Biochemical Engineering Fundamentals, Part 1 - Bailey J., Ollis D. 1989

Kinetics of Enzyme-Catalyzed Reactions
Regulation of Enzyme Activity
Mechanisms of Reversible Regulation of Enzyme Activity

Many of the known Competitive Inhibitors are chemically similar to normal substrates; such inhibitors are called substrate analogs. It is believed that these inhibitors have a Spatial Structure resembling a key that can fit into the "keyhole" of the enzyme's Active Site; however, the "key" does not perfectly fit this "lock," and the reaction does not proceed. Consider, for example, the inhibition of succinic acid dehydrogenation by malonic acid:

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In this case, malonic acid can form a complex with succinate dehydrogenase, but the process stops there.

Competitive inhibition underlies the MECHANISM OF ACTION of one of the sulfonamide drugs, sulfanilamide (streptocide). The structure of the latter is very close to that of n-aminobenzoic acid, an essential vitamin for many Bacteria. Sulfanilamide inhibits the enzyme involved in The conversion of n-aminobenzoic acid to Folic acid, thereby blocking the biochemical machinery of the bacterium, leading to its death.

In another mechanism, called Allosteric Regulation, The behavior of the enzyme-substrate system is typical of non-competitive inhibition. It is believed that The Mechanism of allosteric regulation generally plays a dominant role in non-competitive inhibition and activation. The name "allosteric" (meaning "other shape") was initially given to this mechanism because the structures of many effectors of enzymatic activity differ significantly from those of substrates. From this, it was concluded that the regulatory action of such effectors is based on their binding to a specific regulatory site on the enzyme, distinct from the active site where substrate catalysis occurs. Accordingly, Enzymes possessing both regulatory and catalytic sites were named allosteric enzymes.

Allosteric regulation can either inhibit (decrease) or activate (increase) the catalytic capacity of an enzyme. The process of allosteric regulation is shown schematically in Fig. 3.20. Note that the enzyme is depicted here as consisting of two subunits; it is well known that many Allosteric enzymes are indeed Oligomeric Proteins.

The most convincing Evidence for the validity of the allosteric theory of enzymatic activity came from the experimental study of aspartate transcarbamoylase (ATCase). After separating the enzyme into two subunits, it was found that the inhibitor of the intact enzyme, CTP (cytidine triphosphate), does not affect the larger, catalytically active subunit. Conversely, the smaller subunit is catalytically inactive but binds CTP.

In the absence of experimental evidence like that presented above for ATCase, one cannot be certain that the effector does not bind to the Active Site of the enzyme. From a kinetic standpoint, however, only The Effect of the effector on A number of parameters is of interest, including the affinity of the substrate for the enzyme, the concentration of unbound enzyme, and/or The rate of complex dissociation. In the next section, we will attempt to find mathematical expressions that characterize these effects quantitatively.

FIG. 3.20. In the symmetrical model of allosteric REGULATION OF ENZYMATIC Activity, the binding of activator A and substrate S leads to the catalytically active R-form of the enzyme, while the binding of the inhibitor changes the conformation of all subunits in the oligomeric protein in such a way that the protein molecule assumes the inactive T-form. [From: Loewy A., Siekevitz P., Cell Structure and function. — M.: Mir, 1971, p. 306.]