Inosine-5-monophosphate dehydrogenase 2 (IMPDH2)

Inosine-5-monophosphate dehydrogenase 2 (IMPDH2) is the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis pathway, catalyzing the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) [1, 7]. This enzymatic activity is crucial for maintaining cellular pools of GTP and dGTP, which are required for DNA and RNA synthesis, signal transduction, and cell proliferation [1, 11]. Because activated lymphocytes rely almost exclusively on the de novo pathway rather than the salvage pathway for purine synthesis, IMPDH2 serves as a primary target for immunosuppressive drugs such as mycophenolate mofetil and mizoribine [1, 7]. These agents effectively suppress the expansion of T and B cells, making them essential for preventing organ transplant rejection and treating autoimmune diseases [1, 11]. Furthermore, IMPDH2 is frequently upregulated in various malignancies, including lung, colorectal, and kidney cancers, where it supports the high metabolic demands of tumor growth and is associated with poor prognosis and drug resistance [1, 4, 8]. Beyond its metabolic functions, IMPDH2 has been linked to neurodevelopmental disorders, with specific mutations identified as a cause of juvenile-onset dystonia [13]. Therapeutic targeting of IMPDH2 also shows promise in antiviral and antimicrobial contexts, as the enzyme is critical for the replication of certain viruses and bacterial pathogens [7, 9].

Other names

IMP dehydrogenase 2IMPD 2IMPDH 2Inosine-5'-monophosphate dehydrogenase type IIIMP dehydrogenase IIIMPDH-IIIMP oxireductase 2

IMPDH2 inhibitors act by binding to the enzyme and blocking the conversion of IMP to XMP, which is the rate-limiting step in de novo guanine nucleotide synthesis [1, 7]. This leads to a depletion of intracellular GTP and dGTP pools, resulting in the inhibition of DNA and RNA synthesis and the arrest of cell proliferation, particularly in lymphocytes and cancer cells [1, 5, 11].