1me8
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Inosine Monophosphate Dehydrogenase (IMPDH) From Tritrichomonas Foetus with RVP bound
OverviewOverview
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting, step in GMP biosynthesis. The resulting intracellular pool of guanine, nucleotides is of great importance to all cells for use in DNA and RNA, synthesis, metabolism, and signal transduction. The enzyme binds IMP and, the cofactor NAD(+) in random order, IMP is converted to XMP, NAD(+) is, reduced to NADH, and finally, NADH and then XMP are released sequentially., XMP is subsequently converted into GMP by GMP synthetase. Drugs that, decrease GMP synthesis by inhibiting IMPDH have been shown to have, antiproliferative as well as antiviral activity. Several drugs are in use, that target the substrate- or cofactor-binding site; however, due to, differences between the mammalian and microbial isoforms, most drugs are, far less effective against the microbial form of the enzyme than the, mammalian form. The high resolution crystal structures of the protozoan, parasite Tritrichomonas foetus IMPDH complexed with the inhibitor, ribavirin monophosphate as well as monophosphate together with a second, inhibitor, mycophenolic acid, are presented here. These structures reveal, an active site cation identified previously only in the Chinese hamster, IMPDH structure with covalently bound IMP. This cation was not found, previously in apo IMPDH, IMPDH in complex with XMP, or covalently bound, inhibitor, indicating that the cation-binding site may be, catalysis-dependent. A comparison of T. foetus IMPDH with the Chinese, hamster and Streptococcus pyogenes structures reveals differences in the, active site loop architecture, which contributes to differences in cation, binding during the catalytic sequence and the kinetic rates between, bacterial, protozoan, and mammalian enzymes. Exploitation of these, differences may lead to novel inhibitors, which favor the microbial form, of the enzyme.
About this StructureAbout this Structure
1ME8 is a Single protein structure of sequence from Tritrichomonas foetus with K, NA and RVP as ligands. Active as IMP dehydrogenase, with EC number 1.1.1.205 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site., Prosise GL, Wu JZ, Luecke H, J Biol Chem. 2002 Dec 27;277(52):50654-9. Epub 2002 Sep 13. PMID:12235158
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