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[[Image:3mo7.png|left|200px]]


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==Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP==
The line below this paragraph, containing "STRUCTURE_3mo7", creates the "Structure Box" on the page.
<StructureSection load='3mo7' size='340' side='right'caption='[[3mo7]], [[Resolution|resolution]] 1.35&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[3mo7]] is a 1 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=3MO7 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.35&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=UFT:2-DEOXY-2-FLUOROURIDINE+5-(DIHYDROGEN+PHOSPHATE)'>UFT</scene></td></tr>
{{STRUCTURE_3mo7|  PDB=3mo7  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mo7 OCA], [https://pdbe.org/3mo7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mo7 RCSB], [https://www.ebi.ac.uk/pdbsum/3mo7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mo7 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[https://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 ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN]
<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.


===Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP===
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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3mo7" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_21417464}}, adds the Publication Abstract to the page
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 21417464 is the PubMed ID number.
*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
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== References ==
{{ABSTRACT_PUBMED_21417464}}
<references/>
 
__TOC__
==About this Structure==
</StructureSection>
[[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].
 
==Reference==
<ref group="xtra">PMID:021417464</ref><references group="xtra"/>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Orotidine-5'-phosphate decarboxylase]]
[[Category: Large Structures]]
[[Category: Kotra, L P.]]
[[Category: Kotra LP]]
[[Category: Liu, Y.]]
[[Category: Liu Y]]
[[Category: Pai, E F.]]
[[Category: Pai EF]]

Latest revision as of 11:57, 6 September 2023

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

3mo7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.35Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UMPS_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]

Function

UMPS_HUMAN

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[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Suchi M, Mizuno H, Kawai Y, Tsuboi T, Sumi S, Okajima K, Hodgson ME, Ogawa H, Wada Y. Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am J Hum Genet. 1997 Mar;60(3):525-39. PMID:9042911
  2. ↑ Lewis M, Meza-Avina ME, Wei L, Crandall IE, Bello AM, Poduch E, Liu Y, Paige CJ, Kain KC, Pai EF, Kotra LP. Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5'-Monophosphate Decarboxylase. J Med Chem. 2011 Mar 21. PMID:21417464 doi:10.1021/jm101642g

3mo7, resolution 1.35Å

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