Phosphoribosyl pyrophosphate synthetase 2 (PRPS2)

Phosphoribosyl pyrophosphate synthetase 2 (PRPS2) is a critical rate-limiting enzyme involved in the synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose 5-phosphate and ATP. PRPP is an essential substrate for both de novo and salvage pathways of purine and pyrimidine nucleotide biosynthesis. PRPS2 is closely related to, but functionally distinct from, the PRPS1 isoform; notably, PRPS2 is less sensitive to feedback inhibition by ADP and GDP, which enables persistent nucleotide production in cells with high demand, such as cancer cells overexpressing MYC oncogene[1][4]. PRPS2 expression is post-transcriptionally upregulated in response to proliferative signals and oncogenic MYC activity, functions as a key node integrating protein and nucleotide synthesis, and has been shown to promote cell proliferation and tumorigenesis in various cancers[1][2][3][5]. Mutations in PRPS2 can promote drug resistance in acute lymphoblastic leukemia by altering hexamer stability and reducing feedback inhibition, with important implications for chemoresistance to thiopurines[5]. PRPS2 forms hexameric complexes and can assemble into filaments, a structure required for full enzymatic activity[4]. Given its central metabolic role and regulatory features, PRPS2 represents a promising but challenging therapeutic target, with potential risks of toxicity related to its inhibition in normal proliferating tissues[1][4][5].

Other names

Ribose-phosphate pyrophosphokinase 2PRS-IIPPRibPPhosphoribosyl pyrophosphate synthase IIPRS IIribose-phosphate diphosphokinase 2PRSIIribose-phosphate pyrophosphokinase 2PPRibP synthetasephosphoribosyl pyrophosphate synthase IItesticular secretory protein Li 41

Inhibition of PRPS2 reduces de novo nucleotide synthesis and purine salvage, which can suppress proliferation of rapidly dividing cells, including cancer cells[1]. Drug resistance may occur through mutations in PRPS2 that alter hexamer stability and reduce feedback inhibition[5].