Regulation occurs at many levels. At one level, the cell controls how many molecules of each enzyme it makes by regulating the expression of the gene that encodes that enzyme (discussed in Chapter 7). The cell also controls enzymatic activities by confining sets of enzymes to particular subcellular compartments, whether by enclosing them in a distinct membrane-bounded compartment (discussed in Chapters 12 and 14) or by concentrating them on a protein scaffold (see Figure 3–77). As will be explained later in this chapter, enzymes are also covalently modified to control their activity. The rate of protein destruction by targeted proteolysis represents yet another important regulatory mechanism (see Figure 6–86). But the most general process that adjusts reaction rates operates through a direct, reversible change in the activity of an enzyme in response to the specific small molecules that it binds.
The most common type of control occurs when an enzyme binds a molecule that is not a substrate to a special regulatory site outside the active site, thereby altering the rate at which the enzyme converts its substrates to products. For example, in feedback inhibition, a product produced late in a reaction pathway inhibits an enzyme that acts earlier in the pathway. Thus, whenever large quantities of the final product begin to accumulate, this product binds to the enzyme and slows down its catalytic action, thereby limiting the further entry of substrates into that reaction pathway (Figure 3–55). Where pathways branch or intersect, there are usually multiple points of control by different final products, each of which works to regulate its own synthesis (Figure 3–56). Feedback inhibition can work almost instantaneously, and it is rapidly reversed when the level of the product falls.
Figure 3–55 Feedback inhibition of a single biosynthetic pathway. The end product Z inhibits the first enzyme that is unique to its synthesis and thereby controls its own level in the cell. This is an example of negative regulation.
Figure 3–56 Multiple feedback inhibition.
In this example, which shows the biosynthetic pathways for four different amino acids in bacteria, the red lines indicate positions at which products feed back to inhibit enzymes. Each amino acid controls the first enzyme specific to its own synthesis, thereby controlling its own levels and avoiding a wasteful, or even dangerous, buildup of intermediates. The products can also separately inhibit the initial set of reactions common to all the syntheses; in this case, three different enzymes catalyze the initial reaction, each inhibited by a different product.
Feedback inhibition is negative regulation: it prevents an enzyme from acting. Enzymes can also be subject to positive regulation, in which a regulatory molecule stimulates the enzyme’s activity rather than shutting the enzyme down. Positive regulation occurs when a product in one branch of the metabolic network stimulates the activity of an enzyme in another pathway. As one example, the accumulation of ADP activates several enzymes involved in the oxidation of sugar molecules, thereby stimulating the cell to convert more ADP to ATP.
A striking feature of both positive and negative feedback regulation is that the regulatory molecule often has a shape totally different from the shape of the substrate of the enzyme. This is why the effect on a protein is termed allostery (from the Greek words allos, meaning “other,” and stereos, meaning “solid” or “three-dimensional”). As biologists learned more about feedback regulation, they recognized that the enzymes involved must have at least two different binding sites on their surface—an active site that recognizes the substrates, and a regulatory site that recognizes a regulatory molecule. These two sites must somehow communicate so that the catalytic events at the active site can be influenced by the binding of the regulatory molecule at its separate site on the protein’s surface.