Crystal structures of Tritrichomonasfoetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism.
The enzyme inosine monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide biosynthesis. Because it is up-regulated in rapidly proliferating cells, human type II IMPDH is actively targeted for immunosuppressive, anticancer, and antiviral chemotherapy. The enzyme employs a random-in ordered-out kinetic mechanism where substrate or cofactor can bind first but product is only released after the cofactor leaves. Due to structural and kinetic differences between mammalian and microbial enzymes, most drugs that are successful in the inhibition of mammalian IMPDH are far less effective against the microbial forms of the enzyme. It is possible that with greater knowledge of the structural mechanism of the microbial enzymes, an effective and selective inhibitor of microbial IMPDH will be developed for use as a drug against multi-drug resistant bacteria and protists. The high-resolution crystal structures of four different complexes of IMPDH from the protozoan parasite Tritrichomonas foetus have been solved: with its substrate IMP, IMP and the inhibitor mycophenolic acid (MPA), the product XMP with MPA, and XMP with the cofactor NAD(+). In addition, a potassium ion has been located at the dimer interface. A structural model for the kinetic mechanism is proposed.
Prosise
Glen L
GL
Department of Molecular Biology and Biochemistry University of California, Irvine, CA 92697-3900 USA.
Luecke
Hartmut
H
D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D007291:Inosine Monophosphate / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D009173:Mycophenolic Acid / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D011487:Protein Conformation; D012254:Ribavirin / Q000737:chemistry / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D016835:Tritrichomonas foetus / Q000201:enzymology*; D019820:Xanthine
D004791:Enzyme Inhibitors; D012265:Ribonucleotides; D009243:NAD; D007291:Inosine Monophosphate; D019820:Xanthine; D012254:Ribavirin; C011141:xanthosine monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid