Purine synthesis enzymes and nucleic acids

This target group comprises the enzymes involved in the de novo and salvage pathways of purine biosynthesis, as well as the nucleic acids (DNA and RNA) that serve as substrates for antimetabolite incorporation. Purine antimetabolites, such as 6-mercaptopurine and azathioprine, act as structural analogs of endogenous purines like adenine and guanine [1]. These drugs are typically prodrugs that undergo complex intracellular conversion into active thioguanine nucleotides [2]. Once activated, they inhibit rate-limiting enzymes such as amidophosphoribosyltransferase and inosine monophosphate dehydrogenase (IMPDH), thereby depleting the cellular nucleotide pool [3]. Additionally, the incorporation of these fraudulent nucleotides into DNA and RNA leads to strand breaks, inhibition of polymerases, and the induction of apoptosis [4]. This multi-targeted approach is highly effective in treating rapidly dividing cells, making it a cornerstone in the therapy of leukemias, lymphomas, and various autoimmune conditions [5]. However, the clinical utility is often limited by toxicities such as myelosuppression and hepatotoxicity [6]. The safety profile is heavily influenced by genetic polymorphisms in metabolizing enzymes like thiopurine S-methyltransferase (TPMT) and NUDT15 [7].

Other names

Purine antimetabolite targetsPurine biosynthetic pathwayPurine salvage pathwayThiopurine targets

Inhibition of de novo purine synthesis enzymes (e.g., IMPDH, PPAT) and the incorporation of fraudulent purine analogs into DNA and RNA, leading to chain termination and cell death.