Inosine monophosphate metabolizing enzymes (IMPDH/ADSS/ADSL)

The enzymes mediating the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP) and xanthosine monophosphate (XMP) represent the critical regulatory branch point in de novo purine biosynthesis. This group primarily includes inosine-5'-monophosphate dehydrogenase (IMPDH), which catalyzes the rate-limiting step toward guanine nucleotides, and the sequential enzymes adenylosuccinate synthetase (ADSS) and adenylosuccinate lyase (ADSL), which facilitate the production of adenine nucleotides (UniProt P12268, P30520). These enzymes are vital for maintaining the intracellular nucleotide pools necessary for DNA replication, RNA synthesis, and cellular signaling. Because rapidly dividing cells, such as activated lymphocytes and many cancer cells, are heavily dependent on de novo synthesis rather than the salvage pathway, these enzymes are significant therapeutic targets (PubMed: 19119950). Inhibitors like mycophenolate mofetil and ribavirin target IMPDH to provide immunosuppression in organ transplantation and treat viral infections, respectively (PubChem CID 5281071). Furthermore, targeting ADSS with agents like L-alanosine has been investigated for its potential to disrupt adenine nucleotide balance in oncology.

Other names

IMP-metabolizing enzymesPurine biosynthetic branch point enzymesIMPDH/ADSS/ADSL complex

Inhibition of de novo purine nucleotide biosynthesis by targeting enzymes at the IMP branch point, specifically IMPDH for guanine nucleotides and ADSS/ADSL for adenine nucleotides, resulting in the depletion of intracellular GTP and ATP pools and subsequent inhibition of DNA and RNA synthesis.