THE CHEMISTRY OF. .. A Suicide Enzyme Substrate

WHY DO THESE TOPICS MATTER ] In The Chemistry of... A Suicide Enzyme Substrate, we shall see how 5-fluorouracil works. Then, at the end of this chapter, we will show how the combination of several of these reactions in series, each setting up the next step like dominos falling in a row, can enable the one-pot preparation of a highly important alkaloid known as tropinone. Tropinone contains the core of several useful pharmaceuticals. 

We shall see examples of biochemically relevant conjugate additions in The Chemistry of... Calicheamicin ji Activation for Cleavage of DNA (see Section 19.7B) and in The Chemistry of... A Suicide Enzyme Substrate (Section 19.8). 

Inhibition can be reversible when it simply complexes at the active site preventing further catalysis. The active enzyme under these conditions can be recovered by dialysis. Another form of inhibition is the irreversible type where the active enzyme cannot be recovered by dialysis. A variant of this type of inhibition is suicide inhibition a substrate of the enzyme reacts at the active site to yield an irreversible inhibitor which then reacts directly with groups at the active site [18]. A technique, in situ click chemistry , is related to that of suicide inhibition and involves click chemistry components which complex at the active site of an enzyme and combine to form femtomolar inhibitors. The technique can be used to synthesise inhibitors or by selection from a library of click chemistry components to search structure space of the inhibitor for the drug target [ 19]. 

Clavulanic acid is a mold product with only weak intrinsic antibacterial activity, but it is an excellent irreversible inhibitor of most (3-lactamases. It is believed to acylate the aotive site serine by mimioking the normal substrate. Hydrolysis occurs with some (3-lactamases, but in many cases, subsequent reactions ooour that inhibit the enzyme irreversibly. This leads to its classification as a mechanism-based inhibitor (or so-oalled suicide substrate). The precise chemistry is not well understood (Fig. 38.18), but when clavulanio acid is added to ampicillin and amoxicillin preparations, the potenoy against (3-lactamase-produoing strains is markedly enhanced. 

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