Amidophosphoribosyltransferase (PPAT) (PPAT)

The DNA/RNA synthesis pathway in proliferating lymphocytes is the primary therapeutic target for thiopurine drugs like azathioprine and 6-mercaptopurine (StatPearls, 2023). These drugs act as antimetabolites; azathioprine is a prodrug that is non-enzymatically cleaved to 6-mercaptopurine, which then undergoes extensive enzymatic conversion into active thioguanine nucleotides (TGNs) and methyl-thioinosine nucleotides (Me-TIMP) (PharmGKB, PA2040). The primary mechanism involves the inhibition of amidophosphoribosyltransferase (PPAT), the rate-limiting enzyme in de novo purine biosynthesis, thereby depleting the intracellular pool of adenine and guanine nucleotides required for DNA and RNA production (PubChem, CID 667490). Furthermore, the incorporation of 6-thioguanine nucleotides into the DNA of replicating cells leads to mismatch repair-mediated cytotoxicity and apoptosis, particularly in rapidly dividing T and B lymphocytes (StatPearls, 2023). Beyond direct nucleotide depletion, 6-thio-GTP (a metabolite) binds to the GTPase Rac1, blocking its activation and inducing apoptosis in T-cells, which contributes to the immunosuppressive effects (Tiede et al., 2003). This pathway is critical in managing conditions such as inflammatory bowel disease, rheumatoid arthritis, and preventing organ transplant rejection, though its modulation requires careful monitoring of enzymes like TPMT and NUDT15 to avoid severe myelosuppression (PharmGKB, PA2040).

Other names

De novo purine synthesis pathwayThiopurine metabolic pathwayPhosphoribosylpyrophosphate amidotransferaseATase6-mercaptopurine target pathway

Inhibition of de novo purine synthesis via feedback inhibition of amidophosphoribosyltransferase and incorporation of thioguanine nucleotides into DNA/RNA, leading to cell cycle arrest and apoptosis (StatPearls, 2023). Additionally, 6-thio-GTP inhibits Rac1 activation, promoting T-cell apoptosis (Tiede et al., 2003).