Purine synthesis enzymes and GTP-binding protein Rac1

This target profile describes the dual molecular mechanism of thiopurine drugs, which act by disrupting both metabolic and signaling pathways in leukocytes. The Purine synthesis enzymes component refers to key catalysts in the de novo purine nucleotide biosynthetic pathway, such as amidophosphoribosyltransferase and inosine-5-monophosphate dehydrogenase (IMPDH), which are inhibited by thiopurine metabolites to starve rapidly dividing cells of necessary DNA precursors (Sahara et al., 2012, PMID: 23214306). The GTP-binding protein Rac1 (Ras-related C3 botulinum toxin substrate 1) is a small GTPase essential for T-cell activation, cytoskeletal reorganization, and survival signaling (UniProt P63000). Thiopurines are converted into 6-thioguanosine triphosphate (6-TGP), which binds to Rac1 in place of GTP, preventing its activation by the guanine nucleotide exchange factor Vav1 and subsequently inducing apoptosis in activated T-lymphocytes (Tiede et al., 2003, PMID: 12697743). This synergistic effect on metabolism and signal transduction makes these targets central to the treatment of autoimmune conditions like Crohn disease and various hematologic malignancies.

Other names

Thiopurine targetsIMPDH and Rac16-mercaptopurine targetsInosine-5-monophosphate dehydrogenase and Ras-related C3 botulinum toxin substrate 1

Inhibition of de novo purine synthesis and blockade of Rac1 activation