A potent "fat base" nucleotide inhibitor of IMP dehydrogenase.
Inosine monophosphate dehydrogenase (IMPDH) is a target for anticancer, antiviral, immunosuppressive, and antimicrobial chemotherapy. Thus, IMPDH inhibitors have great potential as chemotherapeutic agents. Here we show that imidazo[4,5-e][1, 4]diazapine nucleotide (I) is a potent inhibitor of both human type II and Escherichia coli IMPDH. I is a slow-binding inhibitor. The values of Kd are 1.4 nM and 53 nM for human and E. coli IMPDH, respectively. Inhibition is reversible, as demonstrated by the recovery of activity upon denaturation and renaturation of the enzyme.I complex. I is not a substrate for IMPDH. I may form a covalent adduct with the active-site Cys of IMPDH. Such an adduct would serve as an analogue for an intermediate in the IMPDH reaction.
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA.
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Hedstrom
D001381:Azepines / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D006148:Guanine Deaminase / Q000037:antagonists & inhibitors; D006150:Guanine Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics
D001381:Azepines; D004791:Enzyme Inhibitors; D006150:Guanine Nucleotides; D007093:Imidazoles; C054358:azepinomycin; D007168:IMP Dehydrogenase; D006148:Guanine Deaminase