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.
Hedstrom
L
L
MS 009, Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA.
D000818:Animals; D015748:Borrelia burgdorferi Group / Q000201:enzymology; D002176:Candida albicans / Q000201:enzymology; D006224:Cricetinae; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000031:analogs & derivatives; D007700:Kinetics; D016296:Mutagenesis; D011010:Pneumocystis / Q000201:enzymology; D013297:Streptococcus pyogenes / Q000201:enzymology; D016835:Tritrichomonas foetus / Q000201:enzymology
D007291:Inosine Monophosphate; D007168:IMP Dehydrogenase