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| | ==Iron-Catalyzed Oxidation Intermediates Captured in A DNA Repair Dioxygenase== | | ==Iron-Catalyzed Oxidation Intermediates Captured in A DNA Repair Dioxygenase== |
| - | <StructureSection load='3o1m' size='340' side='right' caption='[[3o1m]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='3o1m' size='340' side='right'caption='[[3o1m]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3o1m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O1M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O1M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3o1m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O1M FirstGlance]. <br> |
| - | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene><br> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=2YR:2-DEOXY-N-(2-SULFANYLETHYL)CYTIDINE+5-(DIHYDROGEN+PHOSPHATE)'>2YR</scene>, <scene name='pdbligand=ME6:[(2R,3S,5R)-5-(4-AZANYL-3-METHYL-2-OXO-PYRIMIDIN-3-IUM-1-YL)-3-HYDROXY-OXOLAN-2-YL]METHYL+DIHYDROGEN+PHOSPHATE'>ME6</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2YR:2-DEOXY-N-(2-SULFANYLETHYL)CYTIDINE+5-(DIHYDROGEN+PHOSPHATE)'>2YR</scene>, <scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=ME6:[(2R,3S,5R)-5-(4-AZANYL-3-METHYL-2-OXO-PYRIMIDIN-3-IUM-1-YL)-3-HYDROXY-OXOLAN-2-YL]METHYL+DIHYDROGEN+PHOSPHATE'>ME6</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3o1o|3o1o]], [[3o1p|3o1p]], [[3o1r|3o1r]], [[3o1s|3o1s]], [[3o1t|3o1t]], [[3o1u|3o1u]], [[3o1v|3o1v]]</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=3o1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o1m OCA], [https://pdbe.org/3o1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o1m RCSB], [https://www.ebi.ac.uk/pdbsum/3o1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o1m ProSAT]</span></td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">alkB, aidD, b2212, JW2200 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr> | + | </table> |
| - | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3o1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o1m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3o1m RCSB], [http://www.ebi.ac.uk/pdbsum/3o1m PDBsum]</span></td></tr>
| + | == Function == |
| - | <table> | + | [https://www.uniprot.org/uniprot/ALKB_ECOLI ALKB_ECOLI] Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).<ref>PMID:12226668</ref> <ref>PMID:12594517</ref> <ref>PMID:16482161</ref> <ref>PMID:19706517</ref> <ref>PMID:21068844</ref> <ref>PMID:20084272</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase.,Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844<ref>PMID:21068844</ref> | | Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase.,Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844<ref>PMID:21068844</ref> |
| | | | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3o1m" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ecoli]] | + | [[Category: Escherichia coli K-12]] |
| - | [[Category: Cui, Q.]] | + | [[Category: Large Structures]] |
| - | [[Category: Dai, Q.]] | + | [[Category: Cui Q]] |
| - | [[Category: He, C.]] | + | [[Category: Dai Q]] |
| - | [[Category: Hou, G.]] | + | [[Category: He C]] |
| - | [[Category: Jia, G.]] | + | [[Category: Hou G]] |
| - | [[Category: Jian, X.]] | + | [[Category: Jia G]] |
| - | [[Category: Yang, C G.]] | + | [[Category: Jian X]] |
| - | [[Category: Yi, C.]] | + | [[Category: Yang C-G]] |
| - | [[Category: Zhang, W.]] | + | [[Category: Yi C]] |
| - | [[Category: Zheng, G.]] | + | [[Category: Zhang W]] |
| - | [[Category: Demethylase]]
| + | [[Category: Zheng G]] |
| - | [[Category: Jelly-roll fold]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
ALKB_ECOLI Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Mononuclear iron-containing oxygenases conduct a diverse variety of oxidation functions in biology, including the oxidative demethylation of methylated nucleic acids and histones. Escherichia coli AlkB is the first such enzyme that was discovered to repair methylated nucleic acids, which are otherwise cytotoxic and/or mutagenic. AlkB human homologues are known to play pivotal roles in various processes. Here we present structural characterization of oxidation intermediates for these demethylases. Using a chemical cross-linking strategy, complexes of AlkB-double stranded DNA (dsDNA) containing 1,N(6)-etheno adenine (epsilonA), N(3)-methyl thymine (3-meT) and N(3)-methyl cytosine (3-meC) are stabilized and crystallized, respectively. Exposing these crystals, grown under anaerobic conditions containing iron(II) and alpha-ketoglutarate (alphaKG), to dioxygen initiates oxidation in crystallo. Glycol (from epsilonA) and hemiaminal (from 3-meT) intermediates are captured; a zwitterionic intermediate (from 3-meC) is also proposed, based on crystallographic observations and computational analysis. The observation of these unprecedented intermediates provides direct support for the oxidative demethylation mechanism for these demethylases. This study also depicts a general mechanistic view of how a methyl group is oxidatively removed from different biological substrates.
Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase.,Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Falnes PO, Johansen RF, Seeberg E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature. 2002 Sep 12;419(6903):178-82. PMID:12226668 doi:10.1038/nature01048
- ↑ Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, Sundheim O, Bjoras M, Slupphaug G, Seeberg E, Krokan HE. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003 Feb 20;421(6925):859-63. PMID:12594517 doi:10.1038/nature01363
- ↑ Yu B, Edstrom WC, Benach J, Hamuro Y, Weber PC, Gibney BR, Hunt JF. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature. 2006 Feb 16;439(7078):879-84. PMID:16482161 doi:10.1038/nature04561
- ↑ Yu B, Hunt JF. Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14315-20. Epub 2009 Aug 11. PMID:19706517
- ↑ Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844 doi:10.1038/nature09497
- ↑ Holland PJ, Hollis T. Structural and mutational analysis of Escherichia coli AlkB provides insight into substrate specificity and DNA damage searching. PLoS One. 2010 Jan 13;5(1):e8680. PMID:20084272 doi:10.1371/journal.pone.0008680
- ↑ Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844 doi:10.1038/nature09497
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