Inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) (IMPDH2)

Inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) is the rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, catalyzing the NAD-dependent oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) [1, 7]. While the Type I isoform is constitutively expressed at low levels, IMPDH2 is significantly upregulated in proliferating cells, including activated T and B lymphocytes and various malignant cells [10, 14]. This differential expression makes IMPDH2 a critical therapeutic target for immunosuppression in organ transplantation and autoimmune diseases, as well as a potential target for anti-cancer and anti-viral therapies [12, 17]. Drugs such as mycophenolic acid and ribavirin inhibit IMPDH2 to deplete intracellular GTP and dGTP pools, which leads to cell cycle arrest in the G1/S phase and the induction of apoptosis [1, 15]. Beyond its metabolic role, IMPDH2 is involved in ribosomal stress responses and the regulation of nucleolar activity, with its overexpression often serving as a biomarker for poor prognosis in cancers like glioblastoma and prostate cancer [16, 18]. Therapeutic challenges associated with IMPDH2 inhibition include gastrointestinal toxicity and myelosuppression, necessitating careful monitoring of patient response [1, 17]. Genetic variants in IMPDH2 have also been linked to neurodevelopmental disorders such as dystonia, highlighting its importance in neurological health [5, 6].

Other names

IMPDH type IIIMP dehydrogenase 2IMPDH 2IMPDH-IIInosine-5'-monophosphate dehydrogenase type IIIMPDH2

Inhibition of IMPDH2 leads to the depletion of intracellular guanine nucleotide pools (GTP and dGTP), which subsequently inhibits DNA and RNA synthesis, induces cell cycle arrest, and suppresses the proliferation of rapidly dividing cells such as activated lymphocytes and tumor cells.