Inosine-5'-monophosphate dehydrogenase 1 & 2 (IMPDH1 & IMPDH2)

Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1) and Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) are two distinct but highly homologous oxidoreductase enzymes that catalyze the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP). This reaction represents the first committed and rate-limiting step in the de novo biosynthesis of guanine nucleotides. As key regulators of intracellular guanine nucleotide pools, both isoforms are crucial for DNA and RNA synthesis, cellular proliferation, and signal transduction. While their mechanisms and inhibitors largely overlap, their differential tissue expression and regulation contribute to distinct physiological roles and disease associations. IMPDH1 is strongly expressed in tissues with high demands for guanine nucleotides, such as the retina, where specific splice variants are essential for vision, and mutations in IMPDH1 are a known cause of inherited retinal degenerations. IMPDH2, on the other hand, plays a central role in rapidly proliferating cells like tumor cells and activated lymphocytes, and is frequently upregulated in neoplastic and immune tissues. Both IMPDH1 and IMPDH2 are established pharmacological targets in various therapeutic areas, including cancer, immunosuppression, and antiviral therapy. Inhibition of either isoform leads to guanine nucleotide depletion, suppression of DNA and RNA synthesis, and impaired cell growth and proliferation. Their differential tissue expression and regulation underlie both the efficacy and adverse effects of drugs that target them.

Other names

IMPDH1IMPDH2IMP dehydrogenase 1IMP dehydrogenase 2inosine monophosphate dehydrogenase 1inosine monophosphate dehydrogenase 2

Competitive inhibition at the enzyme active site, leading to depletion of guanine nucleotides and inhibition of cell proliferation, particularly in lymphocytes and cancer cells.