1me8: Difference between revisions

Revision as of 14:54, 21 February 2008

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 , and 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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-[[Image:1me8.jpg|left|200px]]<br /><applet load="1me8" size="450" color="white" frame="true" align="right" spinBox="true"
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 '''Inosine Monophosphate Dehydrogenase (IMPDH) From Tritrichomonas Foetus with RVP bound'''<br />
 ==Overview==
-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.
+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 Structure==
-ME8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Tritrichomonas_foetus Tritrichomonas foetus] with K, NA and RVP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ME8 OCA].
+ME8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Tritrichomonas_foetus Tritrichomonas foetus] with <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=RVP:'>RVP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ME8 OCA].
 ==Reference==
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 [[Category: Tritrichomonas foetus]]
 [[Category: Luecke, H.]]
-[[Category: Prosise, G.L.]]
+[[Category: Prosise, G L.]]
 [[Category: Wu, J.]]
 [[Category: K]]
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 [[Category: alpha beta barrel]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 21:21:52 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:54:26 2008''