Inosine-5'-monophosphate dehydrogenase and Adenylosuccinate synthetase (IMPDH/ADSS)

The enzymes responsible for converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) and adenosine monophosphate (AMP) represent the critical branch point in de novo purine biosynthesis. Inosine-5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the synthesis of guanine nucleotides by converting IMP to XMP, while adenylosuccinate synthetase (ADSS) initiates the conversion of IMP toward adenine nucleotides. These enzymes are essential for maintaining the balanced pools of purine nucleotides required for DNA and RNA synthesis, signal transduction, and energy metabolism. Because rapidly proliferating cells, such as activated T and B lymphocytes and cancer cells, are highly dependent on de novo synthesis rather than the salvage pathway, these enzymes are major therapeutic targets. IMPDH, in particular, is the primary target for immunosuppressive drugs like mycophenolate mofetil, which is used to prevent organ transplant rejection and treat autoimmune disorders. Additionally, inhibitors of this pathway are utilized as antiviral and antineoplastic agents to disrupt nucleic acid production in pathogens and malignant cells (StatPearls: NBK554562; PubMed: 10510756).

Other names

IMP-metabolizing enzymesPurine biosynthetic branch point enzymesInosine-5'-monophosphate dehydrogenase (IMPDH)Adenylosuccinate synthetase (ADSS)IMP to XMP/AMP pathway enzymes

Inhibition of IMPDH leads to depletion of intracellular guanine nucleotide pools (GTP/dGTP), which selectively inhibits T and B lymphocyte proliferation as these cells rely heavily on the de novo purine synthesis pathway rather than the salvage pathway (PubMed: 15669577). Inhibition of ADSS/ADSL prevents the formation of adenine nucleotides, though this is less commonly targeted by primary therapeutic agents compared to the IMP-to-XMP branch (UniProt: P30520).