Allosteric Inhibition (Non-Competitive Inhibition): Function, Role & Diseases

In allosteric inhibition, or noncompetitive inhibition, inhibitors bind to the allosteric center of an enzyme, thereby reducing its activity. The binding results in a conformational change that partially or completely blocks the function of the enzyme. Allosteric inhibition is being considered for the treatment of cancer.

What is allosteric inhibition?

In allosteric inhibition, inhibitors bind to the allosteric center of an enzyme, thereby reducing its activity. Inhibition or inhibition in medicine refers to a slowing down, delaying, or blocking of biological processes. The action can thus come to a standstill as a result of inhibition. In biochemistry, inhibition usually corresponds to enzyme inhibition. This type of inhibition can be either competitive or non-competitive. Noncompetitive inhibition is also known as allosteric inhibition. In this type of inhibition, the aim is to bind the inhibitors outside active sites of the processes to be inhibited. The inhibitors used and their binding negatively affect the function of an enzyme involved in the process. The inhibitors used are also referred to as allosteric effectors and, in contrast to competitive inhibition of enzymes, do not attach to the active process center but to other sites of the respective enzyme. They are thus located at the allosteric center of the enzyme and in this way change its conformation. This conformational change makes it impossible or at least difficult for the enzyme to bind a substrate to the active site.

Function and task

Enzymes are essential components of any organism. The body’s own substances are involved in all metabolic processes and catalyze most biochemical reactions. To regulate enzymatic processes, the cells of the body require certain mechanisms to influence the specific activity of enzymes. Enzymes are often activated and their activity regulated via modifications. However, binding to certain substances can also play a role in the regulation of enzyme activities. Binding substances are also called effectors, which, depending on their effect on the enzyme, are referred to either as activators or inhibitors. Activators increase enzymatic activity and promote the associated reaction. Inhibitors decrease enzymatic activities and inhibit the respective reactions. Inhibitors in the active site of the enzyme induce so-called competitive inhibition and occupy the binding sites of the active site. In non-competitive inhibition, inhibitors bind to the allosteric center of a particular enzyme, causing a structural change in the active site. The enzyme loses its function either partially or completely as a result of these processes. Feedback inhibition or end product inhibition is considered a special form of this type of inhibition. In this case, a product of synthesis chains allosterically inhibits an enzyme involved in synthesis. All types of allosteric inhibition can be reversed. This process corresponds to a removal of the allosteric effectors. Any non-competitive inhibition is based on the binding of inhibitor I to the allosteric center of enzyme E. This binding does not affect substrate binding. The inhibitor can bind not only to the free enzyme but also to its enzyme-substrate complex, since it does not have to bind in the binding portion of an enzyme. The respective substrate reacts with an enzyme-inhibitor complex analogously as well. However, a formed enzyme-inhibitor-substrate complex does not cleave off the resulting product. In individual cases of noncompetitive inhibition, the specific behavior of inhibitors may deviate more or less from the normal case.

Diseases and disorders

Inhibitions of enzymatic processes are a vital type of regulation in the human body. They can be disturbed, for example, by genetic defects, so especially by mutations. Such mutations can affect various building blocks of the human body as they play a role in enzyme inhibition. The consequences of a lack of inhibition can be manifold. Elevated uric acid, for example, may be associated with disorders of enzymatic inhibition.If the uric acid concentration in the blood is elevated and is not sufficiently excreted in the urine, the salts are deposited in the joints and can thus promote the formation of gout nodules. The uric acid crystals cause inflammatory reactions in the inner lining of joints, as associated with an acute attack of gout. The elevated uric acid may be due to a defect in allosteric inhibition that promotes increased biosynthesis of so-called purine nucleotides. However, allosteric inhibition not only forms the basis of various diseases, but is now also used by medicine for therapeutic purposes. For example, allosteric inhibition of BCR-ABL is considered a current therapeutic principle in chromosome-positive leukemia. Modern medicine also employs the principle of allosteric inhibition in other areas of cancer therapy. Currently, scientists are increasingly searching for inhibitors in the context of cancer research. In this context, U.S. research groups have discovered the Ral proteins, for example, which appear to be of particular interest for cancer research. However, there is still no sign of an operational drug. Nevertheless, allosteric, non-competitive inhibition in particular is an area that will help shape the future of cancer therapy.