The objectives of the present proposal are (i) to provide information which will improve our understanding of the catalytic mechanism of the aryl sulfotransferases, while (ii) investigating the role of these isozymes in the metabolic disposition of oximes. The aryl sulfotransferases catalyze the sulfation of an enormous variety of hydroxyl containing substrates and are of major importance in the metabolic disposition of many drugs and chemicals. The conjugation reaction can result in """"""""detoxification"""""""" or toxic """"""""bioactivation"""""""" depending on the structural and chemical features of the substrate molecule. Despite their pivotal biochemical role, many questions exist regarding the precise mechanism of these enzymes. To obtain information about the chemical mechanism and active site geometry of the aryl sulfotransferases, the use of oxime substrates is proposed. Oximes are important metabolites of aliphatic amines, whose subsequent metabolism is poorly understood, particularly regarding conjugative processes. The use of oxime substrates to study the aryl sulfotransferases will clarify the role of sulfate conjugation in the metabolic disposition of these compounds. Further, enzymatic sulfation of certain oxime substrates has the potential to catalyze well-known rearrangement and/or dehydration reactions, which should provide a very novel approach to obtaining information about the enzyme's active site. Moreover, the occurrence of such reactions in vivo poses a new potentially toxic biotransformation. Thus, the effect of systematically altered structural and electronic factors on conjugation, rearrangement (dehydration) and in vivo toxicity will be used to probe the active site and mechanism of these isozymes and to investigate the potential for sulfotransferase catalyzed bioactivation of oximes.
| Parker, M H; McCann, D J; Mangold, J B (1994) Sulfation of di- and tricyclic phenols by rat liver aryl sulfotransferase isozymes. Arch Biochem Biophys 310:325-31 |
| Mangold, J B; McCann, D J; Spina, A (1993) Aryl sulfotransferase-IV-catalyzed sulfation of aryl oximes: steric and substituent effects. Biochim Biophys Acta 1163:217-22 |
| Mangold, B L; Erickson, J; Lohr, C et al. (1990) Self-catalyzed irreversible inactivation of rat hepatic aryl sulfotransferase IV by N-hydroxy-2-acetylaminofluorene. Carcinogenesis 11:1563-7 |
| Mangold, J B; Spina, A; McCann, D J (1989) Sulfation of mono- and diaryl oximes by aryl sulfotransferase isozymes. Biochim Biophys Acta 991:453-8 |
| Mangold, J B; Mangold, B L; Spina, A (1986) Rat liver aryl sulfotransferase-catalyzed sulfation and rearrangement of 9-fluorenone oxime. Biochim Biophys Acta 874:37-43 |
