GLUTAMINE AMIDOTRANSFERASE STRUCTURE/FUNCTION/REGULATION

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Glutamine amidotransferases are a family of enzymes that utilize the amide of glutamine in biosynthesis. they provide the main route for incorporation of nitrogen into amino acids, purine and pyrimidine nucleotides, amino sugars and coenzymes. There are 3 glutamine amidotransferases in the pathway for purine nucleotide synthesis. Glutamine PRPP amidotransferase catalyzes step 1 and is the key regulatory enzyme in the de novo pathway. The long term objective of this research is to determine basic mechanisms for glutamine amidotransferase catalysis and regulation as well as gene regulation in microorganisms. There are 4 specific aims. (1) Determine mechanisms for regulation of glutamine PRPP amidotransferase. The experiments focus on two regulatory events: nucleotide endproduct inhibition and processing of an NH2-terminal pro-peptide in the Bacillus subtilis enzyme. (2) Determine mechanisms for genetic regulation of Escherichia coli genes involved in the IMP to AMP and GMP branches of the pathway. (3) Determine how purine bases bind to E. coli pur regulon aporepressor and how this binding promotes the specific holorepressor-DNA interactions. (4) Determine mechanisms for transcriptional regulation of the B. subtilis pur operon which encodes the 10 step pathway to IMP and regulation of genes purA, guaA and guaB for the IMP to AMP and GMP branches. Finally, experiments are planned to determine the importance of B. subtilis pur operon gene overlaps in establishing the translational stoichiometry for enzyme synthesis. Purine metabolism has been a fertile area for development of drugs against a variety of diseases. Two inhibitors of glutamine amidotransferases in the purine pathway, acivicin and triciribine have antineoplastic activity.