Inosine-5'-monophosphate dehydrogenase 1 and 2 (IMPDH1/2)

Inosine-5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, catalyzing the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) [12, 13]. It exists in two isoforms, IMPDH1 and IMPDH2, which share approximately 84% sequence identity but exhibit distinct expression profiles; IMPDH1 is constitutively expressed at low levels, while IMPDH2 is upregulated in proliferating and neoplastic cells [3, 4]. Because rapidly dividing cells like lymphocytes and cancer cells rely heavily on de novo purine synthesis, IMPDH is a critical therapeutic target for immunosuppression and oncology [1, 8]. Drugs such as mycophenolate mofetil and ribavirin inhibit these enzymes to deplete intracellular GTP pools, thereby impairing DNA/RNA synthesis and cell signaling [2, 5]. Beyond its metabolic role, mutations in IMPDH1 are linked to retinal degeneration, and IMPDH2 dysregulation is associated with various malignancies and neurodevelopmental disorders [4, 6]. Therapeutic challenges include managing side effects like gastrointestinal toxicity and myelosuppression, which result from systemic nucleotide depletion [1, 9].

Other names

IMPDHIMP dehydrogenaseInosine-5'-monophosphate dehydrogenase type IInosine-5'-monophosphate dehydrogenase type IIIMPD1IMPD2IMP oxireductase

Uncompetitive inhibition of the E-XMP* intermediate, competitive inhibition with IMP, non-competitive inhibition, and covalent allosteric inhibition [1, 5, 9, 12].