Hypoxanthine-guanine phosphoribosyltransferase is activated via positive cooperativity between guanine and IMP.

Abstract

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme in the purine salvage pathway. Here, the reverse reaction of HGPRT from the thermophilic bacterium Hungateiclostridium thermocellum was studied in the presence of IMP and pyrophosphate. As for the human enzyme, the bacterial HGPRT was activated by guanine. Furthermore, guanine was found to operate as both an activator and an inhibitor. Intriguingly, within the concentration range of guanine where it functions as the activator, the Km value for IMP was not influenced by guanine. Consequently, guanine was found to noncompetitively activate the reverse reaction toward IMP. Here, we propose a reaction scheme that explains the activation mechanism in which the enzyme forms a chimeric oligomer bound to both IMP and guanine.