Target site research, process

Our goal was to determine the specific target site(s) of action of the aryloxyphenoxypropanoate and cyclohexanedione herbicides. We set two simple criteria as prerequisites for identifying physiological processes as possible target sites. The site of action must be affected (1) rapidly (within minutes) and (2) by low concentrations (lipid metabolism because it seemed most sensitive to these herbicides (11.12). 

Due to the high competitiveness of the crop protection market, the research process from synthesis of new chemicals to promotion of lead compounds to the project phase has to be as streamlined as possible. It is imperative not only to eliminate compounds with weak efficacy or phytotoxicity but also chemicals with non-desirable MoA as early as possible from further evaluation and to concentrate on a few promising candidates. Besides phenotypical inspection of treated plants, the target site of a compound is usually determined with specific enzyme assays in test tubes or microtiter plates, which is a time consuming, labor- and costintensive process. It requires either purification of the respective enzyme from plants or preparation of the proteins by heterologous expression in, for example,... 

The great depth and breadth of the research on the toxicity of lead has implicated numerous cellular and molecular mechanisms of action in the CNS. Lead can bind to many different cell components to affect multiple cellular processes, depending on exposure rate and duration, body burden, developmental, nutritional and health status and, ultimately, the concentrations of lead at target sites in specific brain regions. The overall effects of lead exposure on the brain depend, in turn, on perturbations of many complex functions and interrelationships among the diverse cell types and regions of the brain. 

While it has been known for many years that the N-terminal presequence is sufficient to promote mitochondrial targeting and assembly, the subsequent interaction of the precursor molecule with the outer mitochondrial membrane and the uptake of the protein is still an area of active research. There seems little doubt, however, that there are proteins on the outer mitochondrial membrane which are required for the import process. The function of these proteins is uncertain, but they may act as receptors with the subsequent transfer through the membrane at proteinous pores located at contact sites between the inner and outer membranes. Several proteins have been identified which seem to play an important role as either receptor proteins or part of the import channel (Pfanner et al., 1991). Again, not all proteins seem to depend on this mechanism. Cytochrome c, which is loosely associated with the outer aspect of the inner mitochondrial membrane, can cross... 

Figure 42-13. Structure of bovine preproparathyroid hormone. Arrows indicate sites cieaved by processing enzymes in the parathyroid giand (1-5) and in the iiver after secretion of the hormone (4-5). The bioiogicaiiy active region of the moiecuie is fianked by sequence not required for activity on target receptors. (Slightly modified and reproduced, with permission, from Habener JF Recent advances in parathyroid hormone research. Clin Biochem 1981 14 223.)...

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