Ribose-phosphate diphosphokinase (PRPS)

Ribose-phosphate diphosphokinase, also known as phosphoribosyl pyrophosphate synthetase (PRPS), is a rate-limiting enzyme that catalyzes the synthesis of phosphoribosyl pyrophosphate (PRPP) from ATP and ribose 5-phosphate [1, 3]. PRPP serves as an essential precursor for the de novo and salvage pathways of purine and pyrimidine nucleotides, as well as the biosynthesis of amino acids like histidine and tryptophan and cofactors such as NAD [1, 11, 12]. Because of its central role in providing the building blocks for DNA and RNA, the enzyme is highly regulated and frequently hijacked by cancer cells to support rapid proliferation, particularly in MYC-driven malignancies [2, 4]. Mutations in the PRPS genes lead to several human diseases; gain-of-function mutations cause PRPS superactivity, resulting in hyperuricemia and gout, while loss-of-function mutations are associated with neurodegenerative disorders such as Arts syndrome and Charcot-Marie-Tooth disease type X5 [13, 15, 16]. In a therapeutic context, ribose-phosphate diphosphokinase is considered a promising target for oncology, as its inhibition can starve tumor cells of nucleotides needed for survival and replication [3, 5]. Furthermore, specific mutations in the enzyme isoforms PRPS1 and PRPS2 have been identified as drivers of resistance to thiopurine chemotherapies in childhood acute lymphoblastic leukemia [10]. While direct, clinically approved inhibitors are currently limited, research is actively exploring small molecules that target the enzyme's allosteric sites or its cell-cycle-dependent phosphorylation to treat cancer and metabolic conditions [5, 10]. The management of its activity is also critical in treating hereditary metabolic disorders, where monitoring biomarkers like uric acid and PRPP levels is standard practice [11, 16].

Other names

Phosphoribosyl pyrophosphate synthetaseRibose-phosphate pyrophosphokinasePRSPRPP synthetase5-phospho-alpha-D-ribose 1-diphosphate synthetase

Enzyme inhibition to deplete the intracellular pool of phosphoribosyl pyrophosphate (PRPP), thereby suppressing de novo and salvage nucleotide synthesis required for DNA and RNA production.