Covalent binding functional group metabolism

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

Each monomer contains one pyridoxal phosphate and a highly conserved primary structure in the vicinity of the cofactor binding site. The enzymes follow the same catalytic mechanism, a rapid equilibrium random Bi Bi mechanism. However, unlike animal phosphorylases, the microbial and plant enzymes are not subjected to covalent or allosteric control. Within the group of higher plant phosphorylases two types of enzyme have been distinguished which differ in monomer size, peptide pattern, glucan specificity, and intracellular location (1-3). Based on immunochemical studies on leaf tissues (4-5), one enzyme form has been localized in the cytosol whereas the other one resides in the chloroplast. Thus, the two plant phosphorylase types represent non-interconvertible proteins which presumably have entirely different metabolic functions. 

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