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| | <StructureSection load='5eeg' size='340' side='right'caption='[[5eeg]], [[Resolution|resolution]] 2.25Å' scene=''> | | <StructureSection load='5eeg' size='340' side='right'caption='[[5eeg]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5eeg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/As_4.1799 As 4.1799]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EEG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5eeg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_peucetius Streptomyces peucetius]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EEG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=S8M:(2~{R},3~{R},4~{S},5~{S})-2-(6-AMINOPURIN-9-YL)-5-[[(3~{S})-3-AZANYL-3-(1~{H}-1,2,3,4-TETRAZOL-5-YL)PROPYL]SULFANYLMETHYL]OXOLANE-3,4-DIOL'>S8M</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]] 2.255Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5eeh|5eeh]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S8M:(2~{R},3~{R},4~{S},5~{S})-2-(6-AMINOPURIN-9-YL)-5-[[(3~{S})-3-AZANYL-3-(1~{H}-1,2,3,4-TETRAZOL-5-YL)PROPYL]SULFANYLMETHYL]OXOLANE-3,4-DIOL'>S8M</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dnrK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1950 AS 4.1799])</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=5eeg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eeg OCA], [https://pdbe.org/5eeg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eeg RCSB], [https://www.ebi.ac.uk/pdbsum/5eeg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eeg ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carminomycin_4-O-methyltransferase Carminomycin 4-O-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.292 2.1.1.292] </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=5eeg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eeg OCA], [http://pdbe.org/5eeg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eeg RCSB], [http://www.ebi.ac.uk/pdbsum/5eeg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eeg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DNRK_STRPE DNRK_STRPE]] Involved in the biosynthesis of the anthracyclines carminomycin and daunorubicin (daunomycin) which are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers. In vivo, catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the 4-O-position of carminomycin to form daunorubicin. In vitro, it also methylates the anthracyclines rhodomycin D (10-carbomethoxy-13-deoxycarminomycin) and 13-deoxy-carminomycin at the 4-hydroxyl position. It is quite specific with respect to the length of the carbohydrate chain at the C7 position, but it can accept substrates with bulky substituent at C10 position.<ref>PMID:15273252</ref> | + | [https://www.uniprot.org/uniprot/DNRK_STRPE DNRK_STRPE] Involved in the biosynthesis of the anthracyclines carminomycin and daunorubicin (daunomycin) which are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers. In vivo, catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the 4-O-position of carminomycin to form daunorubicin. In vitro, it also methylates the anthracyclines rhodomycin D (10-carbomethoxy-13-deoxycarminomycin) and 13-deoxy-carminomycin at the 4-hydroxyl position. It is quite specific with respect to the length of the carbohydrate chain at the C7 position, but it can accept substrates with bulky substituent at C10 position.<ref>PMID:15273252</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: As 4 1799]] | |
| - | [[Category: Carminomycin 4-O-methyltransferase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: NatPro, Enzyme Discovery for Natural Product Biosynthesis]] | + | [[Category: Streptomyces peucetius]] |
| - | [[Category: Phillips, G N]] | + | [[Category: Phillips Jr GN]] |
| - | [[Category: Singh, S]] | + | [[Category: Singh S]] |
| - | [[Category: Thorson, J S]] | + | [[Category: Thorson JS]] |
| - | [[Category: Wang, F]] | + | [[Category: Wang F]] |
| - | [[Category: Enzyme discovery for natural product biosynthesis]]
| + | |
| - | [[Category: Natpro]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Psi-biology]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Unnatural substrate]]
| + | |
| Structural highlights
Function
DNRK_STRPE Involved in the biosynthesis of the anthracyclines carminomycin and daunorubicin (daunomycin) which are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers. In vivo, catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the 4-O-position of carminomycin to form daunorubicin. In vitro, it also methylates the anthracyclines rhodomycin D (10-carbomethoxy-13-deoxycarminomycin) and 13-deoxy-carminomycin at the 4-hydroxyl position. It is quite specific with respect to the length of the carbohydrate chain at the C7 position, but it can accept substrates with bulky substituent at C10 position.[1]
Publication Abstract from PubMed
S-adenosyl-L-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.
Functional AdoMet isosteres resistant to classical AdoMet degradation pathways.,Huber TD, Wang F, Singh S, Johnson BR, Zhang J, Sunkara M, Van Lanen SG, Morris AJ, Phillips GN, Thorson JS ACS Chem Biol. 2016 Jun 28. PMID:27351335[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jansson A, Koskiniemi H, Mantsala P, Niemi J, Schneider G. Crystal structure of a ternary complex of DnrK, a methyltransferase in daunorubicin biosynthesis, with bound products. J Biol Chem. 2004 Sep 24;279(39):41149-56. Epub 2004 Jul 24. PMID:15273252 doi:10.1074/jbc.M407081200
- ↑ Huber TD, Wang F, Singh S, Johnson BR, Zhang J, Sunkara M, Van Lanen SG, Morris AJ, Phillips GN, Thorson JS. Functional AdoMet isosteres resistant to classical AdoMet degradation pathways. ACS Chem Biol. 2016 Jun 28. PMID:27351335 doi:http://dx.doi.org/10.1021/acschembio.6b00348
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