Regulation of Enzyme Activity ,Covalent Regulation and Feedback Inhibition

The rates of metabolic reactions need to be continually adjusted to meet the bodies varying demands. Reactions controlled by enzymes can be controlled by either increasing or decreasing enzyme concentration. However, finer control of enzyme activity can be achieved by changing the activity of existing enzyme molecules. Allosteric Regulation    Enzyme molecules may possess a site distinct from the active site called a regulatory site. The regulatory site has an affinity for certain molecules called modulators. When the modulator molecule binds to the regulatory site it effects a change in the enzyme conformation that alters the enzyme catalytic rate or affinity of the substrate or both. This type of regulation is called allosteric (allo- other; steric - shape).    Modulators involved in allosteric regulation can either increase (stimulate) or decrease (inhibit) enzyme activity. Enzymes can have more than one regulatory site and be affected by more than one modulator. Covalent Regulation    An enzyme may change following covalent bonding of a chemical group to a site on the enzyme. Enzymes are necessary to both  form and to break these covalent bonds. An example of covalent regulation is the phosphorylation and dephosphorylation of enzyme molecules    Protein kinase is an enzyme that catalyzes the addition of a phosphate group E + Pi ® E-P    Phosphatase is an enzyme that catalyzes dephosphorylation E-P ® E + Pi Feedback Inhibition    Reactions are normally linked together in chains or pathways where the product of one reaction becomes the reactant of the next reaction in the pathway, and so forth. E1 ® E2 ® E3 ® A B C D In the body it is important that the pathway produces a product at a controlled rate to meet the needs of the body. One way this is accomplished is by feedback inhibition. This occurs when a product downstream of a pathway regulates the enzyme of an upstream reaction. This would happen in the example above if C were an allosteric inhibitor of E2 , the enzyme that produces C.    Feedback inhibition helps to keep the reactions going at a steady rate. So, in the same example, if the concentration of C increases, C inhibits E2, which causes the concentration of C to decline. If the concentration of C decreases, the inhibition of E2 lessens, and more C is produced.    However, feedback inhibition is also a means by which the body can respond to the changing needs of the body. In this example again if the final product D is used up at a faster rate, the third reaction increases and reduces the concentration of C. This decrease in the concentration of C in turn decreases the inhibition on E2.    Probably the most efficient way to control a pathway is to have the end product inhibit a reaction occurring upstream. This is referred to as end-product inhibition and in the same example would work well if the product D allosterically inhibited E1 that catalyzed the first reaction in the pathway.    Less commonly a substrate will stimulate or activate an enzyme catalyzing a reaction downstream. This is called feedforward activation. In the example above this would occur if B allosterically stimulated E3.