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Date of Award
Steven M. Firestine
INVESTIGATION OF THE INHIBITORY MECHANISM OF ISATIN
TOWARDS THE MICROBIAL ENZYME N5-CAIR SYNTHETASE
Cale C. Streeter
Isatin has been identified in a diverse range of organisms, including microorganism, plants, invertebrates and vertebrates. In the species that have been investigated, the biosynthesis, metabolism and biological role of isatin is not fully understood. Over the past 40 years, one of the most studied biological roles of isatin is the ability of exogenous isatin to exhibit cytotoxic effects in multiple cancer cell lines, bacteria, fungi, algae and protozoa. To date, the mechanism of cytotoxicity is unknown.
In de novo purine biosynthesis, microbes convert the intermediate AIR (5-aminoimidazole ribonucleotide) to CAIR via two enzymes – N5-CAIR synthetase and N5-CAIR mutase, while vertebrates utilize one enzyme, AIR carboxylase. A HTS identified compounds with an isatin (indole-2,3-dione) core as potential inhibitors of the microbial enzyme N5-CAIR synthetase. Investigation into the mechanism of inhibition have identified that the substrate, AIR (5-aminoimidazole ribonucleotide), reacts with isatin in a reversible manner based on the following evidence. (1) Inhibition of the enzymatic assay is time dependent and is correlated to the incubation of the substrate with the inhibitor. (2) Inhibition of bromo isatins correlate with the reaction rates of bromo isatins with model 5-amino diazoles. (3) The products of methyl-isatin and model 5-amino diazoles have been characterized and exhibit a unique carbon-carbon reaction. (4) AIR is recovered from the AIR-isatin product.
Prior research and the above findings provide the following hypothesis into the mechanism of action of isatin cytotoxicity: The cytotoxicity of isatin is due to an accumulation of multiple dysfunctional pathways including, disruption of purine biosynthesis, the formation of DNA and protein adducts and depletion of antioxidants. Further understanding of the mechanism of action will be useful to investigators pursuing isatin and isatin analogs as an anti-cancer agent.
Streeter, Cale Charles, "Investigation Of The Inhibitory Mechanism Of Isatin Towards The Microbial Enzyme N5-Cair Synthetase" (2017). Wayne State University Dissertations. 2211.