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| | <StructureSection load='3g4c' size='340' side='right'caption='[[3g4c]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='3g4c' size='340' side='right'caption='[[3g4c]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3g4c]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Atcc_43589 Atcc 43589]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3G4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G4C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3g4c]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Thermotoga_maritima Thermotoga maritima]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3G4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G4C FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">thy1, thyX, TM_0449 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=2336 ATCC 43589])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thymidylate_synthase_(FAD) Thymidylate synthase (FAD)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.148 2.1.1.148] </span></td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3g4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g4c OCA], [https://pdbe.org/3g4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g4c RCSB], [https://www.ebi.ac.uk/pdbsum/3g4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g4c ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3g4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g4c OCA], [https://pdbe.org/3g4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g4c RCSB], [https://www.ebi.ac.uk/pdbsum/3g4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g4c ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/THYX_THEMA THYX_THEMA]] Catalyzes the formation of dTMP and tetrahydrofolate from dUMP and methylenetetrahydrofolate.
| + | [https://www.uniprot.org/uniprot/THYX_THEMA THYX_THEMA] Catalyzes the formation of dTMP and tetrahydrofolate from dUMP and methylenetetrahydrofolate. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc 43589]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kohen, A]] | + | [[Category: Thermotoga maritima]] |
| - | [[Category: Lesley, S A]] | + | [[Category: Kohen A]] |
| - | [[Category: Mathews, I I]] | + | [[Category: Lesley SA]] |
| - | [[Category: Dump complex]] | + | [[Category: Mathews II]] |
| - | [[Category: Fad]]
| + | |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Ftd]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: Nucleotide biosynthesis]]
| + | |
| - | [[Category: S88c mutation]]
| + | |
| - | [[Category: Thyx]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
THYX_THEMA Catalyzes the formation of dTMP and tetrahydrofolate from dUMP and methylenetetrahydrofolate.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Biosynthesis of the DNA base thymine depends on activity of the enzyme thymidylate synthase to catalyse the methylation of the uracil moiety of 2'-deoxyuridine-5'-monophosphate. All known thymidylate synthases rely on an active site residue of the enzyme to activate 2'-deoxyuridine-5'-monophosphate. This functionality has been demonstrated for classical thymidylate synthases, including human thymidylate synthase, and is instrumental in mechanism-based inhibition of these enzymes. Here we report an example of thymidylate biosynthesis that occurs without an enzymatic nucleophile. This unusual biosynthetic pathway occurs in organisms containing the thyX gene, which codes for a flavin-dependent thymidylate synthase (FDTS), and is present in several human pathogens. Our findings indicate that the putative active site nucleophile is not required for FDTS catalysis, and no alternative nucleophilic residues capable of serving this function can be identified. Instead, our findings suggest that a hydride equivalent (that is, a proton and two electrons) is transferred from the reduced flavin cofactor directly to the uracil ring, followed by an isomerization of the intermediate to form the product, 2'-deoxythymidine-5'-monophosphate. These observations indicate a very different chemical cascade than that of classical thymidylate synthases or any other known biological methylation. The findings and chemical mechanism proposed here, together with available structural data, suggest that selective inhibition of FDTSs, with little effect on human thymine biosynthesis, should be feasible. Because several human pathogens depend on FDTS for DNA biosynthesis, its unique mechanism makes it an attractive target for antibiotic drugs.
An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene.,Koehn EM, Fleischmann T, Conrad JA, Palfey BA, Lesley SA, Mathews II, Kohen A Nature. 2009 Apr 16;458(7240):919-23. PMID:19370033[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Koehn EM, Fleischmann T, Conrad JA, Palfey BA, Lesley SA, Mathews II, Kohen A. An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene. Nature. 2009 Apr 16;458(7240):919-23. PMID:19370033 doi:10.1038/nature07973
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