IMPDH

Inosine-5'-monophosphate dehydrogenase (IMPDH) is a NAD+-dependent enzyme that catalyzes the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first committed step in de novo guanine nucleotide synthesis. The XMP product is then amidated by GMP synthetase to GMP, which provides guanine nucleotides including GTP essential for various cellular processes. This reaction links energy metabolism to the synthesis of guanine nucleotides and helps regulate cellular pools of GTP and dGTP, particularly in proliferating cells.

In humans, IMPDH exists mainly as two isoforms, IMPDH1 and IMPDH2, encoded by separate genes. IMPDH2 is widely expressed and upregulated in proliferating cells, while IMPDH1 is enriched in the retina and some neural tissues. Mutations in IMPDH1 have been associated with inherited retinal diseases, such as retinitis pigmentosa. The enzyme can form tetramers and, under certain cellular conditions, assemble into higher-order filamentous structures known as cytoophidia; this polymerization is influenced by nucleotide levels and may modulate activity.

IMPDH contains a catalytic core and regulatory CBS (cystathionine beta-synthase) domains that bind adenine nucleotides. Binding of ATP or GTP to these regulatory regions can affect enzyme activity and polymerization, linking nucleotide status to flux through the de novo pathway.

Pharmacologically, IMPDH is a target for immunosuppression and antiviral therapy. Mycophenolic acid (MPA) and related prodrugs inhibit IMPDH, suppressing lymphocyte proliferation and serving in organ transplantation management. Other inhibitors, including ribavirin and mizoribine, have antiviral activity partly through IMPDH inhibition. Inhibition can cause leukopenia and anemia, and therapeutic use requires careful management of side effects.