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| | ==Binding and structural studies of a 5,5-difluoromethyl adenosine nucleoside with the fluorinase enzyme== | | ==Binding and structural studies of a 5,5-difluoromethyl adenosine nucleoside with the fluorinase enzyme== |
| - | <StructureSection load='5fiu' size='340' side='right' caption='[[5fiu]], [[Resolution|resolution]] 1.84Å' scene=''> | + | <StructureSection load='5fiu' size='340' side='right'caption='[[5fiu]], [[Resolution|resolution]] 1.84Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fiu]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FIU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FIU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fiu]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_cattleya Streptomyces cattleya]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FIU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FIU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene>, <scene name='pdbligand=Y3J:5,5-DIFLUOROMETHYL+ADENOSINE'>Y3J</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]] 1.84Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosyl-fluoride_synthase Adenosyl-fluoride synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.63 2.5.1.63] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene>, <scene name='pdbligand=Y3J:5,5-DIFLUOROMETHYL+ADENOSINE'>Y3J</scene></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=5fiu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fiu OCA], [http://pdbe.org/5fiu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fiu RCSB], [http://www.ebi.ac.uk/pdbsum/5fiu PDBsum]</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=5fiu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fiu OCA], [https://pdbe.org/5fiu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fiu RCSB], [https://www.ebi.ac.uk/pdbsum/5fiu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fiu ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FLA_STRCT FLA_STRCT]] Involved in the biosynthesis of fluorometabolites. Catalyzes the formation of a C-F bond by combining S-adenosyl-L-methionine (SAM) and fluoride to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA) and L-methionine. It can also use 2'-deoxyadenosine in place of adenosine as substrate.<ref>PMID:12860396</ref> <ref>PMID:14765200</ref> <ref>PMID:16370017</ref> <ref>PMID:16604208</ref> <ref>PMID:16720268</ref> <ref>PMID:17985882</ref> | + | [https://www.uniprot.org/uniprot/FLA_STRCT FLA_STRCT] Involved in the biosynthesis of fluorometabolites. Catalyzes the formation of a C-F bond by combining S-adenosyl-L-methionine (SAM) and fluoride to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA) and L-methionine. It can also use 2'-deoxyadenosine in place of adenosine as substrate.<ref>PMID:12860396</ref> <ref>PMID:14765200</ref> <ref>PMID:16370017</ref> <ref>PMID:16604208</ref> <ref>PMID:16720268</ref> <ref>PMID:17985882</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenosyl-fluoride synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Hagan, D O]] | + | [[Category: Streptomyces cattleya]] |
| - | [[Category: McMahon, S A]] | + | [[Category: McMahon SA]] |
| - | [[Category: Naismith, J H]] | + | [[Category: Naismith JH]] |
| - | [[Category: Thompson, S]] | + | [[Category: O'Hagan D]] |
| - | [[Category: Difluoromethyl]] | + | [[Category: Thompson S]] |
| - | [[Category: Fluorinase]]
| + | |
| - | [[Category: Isothermal titration calorimetry]]
| + | |
| - | [[Category: Transferase]]
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| Structural highlights
Function
FLA_STRCT Involved in the biosynthesis of fluorometabolites. Catalyzes the formation of a C-F bond by combining S-adenosyl-L-methionine (SAM) and fluoride to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA) and L-methionine. It can also use 2'-deoxyadenosine in place of adenosine as substrate.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F2DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F2DA7 was found, however, not to undergo the enzyme catalysed reaction with l-selenomethionine, unlike FDA 2, which undergoes reaction with l-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F2DA7 and tartrate was solved to 1.8A, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.
Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme.,Thompson S, McMahon SA, Naismith JH, O'Hagan D Bioorg Chem. 2015 Nov 18;64:37-41. doi: 10.1016/j.bioorg.2015.11.003. PMID:26642178[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schaffrath C, Deng H, O'Hagan D. Isolation and characterisation of 5'-fluorodeoxyadenosine synthase, a fluorination enzyme from Streptomyces cattleya. FEBS Lett. 2003 Jul 17;547(1-3):111-4. PMID:12860396
- ↑ Dong C, Huang F, Deng H, Schaffrath C, Spencer JB, O'Hagan D, Naismith JH. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature. 2004 Feb 5;427(6974):561-5. PMID:14765200 doi:http://dx.doi.org/10.1038/nature02280
- ↑ Deng H, Cobb SL, McEwan AR, McGlinchey RP, Naismith JH, O'Hagan D, Robinson DA, Spencer JB. The fluorinase from Streptomyces cattleya is also a chlorinase. Angew Chem Int Ed Engl. 2006 Jan 23;45(5):759-62. PMID:16370017 doi:http://dx.doi.org/10.1002/anie.200503582
- ↑ Cobb SL, Deng H, McEwan AR, Naismith JH, O'Hagan D, Robinson DA. Substrate specificity in enzymatic fluorination. The fluorinase from Streptomyces cattleya accepts 2'-deoxyadenosine substrates. Org Biomol Chem. 2006 Apr 21;4(8):1458-60. Epub 2006 Mar 8. PMID:16604208 doi:10.1039/b600574h
- ↑ Huang F, Haydock SF, Spiteller D, Mironenko T, Li TL, O'Hagan D, Leadlay PF, Spencer JB. The gene cluster for fluorometabolite biosynthesis in Streptomyces cattleya: a thioesterase confers resistance to fluoroacetyl-coenzyme A. Chem Biol. 2006 May;13(5):475-84. PMID:16720268 doi:http://dx.doi.org/S1074-5521(06)00084-6
- ↑ Zhu X, Robinson DA, McEwan AR, O'Hagan D, Naismith JH. Mechanism of enzymatic fluorination in Streptomyces cattleya. J Am Chem Soc. 2007 Nov 28;129(47):14597-604. Epub 2007 Nov 7. PMID:17985882 doi:10.1021/ja0731569
- ↑ Thompson S, McMahon SA, Naismith JH, O'Hagan D. Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme. Bioorg Chem. 2015 Nov 18;64:37-41. doi: 10.1016/j.bioorg.2015.11.003. PMID:26642178 doi:http://dx.doi.org/10.1016/j.bioorg.2015.11.003
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