhibition. Another difference between competitive and noncompetitive inhibition is that the competitive inhibitors are similar in conformation to the substrate while noncompetitive inhibitors have a different conformation to the substrate.
In competitive inhibition, molecules compete with the substrate for binding to the active site of the enzyme while in noncompetitive inhibition, molecules bind to the enzyme at a site other than the active site of the enzyme. Hence, this is one other difference between competitive and noncompetitive inhibition. One more difference between competitive and noncompetitive inhibition is that competitive inhibitors compete with the substrate for the binding to the active site of the enzyme while noncompetitive inhibitors bind to the enzyme-substrate complex.
Moreover, competitive inhibitors block the active site of the enzyme while noncompetitive inhibitors are responsible for the distortion in size or the shape of the active site of the enzyme, destabilizing the enzyme-substrate complex. Duration is another difference between competitive and noncompetitive inhibition. Competitive inhibitors dissociate from the enzyme within a short period of time while noncompetitive inhibitors remain binding to the enzyme for a considerable time period until the substrate becomes unavailable.
Methotrexate has no effect on them and their Km values are unchanged. Why then, does Km appear higher in the presence of a competitive inhibitor. The reason is that the competitive inhibitor is reducing the amount of active enzyme at lower concentrations of substrate. Studies of competitive inhibition have provided helpful information about certain enzyme-substrate complexes and the interactions of specific groups at the active sites.
As a result, pharmaceutical companies have synthesized drugs that competitively inhibit metabolic processes in bacteria and certain cancer cells.
Many drugs are competitive inhibitors of specific enzymes. A second type of inhibition employs inhibitors that do not resemble the substrate and bind not to the active site, but rather to a separate site on the enzyme rectangular site below. The effect of binding a non-competitive inhibitor is significantly different from binding a competitive inhibitor because there is no competition.
In the case of competitive inhibition, the effect of the inhibitor could be reduced and eventually overwhelmed with increasing amounts of substrate. This was because increasing substrate made increasing percentages of the enzyme active.
With non-competitive inhibition, increasing the amount of substrate has no effect on the percentage of enzyme that is active. Indeed, in non-competitive inhibition, the percentage of enzyme inhibited remains the same through all ranges of [S]. This means, then, that non-competitive inhibition effectively reduces the amount of enzyme by the same fixed amount in a typical experiment at every substrate concentration used The effect of this inhibition is shown above.
As you can see, Vmax is reduced in non-competitive inhibition compared to uninhibited reactions. This makes sense if we remember that Vmax is dependent on the amount of enzyme present. Reducing the amount of enzyme present reduces Vmax. Additionally, KM for non-competitively inhibited reactions does not change from that of uninhibited reactions. This is because, as noted previously, one can only measure the KM of active enzymes and KM is a constant for a given enzyme.
Feedback inhibition is a normal biochemical process that makes use of noncompetitive inhibitors to control some enzymatic activity. In this process, the final product inhibits the enzyme that catalyzes the first step in a series of reactions. Feedback inhibition is used to regulate the synthesis of many amino acids.
For example, bacteria synthesize isoleucine from threonine in a series of five enzyme-catalyzed steps. As the concentration of isoleucine increases, some of it binds as a noncompetitive inhibitor to the first enzyme of the series threonine deaminase , thus bringing about a decrease in the amount of isoleucine being formed.
A third type of enzymatic inhibition is that of uncompetitive inhibition, which has the odd property of a reduced V max as well as a reduced Km. The explanation for these seemingly odd results is due to the fact that the uncompetitive inhibitor binds only to the enzyme-substrate ES complex. The inhibitor-bound complex forms mostly under concentrations of high substrate and the ES-I complex cannot release product while the inhibitor is bound, thus result in reduced V max. The reduced Km is a bit harder to conceptualize.
The answer lies in the fact that the inhibitor-bound complex effectively reduces the concentration of the ES complex. Decreases in free enzyme correspond to an enzyme with greater affinity for its substrate. In competitive inhibition the substrate and the inhibitor compete for the same active site on the enzyme.
With noncompetitive inhibition the substrate and the inhibitor bind to different active sites on the enzyme, forming an enzyme—substrate—inhibitor, or ESI complex. The formation of an ESI complex decreases catalytic efficiency because only the enzyme—substrate complex reacts to form the product. Finally, in uncompetitive inhibition the inhibitor binds to the enzyme—substrate complex, forming an inactive ESI complex. An irreversible inhibitor inactivates an enzyme by bonding covalently to a particular group at the active site.
The inhibitor-enzyme bond is so strong that the inhibition cannot be reversed by the addition of excess substrate. The nerve gases, especially Diisopropyl fluorophosphate DIFP , irreversibly inhibit biological systems by forming an enzyme-inhibitor complex with a specific OH group of serine situated at the active sites of certain enzymes.
The peptidases trypsin and chymotrypsin contain serine groups at the active site and are inhibited by DIFP. In contrast to the first three types of inhibition, which involve reversible binding of the inhibitor to the enzyme, suicide inhibition is irreversible because the inhibitor becomes covalently bound to the enzyme during the inhibition and thus cannot be removed.
Suicide inhibition rather closely resembles competitive inhibition because the inhibitor generally resembles the substrate and binds to the active site of the enzyme. The primary difference is that the suicide inhibitor is chemically reactive in the active site and makes a bond with it that precludes its removal. Such a mechanism is that employed by penicillin Figure 5. Since the normal function of the enzyme is to make a bond necessary for the peptidoglycan complex of the bacterial cell wall, the cell wall cannot properly form and bacteria cannot reproduce.
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