Kinetic Properties of Adenine Nucleotide Analogues Against Purified 5-Phosphoribosyl-1-pyrophosphate Synthetases fromE. coli, Rat Liver and Human Erythrocytes

Abstract

Abstract The nucleoside analogue 2′,3′-dideoxyadenosine (ddA), the phosphonate isostere of 2′,3′-dideoxy-2′,3′-didehydro-adenosine (d4A) 5′-monophosphate (d4API), and the acyclic nucleoside phosphonates PMEoA, PMEA, FPMPA and PMPA are potent and selective antiretroviral agents. We found that these compounds are recognized as substrates by the PRPP synthetases from E. coli, rat liver and human erythrocytes, as their monophosphate and triphosphate form in the reverse and forward reaction, respectively. In particular, ddA-5′-monophosphate (ddAMP) and ddA-5′-triphosphate proved to be excellent substrates for the enzymes. D4API was a relatively good substrate of the rat liver and human erythrocyte PRPP synthetases. The acyclic nucleoside phosphonates were rather poor substrates, as evident from their low Vmax values. None of the PRPP synthetases are found to act stereospecifically: they recognized both the S- and R-enantiomers of FPMPA and PMPA in a comparably efficient manner. Our data indicate that PRPP synt...