Inosine-5′-monophosphate dehydrogenase 2 (IMPDH2)

Inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, catalyzing the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) [UniProt: P12268; Hedstrom, L. (2009) Chem Rev]. While two isoforms exist, Type II is specifically upregulated in activated T and B lymphocytes and many cancer cells, whereas Type I is constitutively expressed in most tissues [Allison, A. C., & Eugui, E. M. (2000) Immunopharmacology; Natsumeda, Y., et al. (1990) J Biol Chem]. This differential expression makes IMPDH2 a critical therapeutic target for immunosuppression and oncology, as rapidly dividing cells rely heavily on the de novo pathway rather than the salvage pathway for purine synthesis [StatPearls: Mycophenolate]. Inhibition of IMPDH2 by drugs such as mycophenolic acid leads to the depletion of intracellular GTP and dGTP pools, resulting in cell cycle arrest in the S phase and inhibition of DNA synthesis [Hedstrom, L. (2009) Chem Rev]. Consequently, IMPDH2 inhibitors are widely utilized to prevent organ transplant rejection and treat various autoimmune diseases and malignancies [StatPearls: Mycophenolate; Allison, A. C., & Eugui, E. M. (2000) Immunopharmacology].

Other names

IMPDH IIIMPD2Inosine-5'-monophosphate dehydrogenase type 2IMP dehydrogenase 2Inosine-5′-monophosphate dehydrogenase, type II > type I

Reversible or irreversible inhibition of the enzyme's catalytic site, leading to depletion of intracellular guanosine triphosphate (GTP) and deoxyguanosine triphosphate (dGTP) pools [Hedstrom, L. (2009) Chem Rev; Allison, A. C., & Eugui, E. M. (2000) Immunopharmacology].