PRPP (phosphoribosyl-pyrophosphate) is a key metabolite that plays a central role in many life processes, such as in the de novo and salvages biosynthesis of purine and pyrimidine nucleotides and therefore is essential for life. The Saccharomyces cerevisiae genome contains five paralogous PRS genes which exist as two complexes, one of which is a heterodimer, Prs1/Prs3 and the other, a heterotrimer, Prs2/Prs4/Prs5. Prs1 and Prs5 are distinguished by the presence of one and two NHRs (Non-Homologous Regions), respectively. Physical evidence for the genetically-defined Prs1/Prs3 complex was obtained by showing that in the absence of Prs3, Prs1 is unstable. In addition to interacting with Prs3, Prs1also interacts with Slt2, the MAPK of the Cell Wall Integrity (CWI) pathway. Point mutations in PRS1 corresponding to missense mutations associated with human neuropathies or in the signature divalent cation- and/or PRPP-binding sites of Prs polypeptides interfere with CWI signalling resulting in temperature and/or caffeine sensitivity. The C-terminally located NHR5-2 of Prs5 is unusual in that it contains three potential phosphorylation sites. Mutation of these amino acid residues impinges on the expression of the transcription factor, Rlm1, an endpoint of the CWI pathway and reduces the temperature-dependent transcription of FKS2, the gene encoding the stress-induced catalytic subunit of 1, 3-β-glucan synthase essential for maintaining CWI. The results of our study support the hypothesis that the PRS gene family links, as a result of gene duplication and acquisition of NHRs, primary metabolism with CWI signalling in S. cerevisiae.