Aspartate transcarbamoylase (ATCase) plays a key role in the second step of de novo pyrimidine biosynthesis in eukaryotes and has been proposed to be a target to suppress cell proliferation in E. coli, human cells and the malarial parasite. We hypothesized that a library of ATCase inhibitors developed for malarial ATCase (PfATCase) may also contain inhibitors of the tubercular ATCase and provide a similar inhibition of cellular proliferation. Of the 70 compounds screened, 10 showed single-digit micromolar inhibition in an in vitro activity assay and were tested for their effect on M. tuberculosis cell growth in culture. The most promising compound demonstrated a MIC of 4 μM. A model of MtbATCase was generated using the experimental coordinates of PfATCase. In silico docking experiments showed this compound can occupy a similar allosteric pocket on MtbATCase to that seen on PfATCase, explaining the observed species selectivity seen for this compound series.
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Mechanism of Nucleotide-Dependent Allosteric Regulation in Aspartate Transcarbamoylase.
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Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Discovered nearly 70 years ago, the allosteric regulation of aspartate transcarbamoylase (ATCase) is discussed in every biochemistry textbook. ATCase catalyzes the first step in pyrimidine biosynthesis. Despite extensive research, the mechanism by which this enzyme is regulated by pyrimidine and purine nucleotides has remained elusive.
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