Purine synthesis and utilization pathway

The purine synthesis and utilization pathway via thiopurine metabolites is a complex metabolic network responsible for the activation and catabolism of thiopurine immunosuppressants such as azathioprine and 6-mercaptopurine (PharmGKB, 2021). This pathway involves the conversion of prodrugs by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into thio-inosine monophosphate (TIMP), which is subsequently transformed into active thioguanine nucleotides (TGNs) (StatPearls, 2023). These active metabolites exert their therapeutic effects by incorporating into DNA and RNA, causing structural damage and inhibiting de novo purine synthesis, which effectively suppresses the proliferation of T-lymphocytes and other rapidly dividing cells (PubMed, 2018). The pathway is critically regulated by enzymes like thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15), which serve to clear or detoxify intermediate metabolites (CPIC, 2018). Clinically, this pathway is central to the treatment of acute lymphoblastic leukemia, inflammatory bowel disease, and autoimmune conditions (NIH, 2022). Genetic variations in the enzymes within this pathway are vital biomarkers, as deficiencies can lead to severe, potentially fatal myelosuppression due to the accumulation of toxic metabolites (Mayo Clinic, 2023).

Other names

Thiopurine metabolic pathwayThiopurine S-methylation pathwayPurine salvage and de novo synthesis pathwayThiopurine activation and catabolism pathway

Thiopurine prodrugs are enzymatically converted into thioguanine nucleotides (TGNs) which incorporate into DNA and RNA, leading to cell cycle arrest and apoptosis; they also inhibit de novo purine synthesis via feedback inhibition of phosphoribosyl pyrophosphate (PRPP) amidotransferase (StatPearls, 2023; PharmGKB, 2021).