Inhibitors hydrolytic reactions

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

Tran-Minh et al. (1986) fixed BuChE in a film of 10 nn thickness around the active tip of a pH glass electrode and measured the pH decrease during substrate hydrolysis. The electrode was inserted into a flow-through cell. When a steady pH value in 5 mmolA butyrylthiocholine solution was reached, a competitive inhibitor, e.g. carbamate, was injected. The inhibition of the hydrolytic reaction resulted in an in-... 

An extensive kinetic study of the hydrolysis of another cholinesterase inhibitor, isopropylmethylphosphonofluoridate (Sarin), in the presence of a variety of metal chelates, confirmed the formation of intermediates chelated to the oxygen and fluorine atoms in the hydrolytic reaction 64). 

The presence of fluorine strongly destabihzes a carbocation centered on the jS carbon because only the inductive effect takes place. " The effect on solvolysis or protonation reaction of double bonds can be very important. The destabilization of carbenium and alkoxycarbenium ions plays an importantrole in the design of enzyme inhibitors (cf Chapter 7) and in the hydrolytic metabolism of active molecules (cf. Chapter 3). 

As compared with the hydrolytic polymerization, the base catalysed polymerization is essentially more sensitive towards impurities. The inhibition or retardation by traces of various foreign substances follows from the extremely low concentrations of the imide formed by the disproportionation reaction ranging about in the order of magnitude 10 2mol-%, and from the high reactivity of the imide. The imides are the key intermediate in the polymerization mechanism and hence every substance which is able to react with imides acts either as an inhibitor or as a retarder of the base catalysed polymerization of caprolactam (67). 

Compounds effecting a stable intermediate in the course of enzymatic catalysis are a sort of mechanism-based inhibitor. However, in this case, the enzymatic activity lost by the formation of the intermediate can regenerate after a certain period. Compounds of this class are often observed for hydrolytic enzymes. The formation of an acyl enzyme intermediate (EA) is a characteristic feature of the reaction catalyzed by these enzymes, as shown in Eq. (6). Esters of p-guanidinobenzoate (9), which were discussed in Sect. 4.1, behave as transient inhibitors of trypsin due to the formation of a relatively stable acyl enzyme. A similar type of inhibition occurs in the temporary... 

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