IMP dehydrogenase: mechanism of action and inhibition

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to XMP with the concomitant reduction of NAD to NADH. This reaction is the rate-limiting step in guanine nucleotide biosynthesis. IMPDH is a proven target for immunosuppressive, anticancer and antiviral chemotherapy, and may also be a target for antimicrobial agents. IMPDH is activated by monovalent cations, and one monovalent cation binding site appears to have been identified. The mechanism of IMPDH involves formation and hydrolysis of a covalent enzyme intermediate (E-XMP*) in a reaction reminiscent of glyceraldehyde-3-phosphate dehydrogenase. Substrates bind to IMPDH in a random order, hydride transfer is fast and NADH release precedes hydrolysis of E-XMP*. The hydrolysis of E-XMP* is at least partially rate-limiting. Two inhibitors, mizoribine-monophosphate and a fat base nucleotide appear to act as transition state analogs. In contrast, MPA inhibits by sequestering E-XMP.