3mo7: Difference between revisions
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==Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP== | |||
<StructureSection load='3mo7' size='340' side='right' caption='[[3mo7]], [[Resolution|resolution]] 1.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mo7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MO7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MO7 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=UFT:2-DEOXY-2-FLUOROURIDINE+5-(DIHYDROGEN+PHOSPHATE)'>UFT</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2eaw|2eaw]], [[2p1f|2p1f]], [[3bgg|3bgg]], [[3bgj|3bgj]], [[3g3d|3g3d]], [[3bko|3bko]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gi|13960142, OK/SW-cl.21, UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3mo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mo7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mo7 RCSB], [http://www.ebi.ac.uk/pdbsum/3mo7 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/PYR5_HUMAN PYR5_HUMAN]] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[http://omim.org/entry/258900 258900]]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.<ref>PMID:9042911</ref> | |||
== Function == | |||
== | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | |||
Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 +/- 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations. | |||
Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5'-Monophosphate Decarboxylase.,Lewis M, Meza-Avina ME, Wei L, Crandall IE, Bello AM, Poduch E, Liu Y, Paige CJ, Kain KC, Pai EF, Kotra LP J Med Chem. 2011 Mar 21. PMID:21417464<ref>PMID:21417464</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Phosphoribosyltransferase|Phosphoribosyltransferase]] | *[[Phosphoribosyltransferase|Phosphoribosyltransferase]] | ||
*[[Uridine 5'-monophosphate synthase|Uridine 5'-monophosphate synthase]] | *[[Uridine 5'-monophosphate synthase|Uridine 5'-monophosphate synthase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Orotidine-5'-phosphate decarboxylase]] | [[Category: Orotidine-5'-phosphate decarboxylase]] | ||
[[Category: Kotra, L P | [[Category: Kotra, L P]] | ||
[[Category: Liu, Y | [[Category: Liu, Y]] | ||
[[Category: Pai, E F | [[Category: Pai, E F]] | ||
[[Category: 2'-fluoro-6-iodo-ump]] | [[Category: 2'-fluoro-6-iodo-ump]] | ||
[[Category: Lyase]] | [[Category: Lyase]] | ||
[[Category: Orotidine 5'-monophosphate decarboxylase]] | [[Category: Orotidine 5'-monophosphate decarboxylase]] | ||
[[Category: Ump synthase]] | [[Category: Ump synthase]] | ||
Revision as of 18:19, 18 December 2014
Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMPCrystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP
Structural highlights
Disease[PYR5_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:258900]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.[1] FunctionPublication Abstract from PubMedFluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 +/- 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations. Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5'-Monophosphate Decarboxylase.,Lewis M, Meza-Avina ME, Wei L, Crandall IE, Bello AM, Poduch E, Liu Y, Paige CJ, Kain KC, Pai EF, Kotra LP J Med Chem. 2011 Mar 21. PMID:21417464[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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