Purine biosynthetic enzymes

Purine biosynthetic enzymes are a group of proteins responsible for the de novo synthesis and salvage of purine nucleotides, which are essential building blocks for DNA and RNA production (NIH, 2022). This target system is primarily modulated by thiopurine antimetabolites, such as 6-thioguanine and 6-mercaptopurine, which are converted intracellularly into active 6-thioguanine nucleotides (6-TGNs). These 6-TGNs exert their therapeutic effects by providing pseudo-feedback inhibition of the rate-limiting enzyme amidophosphoribosyltransferase, thereby halting the production of endogenous purines (PharmGKB, 2021). Furthermore, 6-TGNs are incorporated into the DNA and RNA of rapidly dividing cells, such as malignant leukocytes or activated T-cells, leading to structural damage, cell cycle arrest, and apoptosis (StatPearls, 2023). This mechanism is widely utilized in the treatment of acute lymphoblastic leukemia and various inflammatory conditions like Crohn's disease and ulcerative colitis (DrugBank, 2024). Monitoring of enzymes like TPMT and NUDT15 is critical for patient safety, as genetic variations can lead to toxic accumulations of 6-TGNs.

Other names

De novo purine biosynthetic pathwayPurine metabolism enzymesThiopurine targetsAmidophosphoribosyltransferase (PPAT) pathway

Thiopurine drugs act as prodrugs that are metabolically converted into 6-thioguanine nucleotides (6-TGNs). These nucleotides inhibit the de novo purine synthesis pathway through feedback inhibition of the rate-limiting enzyme amidophosphoribosyltransferase and are also incorporated into DNA and RNA, leading to strand breaks and cytotoxicity (DrugBank, 2024; StatPearls, 2023).