Prps2, or phosphoribosyl pyrophosphate synthetase 2, is a rate-limiting enzyme in purine and pyrimidine nucleotide synthesis. It transfers pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids [2]. There are three PRPS isoforms in the human genome, with Prps2 sharing 95% sequence identity with Prps1, but being less sensitive to allosteric inhibition and specifically upregulated in certain cancers at the translational level [2].

PRPS2 mutations are associated with acute lymphoblastic leukemia (ALL) relapse. Specifically, these mutations influence Prps1/2 hexamer stability, mediate purine metabolism on thiopurine treatment, lead to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance. The 3-amino acid insertion in Prps2 causes steric clash to the hexamer interface, resulting in low enzyme activity, and the Prps2 P173R mutation increases thiopurine resistance in xenograft models [1]. In non-small cell lung cancer, Prps2 enhances cisplatin resistance by promoting exosome-mediated macrophage M2 polarization [3]. In osteosarcoma, higher Prps2 protein level is related to tumour proliferation and recurrence, making it an independent prognostic marker and potential therapeutic target [4]. In male infertility-related studies, Prps2 depletion in mouse testes leads to hypospermatogenesis and accelerated apoptosis of spermatogenic cells, and its expression correlates with Sertoli-cell only syndrome in patients [5,6].

In conclusion, Prps2 is crucial for nucleotide synthesis and is involved in multiple biological processes and disease conditions. Research on Prps2, especially through in vivo models like xenograft and mouse models, has revealed its role in cancer drug resistance, tumour prognosis, and male infertility, providing potential targets for disease diagnosis and treatment.