IMP dehydrogenase : structural aspects of inhibitor binding.
Inosine monophosphate dehydrogenase (IMPDH, E.C. 1.1.1.205) is recognized as an important target for both antileukemic and immunosuppressive therapy. IMPDH catalyzes the NAD-dependent oxidation of inosine 5 monophosphate (IMP) to xanthosine 5 monophosphate. Several classes of IMPDH inhibitors are now in use or under development. These include agents that bind at either the substrate site (e.g. ribavirin and mizoribine) or at the NAD site (mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide). All suffer from some degree of toxicity and/or susceptibility to metabolic inactivation. The finding that IMPDH exists as two isoforms, one of which (type II) is induced in tumor cells, has led to the search for potentially more effective isoform-specific agents. Recently, a number of crystal structures of IMPDH have become available. These include structures of the human type II, hamster, Tritrichomonas foetus, Streptococcus pyogenes and Borrelia burgdorferi enzymes. Each structure crystallizes as a tetramer of a/b barrels, with the active site located partly at the monomer-monomer interface. The substrate and cofactor bind in a continuous cleft on the C-terminal face of each barrel. The IMP base is well positioned to stack against the NAD nicotinamide ring to facilitate hydride transfer. The active site cleft is further bounded by a highly flexible flap and loop. These structures reveal enzyme-ligand interactions which suggest strategies for the design of improved inhibitors.
Goldstein
B M
BM
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, 14642, USA. barry_goldstein@urmc.rochester.edu
Colby
T D
TD
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D015748:Borrelia burgdorferi Group / Q000201:enzymology; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013297:Streptococcus pyogenes / Q000201:enzymology; D016835:Tritrichomonas foetus / Q000201:enzymology
D000596:Amino Acids; D007168:IMP Dehydrogenase