Feedback Inhibition

Feedback inhibition (or end product inhibition) is a mechanism for the inhibition of preformed enzymes that is seen primarily in the regulation of whole biosynthetic pathways, e.g. pathways involved in the synthesis of the amino acids. Such pathways usually involve many enzymatic steps, and the final (end) product is many steps removed from the starting substrate. By this mechanism, the final product is able to feed back to the first step in the pathway and to regulate its own biosynthesis.

In feedback inhibition, the end product of a biosynthetic pathway inhibits the activity of the first enzyme that is unique to the pathway, thus controlling production of the end product. The first enzyme in the pathway is an allosteric enzyme. Its allosteric site will bind to the end product (e.g. amino acid) of the pathway which alters its active site so that it cannot mediate the enzymatic reaction which initiates the pathway. Other enzymes in the pathway remain active, but they do not see their substrates. The pathway is shut down as long as adequate amounts of the end product are present. If the end product is used up or disappears, the inhibition is relieved, the enzyme regains its activity, and the organism can resume synthesis of the end product. Thus, if a E. coli bacterium swims out of a glucose minimal medium into milk or some other medium rich in growth factors, the bacterium can stop synthesizing any of the essential metabolites that are made available directly from the new environment.

One of the most intensely studied bacterial pathways is the pathway of tryptophan biosynthesis (Figure 3). The pathway of tryptophan biosynthesis is regulated by feed back inhibition. Tryptophan is the effector molecule for allosteric enzyme a. When the end product of the pathway (tryptophan) attaches to enzyme a, the enzyme is inactive and can no longer join glutamine and chorismic acid into anthranilate. If tryptophan is disjoined from the enzyme the pathway is resumed, and tryptophan synthesis will continue. Tryptophan biosynthesis is also regulated at a genetic level by the processes of enzyme repression (below) and attenuation.

Note: In the case of feedback inhibition (above), the signal molecule, tryptophan, is a negative effector of Enzyme a in the pathway of tryptophan biosynthesis, because when it binds to Enzyme a, it inactivates the enzyme. In enzyme repression (below) tryptophan is a signal molecule that acts as a positive effector of the trp repressor protein because when it binds to the repressor it activates the protein, so that it binds to the trp DNA.

Figure 3. The pathway of tryptophan biosynthesis in E. coli. The pathway is regulated by the process of feedback inhibition. Tryptophan (trp), the end product of the pathway, is the effector molecule that binds to the allosteric site of Enzyme a, the first enzyme in the pathway. When trp is bound to the enzyme the catalytic (active) site of Enzyme a is altered so that it is unable to react with its substrates and the synthesis of anthranilate is inhibited.

If a metabolic pathway branches, leading to the synthesis of two amino acids, each end product (amino acid) can control its own synthesis without affecting the other (Figure 4). For example, the amino acids proline and arginine are both synthesized from glutamic acid. Each amino acid can regulate the first enzyme unique to its own synthesis without affecting the other, so that a surplus of arginine will not shut off the synthesis of proline and vice versa.

Figure 4. Generalized scheme for regulation of a branched metabolic pathway by the process of feedback inhibition.