Allosteric Regulatory Enzymes

All enzymes are remarkable since they have the ability to increase the rate of a chemical reaction, often by more than a billion fold. Allosteric enzymes are even more amazing because they have the additional ability to change their rate in response to cellular activators or inhibitors. This enables them to control the pathway in which they are the regulatory enzyme. Since the effector molecules represent the current status of the cell for a given metabolic pathway, this results in very responsive and balanced metabolic states, and makes it possible for cells and organisms to be appropriately dynamic, and responsive, in a changing environment. This book provides a logical introduction to the limits for enzyme function, as dictated by the factors that are the limits for life. This book presents a complete description of all the mechanisms used for changing enzyme activity. Eight enzymes are used as model systems, because they have been studied extensively. Wherever possible, the human form of the enzyme is used to illustrate the regulatory features.

While authors often emphasize the few enzymes that have the most remarkable catalytic rates, this survey of enzymes has led to the author’s appreciation of some important general conclusions:

1. Most enzymes are not exceptionally fast; they are always good enough for their specific catalytic step.

2. Although enzymes could always be much faster if they changed so as to bind their substrates more weakly, actual enzymes must be able to discriminate in favor of their special substrate, and therefore they have sacrificed speed to obtain better binding. This means that specific control of individual metabolic steps is more important than overall speed.

3. Results for many hundreds of enzymes establish that a lower limit for a normal catalytic activity is 1 s-1. Most enzymes have a catalytic rate between 10 and 300 s-1.

4. Allosteric regulation always results in a change in the enzyme's affinity for its substrate. Even V-type enzymes (named for their large change in catalytic velocity) always have a corresponding change in affinity for their substrate.

Thomas Traut has a PhD in molecular biology, and has studied enzymes since 1974. As a professor at the University of North Carolina at Chapel Hill he has focused on enzyme regulation, and taught advanced enzymology to graduate students. Important findings from his research helped to define the mechanism of allosteric control for dissociating enzymes. In this group the active form of the enzyme is normally oligomeric (trimer, tetramer, hexamer, etc.) and the dissociated subunit has little or no activity. With the solution of crystal structures for these enzymes by other laboratories, it became established that these dissociating enzymes had the active site at the interface of two adjacent subunits. Therefore, only the oligomer could have a complete active site. Since binding of the substrate, or of an effector, stabilizes two adjacent subunits in contact, this from of regulation is an efficient form of conformational control.

Additional studies helped to establish the correspondence between the subunit size of an enzyme and the number of independent ligand binding sites. Modules are the smallest units of folded protein structure. They are normally 3 - 7 kDa in size, and can bind one ligand. Catalytic sites, or regulatory sites, are frequently formed by two adjacent modules. The total size of a protein subunit then gives a good estimate of the number of such different ligand binding sites.