Target site interactions

The effect of any chemical at a biological target depends on its ability to attain a target site concentration that exceeds the threshold required to ehcit the response. The intensity and duration of the response depends on the toxicokinetic properties of the compound (absorption, distribution, metabolism, and excretion) and the nature of the target site interaction (reversible, irreversible). If recovery is complete between successive exposures, no cumulative toxicity is to be expected. However, a short-term acute exposure could potentially add to the long-term burden of a persistent chemical and be relevant for the magnitude of the chronic effect. 

Like many other typical bacterial secondary metabolites, AGAs tend to be produced as complex product mixtures released from their producing cells. We interpret this as a strong sign for ongoing evolution of the respective pathways and ligand-target site interactions. In other words the biochemical interactions... 

The major difference between OPs and carbamates is in their metabolic fate. This strongly indicates that metabolism and detoxification are the most important factors in resistance evolution. The current emphasis on target site interactions and their associated resistance mechanisms reflects their perceived practical importance, the importance of their study for the development of new insecticidal molecules, and the fundability of such research. But detailed studies of the biochemical characteristics and physiological behavior of the enzymes involved in insecticide metabolism and detoxification are still very important. 

A. Target-Site Interactions and General Effects on Bacterial and Eukaryotic Cells... 

Some of the best evidence of links between effects at different organizational levels comes from studies with OPs, where levels of AChE inhibition have been compared with associated neurophysiological and behavioral effects. In adopting this approach, however, the picture is complicated by mounting evidence for these compounds acting on target sites other than AChE, as discussed in Section 16.3. Thus, behavioral disturbances caused by an OP may be the outcome of interaction with both AChE and one or more other sites of action. The following account, however, will be concerned with situations where effects of OPs are closely related to levels of AChE inhibition. More complex scenarios will be discussed in the next section. 

Many examples of mobile elements are found in bacteria, where they are called transpo-sons. Bacterial transposons have terminal repeat sequences that both code for the enzymes catalyzing the process of transposition (transposases) and physically interact with these enzymes to bring them to the DNA target site. At this site the DNA-bound transposase presumably catalyzes the endonucleolytic cleavage of the terminal repeat sequence of the trahsposon and also catalyzes a similar sequence in the target DNA. 

Douthwaite, S. and Champney, W.S. (2001) Structures of ketolides and macrolides determine their mode of interaction with the ribosomal target site. The Journal of Antimicrobial Chemotherapy, 48 (Suppl 2), 1. 

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