PRPS1 encodes phosphoribosyl pyrophosphate synthetase 1, a key enzyme catalyzing the synthesis of phosphoribosylpyrophosphate (PRPP), the essential substrate for de novo nucleotide and NAD synthesis 1. The enzyme functions as a homodimer and is regulated through multiple post-translational modifications: O-GlcNAcylation by OGT promotes hexamer formation and relieves product-mediated feedback inhibition, boosting activity 1, while cytosolic CLOCK acetylation at K29 stabilizes PRPS1/2 and enhances nucleotide synthesis 2. PRPS1 mutations cause a disease spectrum determined by residual enzyme activity 3. Gain-of-function mutations result in PRPS1 superactivity, causing hyperuricemia, ataxia, and postlingual hearing loss 4. Loss-of-function mutations produce graded severity: mild deficiency causes X-linked nonsyndromic deafness (DFNX-2), moderate deficiency causes Charcot-Marie-Tooth disease-5 (CMTX5), and severe deficiency causes Arts syndrome with optic/peripheral neuropathy and CNS impairment 4. In acute lymphoblastic leukemia, PRPS1 mutations occur in 65% of early relapses, conferring drug resistance 5. S-adenosylmethionine supplementation shows promise for PRPS1-deficient patients 4. PRPS1 downregulation has been identified as a diagnostic biomarker for Kawasaki disease 6.