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The continued rise of antibiotic-resistant infections coupled with the limited pipeline of new antimicrobial agents highlights the pressing need for the development of new antibacterial agents. One potential pathway for new agents is de novo purine biosynthesis where studies have shown that bacteria and lower eukaryotes synthesize purines differently than humans. Microorganisms utilize two enzymes, N5-CAIR synthetase and N5-CAIR mutase, to convert 5-aminoimidazole ribonucleotide (AIR) into 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) through the intermediate N5-carboxy-5-aminoimidazole ribonucleotide (N5-CAIR). In contrast, vertebrates directly convert AIR to CAIR via the enzyme AIR carboxylase. A high-throughput screen against N5-CAIR synthetase identified a group of compounds with a 2,3-indolinedione (isatin) core that inhibited the enzyme. While initial studies suggested that isatins inhibited the enzyme by a non-competitive mechanism, here we show that isatins inhibit N5-CAIR synthetase by a substrate depletion mechanism. Unexpectedly, we found that isatin reacts rapidly and reversibly with the substrate AIR. The rate of the reaction is dependent upon the substituents on the phenyl moiety of isatin, with 5- and 7-bromoisatin being faster than 4-bromoisatin. This reactivity between AIR and isatin highlights distinctive properties of AIR which should provide insight into the unique mechanism required to carboxylate AIR in purine biosynthesis. In addition, these studies suggest that care should be taken when exploring isatin compounds since the biological activity of isatins could be a result of their reactivity.
This article was published in the following journal.
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