3bar
From Proteopedia
(New page: 200px<br /><applet load="3bar" size="350" color="white" frame="true" align="right" spinBox="true" caption="3bar, resolution 1.90Å" /> '''Crystal structure of...) |
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==Overview== | ==Overview== | ||
| - | Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug | + | Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities. |
==About this Structure== | ==About this Structure== | ||
| - | 3BAR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=U5P:'>U5P</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] Known structural/functional Sites: <scene name='pdbsite=AC1:U5p Binding Site For Residue A 3000'>AC1</scene> and <scene name='pdbsite=AC2:U5p Binding Site For Residue B 3000'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BAR OCA]. | + | 3BAR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=U5P:'>U5P</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] Known structural/functional Sites: <scene name='pdbsite=AC1:U5p+Binding+Site+For+Residue+A+3000'>AC1</scene> and <scene name='pdbsite=AC2:U5p+Binding+Site+For+Residue+B+3000'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BAR OCA]. |
==Reference== | ==Reference== | ||
| - | Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Jan 12 | + | Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Feb 14;51(3):439-448. Epub 2008 Jan 12. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18189347 18189347] |
[[Category: Orotidine-5'-phosphate decarboxylase]] | [[Category: Orotidine-5'-phosphate decarboxylase]] | ||
[[Category: Plasmodium falciparum]] | [[Category: Plasmodium falciparum]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bello, A | + | [[Category: Bello, A M.]] |
| - | [[Category: Kotra, L | + | [[Category: Kotra, L P.]] |
[[Category: Lau, W.]] | [[Category: Lau, W.]] | ||
[[Category: Liu, Y.]] | [[Category: Liu, Y.]] | ||
| - | [[Category: Pai, E | + | [[Category: Pai, E F.]] |
[[Category: Poduch, E.]] | [[Category: Poduch, E.]] | ||
[[Category: U5P]] | [[Category: U5P]] | ||
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[[Category: pyrimidine biosynthesis]] | [[Category: pyrimidine biosynthesis]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:04:37 2008'' |
Revision as of 17:04, 21 February 2008
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Crystal structure of Plasmodium falciparum orotidine 5'-phosphate decarboxylase covalently modified by 6-azido-UMP
Overview
Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.
About this Structure
3BAR is a Single protein structure of sequence from Plasmodium falciparum with as ligand. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Known structural/functional Sites: and . Full crystallographic information is available from OCA.
Reference
Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Feb 14;51(3):439-448. Epub 2008 Jan 12. PMID:18189347
Page seeded by OCA on Thu Feb 21 19:04:37 2008
