Inosine-5'-monophosphate dehydrogenase (IMPDH) and other purine synthesis enzymes (IMPDH)

Inosine-5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides, catalyzing the NAD+-dependent oxidation of IMP to XMP (PubMed: 10858544). This pathway is essential for providing the precursors required for DNA and RNA synthesis, particularly in rapidly proliferating cells such as activated T and B lymphocytes, which lack a robust salvage pathway (PubMed: 15743404). Other enzymes in the purine synthesis pathway, such as amidophosphoribosyltransferase and adenylosuccinate synthetase, also serve as critical checkpoints for nucleotide homeostasis (StatPearls: Biochemistry, Purine Synthesis). Pharmacological inhibition of these enzymes, most notably IMPDH by drugs like mycophenolate mofetil and ribavirin, results in the depletion of intracellular GTP pools (PubChem: CID 5281071). This depletion leads to the arrest of the cell cycle and suppression of the immune response, making these enzymes vital targets for immunosuppression in organ transplantation and autoimmune disorders, as well as for antiviral and anticancer therapies (PubMed: 11322731). The therapeutic utility of targeting this pathway is balanced by safety concerns such as myelosuppression and gastrointestinal toxicity due to the systemic requirement for nucleotide production (NIH: LiverTox).

Other names

IMPDHIMP oxidoreductasePurine biosynthetic enzymesDe novo purine synthesis pathway enzymes

Inhibition of de novo purine nucleotide biosynthesis, primarily through the non-competitive or uncompetitive inhibition of IMPDH, which depletes intracellular guanosine nucleotide pools and halts DNA/RNA synthesis.