Mechanisms of Enzyme Inhibition

The equations given in Table 9.1 simply describe the inhibition behaviors of enzymes and thus can be called phenomenological expressions. However, it is important to describe basic mechanisms, in the way that Michaelis and Menten did for a single enzyme. The mechanisms account for the form of the inhibition equations. 

By using the steady-state analysis of Briggs and Haldane, it is possible to show that 

This equation predicts that the slope of a Lineweaver-Burk plot will increase with increasing inhibitor concentration, but the intercept on the l/v0 axis (1/Kmax) will not change. A series of plots for several experiments with different concentrations of inhibitor will all have the same l/u0 intercept as shown in Fig. 9-4(a), indicating that competitive inhibition does not alter Kmax. 

This equation corresponds to that for mixed inhibition (Table 9.1) if Kt 4= K r However, if = K t, then pure noncompetitive inhibition is the result. Thus, it can be seen that, mechanistically speaking, pure noncompetitive inhibition is a special case of mixed inhibition. 

The double reciprocal form of Eq. (9.41) for pure noncompetitive inhibition is  

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Covalent inactivation that results from an inherent chemical reactivity of the inhibitory molecule is often too indiscriminant for use as a mechanism of enzyme inhibition in human medicine. 

Computation and Modeling of Molecular Recognition Intermolecular Interactions in Molecular Recognition Mechanisms of Enzyme Inhibition Protein-Ligand Interactions... 

Bernhard SA, Orgel LE. Mechanism of enzyme inhibition by phosphate esters. Science 1959 130 625-626. 

Enzyme Inhibition, Mechanisms of Enzyme Inhibition, Tools to Study Enzyme Kinetics, Techniques to Study Kinetic Isotope Effects Enzyme Catalysis, Chemistry of... 

Figure 2.10. Mechanism of enzyme inhibition by saccharin based inhibitors. Only if R contains a leaving group, eg. (15-4), does the inhibitor progress to a dicovalently linked enzyme.

It seems that the pharmacological activities showed by different iridoids are due to their genine, like aucubin. The structural similarity between the aglycone and glutaraldehyde suggests a similar mechanism of enzyme inhibition through protein cross-linking by Schiff reactions. 

Figure 2.6 Acetylcholinesterase inhibitors (ACHI) prevent acetylcholine degradation by inhibiting the enzyme acetylcholinesterase. The mechanisms of enzyme inhibition are described in the text (left).

Anastrozole (Fig. 46.11) is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is hormone-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postmenopausal breast cancer. Anastrozole. a benzyltriazole derivative, competes with the natural substrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the heme iron atom of the aromatase enzyme complex (161,162). This coordination ultimately prevents aromatization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole. estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other hormone, including cortisol and aldosterone. 

The mechanisms of enzyme inhibition fall into three main types, and they yield particular forms of modified Michaelis-Menten equations. These can be derived for single-substrate/single-product enzymic reactions using the steady-state analysis of Sec. 5.10, as follows. 

Novel Mechanisms of Enzyme Inhibition with Organometallic Compounds 119... 

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