Phosphoribosyltranferases (PRTs) catalyse the transfer of the sugar, ribose 5-phosphate to a nitrogenous base. We have examined catalysis by two PRT enzymes, both of which play key roles in amino acid biosynthesis, and have been identified as new targets for antimicrobial therapeutics.
ATP phosphoribosyltransferase (ATP-PRT) catalyses the first step of histidine biosynthesis resulting in the transfer of a phosphoribosyl unit to ATP. We have carried out kinetic isotope effect measurements to determine the mechanism of this reaction for ATP-PRT enzymes the pathogens Campylobacter jejuni and Mycobacterium tuberculosis. We are currently using this information to design transition state analogues as inhibitors of this enzyme.
Anthranilate phosphoribosyltransferase (An-PRT) catalyses the formation of phosphoribosyl anthranilate in the biosynthetic pathway for tryptophan. Our results with substrate analogues and inhibitors of An-PRT from Mycobacterium tuberculosis reveal how a substrate binding channel both protects an enzyme-bound reactive intermediate and acts as an Achilles heel by providing a mechanism for inhibition.
1 - Mittelstädt, G.; Moggré, G.-J.; Panjikar, S.; Nazmi, A. R.; Parker, E. J. Protein Sci. 2016, 25, 1492.
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3 - Moggré GJ, Poulin MB, Tyler PC, Schramm VL & Parker EJ. 2017, Transition state analysis of adenosine triphosphate phosphoribosyltransferase. ACS Chemical Biology 12, 2662-70.