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Allosteric Inhibition of Acinetobacter baumannii ATP Phosphoribosyltransferase by Protein:Dipeptide and Protein:Protein Interactions. 2022

Benjamin J Read, and Gemma Fisher, and Oliver L R Wissett, and Teresa F G Machado, and John Nicholson, and John B O Mitchell, and Rafael G da Silva
School of Biology, Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom.

ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis in bacteria, namely, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate. Catalytic (HisGS) and regulatory (HisZ) subunits assemble in a hetero-octamer where HisZ activates HisGS and mediates allosteric inhibition by histidine. In Acinetobacter baumannnii, HisGS is necessary for the bacterium to persist in the lung during pneumonia. Inhibition of ATPPRT is thus a promising strategy for specific antibiotic development. Here, A. baumannii ATPPRT is shown to follow a rapid equilibrium random kinetic mechanism, unlike any other ATPPRT. Histidine noncompetitively inhibits ATPPRT. Binding kinetics indicates histidine binds to free ATPPRT and to ATPPRT:PRPP and ATPPRT:ATP binary complexes with similar affinity following a two-step binding mechanism, but with distinct kinetic partition of the initial enzyme:inhibitor complex. The dipeptide histidine-proline inhibits ATPPRT competitively and likely uncompetitively, respectively, against PRPP and ATP. Rapid kinetics analysis shows His-Pro binds to the ATPPRT:ATP complex via a two-step binding mechanism. A related HisZ that shares 43% sequence identity with A. baumannii HisZ is a tight-binding allosteric inhibitor of A. baumannii HisGS. These findings lay the foundation for inhibitor design against A. baumannii ATPPRT.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D004151 Dipeptides Peptides composed of two amino acid units. Dipeptide
D006639 Histidine An essential amino acid that is required for the production of HISTAMINE. Histidine, L-isomer,L-Histidine,Histidine, L isomer,L-isomer Histidine
D001276 ATP Phosphoribosyltransferase An enzyme that catalyzes the first step of the pathway for histidine biosynthesis in Salmonella typhimurium. ATP reacts reversibly with 5-phosphoribosyl-1-pyrophosphate to yield N-1-(5'-phosphoribosyl)-ATP and pyrophosphate. EC 2.4.2.17. Phosphoribosyl-ATP Pyrophosphorylase,Phosphoribosyl ATP Pyrophosphorylase,Phosphoribosyltransferase, ATP,Pyrophosphorylase, Phosphoribosyl-ATP
D040981 Acinetobacter baumannii A species of gram-negative, aerobic bacteria, commonly found in the clinical laboratory, and frequently resistant to common antibiotics. Bacterium anitratum

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