A chemical biology approach to deciphering the role of hypoxia on purine biosynthesis

Purines are more than just the building blocks for DNA and RNA; they are key metabolites that are critical for cellular function. Purines constitute the cellular energy unit adenosine triphosphate (ATP), the key signalling molecule guanosine triphosphate (GTP), and the substrates and cofactors for a variety of cellular pathways. There are two paths for purine production in cells: recycling of existing bases via a salvage pathway and de novo synthesis of the purine precursor inosine monophosphate (IMP) from phosphoribosyl pyrophosphate (PRPP) by six enzymes in ten steps. One physiological factor that significantly alters cell metabolism is hypoxia (low cellular oxygen levels). Here, we will use various chemical biology tools to decipher the effect of hypoxia on the purine biosynthesis pathways on a molecular level. This will include the synthesis of a range of chemical molecules with which to probe these pathways, including novel inhibitors of enzymes in this pathway and pull-down probes. These chemical tools will be combined with metabolomic and proteomic analysis of cells treated with these compounds. At the end of this project, we will have a better understanding of the effect of hypoxia on the synthesis of this critical class of metabolites. Given the importance of hypoxia in tumours, our findings are expected to lead to new approached for treating cancers in the medium to long term.