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| | <StructureSection load='2h7x' size='340' side='right'caption='[[2h7x]], [[Resolution|resolution]] 1.85Å' scene=''> | | <StructureSection load='2h7x' size='340' side='right'caption='[[2h7x]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2h7x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/As_4.1526 As 4.1526]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H7X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2h7x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_venezuelae Streptomyces venezuelae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H7X FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PSX:[(2S,3R,4S)-2,4-DIHYDROXY-3-METHYLHEXYL]PHOSPHONIC+ACID'>PSX</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.85Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1mna|1mna]], [[2h7y|2h7y]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PSX:[(2S,3R,4S)-2,4-DIHYDROXY-3-METHYLHEXYL]PHOSPHONIC+ACID'>PSX</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pikAIV ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=54571 AS 4.1526])</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=2h7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7x OCA], [https://pdbe.org/2h7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h7x RCSB], [https://www.ebi.ac.uk/pdbsum/2h7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h7x 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=2h7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7x OCA], [https://pdbe.org/2h7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h7x RCSB], [https://www.ebi.ac.uk/pdbsum/2h7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h7x ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PIKA4_STRVZ PIKA4_STRVZ] Involved in the biosynthesis of 12- and 14-membered ring macrolactone antibiotics such as methymycin and neomethymycin, and pikromycin and narbomycin, respectively. Component of the pikromycin PKS which catalyzes the biosynthesis of both precursors 10-deoxymethynolide (12-membered ring macrolactone) and narbonolide (14-membered ring macrolactone). Chain elongation through PikAI, PikAII and PikAIII followed by thioesterase catalyzed termination results in the production of 10-deoxymethynolide, while continued elongation through PikAIV, followed by thioesterase (TE) catalyzed cyclization results in the biosynthesis of the narbonolide. The thioesterase can use a series of diketide-N-acetylcysteamine (SNAC) thioesters, but has a strong preference for the 2-methyl-3-ketopentanoyl-SNAC over the stereoisomers of 2-methyl-3-hydroxyacyl-SNAC (PubMed:12379101, PubMed:12733905).<ref>PMID:10421766</ref> <ref>PMID:10676969</ref> <ref>PMID:12379101</ref> <ref>PMID:12733905</ref> <ref>PMID:16969372</ref> <ref>PMID:17719493</ref> <ref>PMID:19027305</ref> |
| | == 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: As 4 1526]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Akey, D L]] | + | [[Category: Streptomyces venezuelae]] |
| - | [[Category: Fecik, R A]] | + | [[Category: Akey DL]] |
| - | [[Category: Giraldes, J W]] | + | [[Category: Fecik RA]] |
| - | [[Category: Kittendorf, J D]] | + | [[Category: Giraldes JW]] |
| - | [[Category: Sherman, D H]] | + | [[Category: Kittendorf JD]] |
| - | [[Category: Smith, J S]] | + | [[Category: Sherman DH]] |
| - | [[Category: Alpha-beta hydrolase]] | + | [[Category: Smith JS]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Thioesterase]]
| + | |
| Structural highlights
Function
PIKA4_STRVZ Involved in the biosynthesis of 12- and 14-membered ring macrolactone antibiotics such as methymycin and neomethymycin, and pikromycin and narbomycin, respectively. Component of the pikromycin PKS which catalyzes the biosynthesis of both precursors 10-deoxymethynolide (12-membered ring macrolactone) and narbonolide (14-membered ring macrolactone). Chain elongation through PikAI, PikAII and PikAIII followed by thioesterase catalyzed termination results in the production of 10-deoxymethynolide, while continued elongation through PikAIV, followed by thioesterase (TE) catalyzed cyclization results in the biosynthesis of the narbonolide. The thioesterase can use a series of diketide-N-acetylcysteamine (SNAC) thioesters, but has a strong preference for the 2-methyl-3-ketopentanoyl-SNAC over the stereoisomers of 2-methyl-3-hydroxyacyl-SNAC (PubMed:12379101, PubMed:12733905).[1] [2] [3] [4] [5] [6] [7]
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
Polyketides are a diverse class of natural products having important clinical properties, including antibiotic, immunosuppressive and anticancer activities. They are biosynthesized by polyketide synthases (PKSs), which are modular, multienzyme complexes that sequentially condense simple carboxylic acid derivatives. The final reaction in many PKSs involves thioesterase-catalyzed cyclization of linear chain elongation intermediates. As the substrate in PKSs is presented by a tethered acyl carrier protein, introduction of substrate by diffusion is problematic, and no substrate-bound type I PKS domain structure has been reported so far. We describe the chemical synthesis of polyketide-based affinity labels that covalently modify the active site serine of excised pikromycin thioesterase from Streptomyces venezuelae. Crystal structures reported here of the affinity label-pikromycin thioesterase adducts provide important mechanistic insights. These results suggest that affinity labels can be valuable tools for understanding the mechanisms of individual steps within multifunctional PKSs and for directing rational engineering of PKS domains for combinatorial biosynthesis.
Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels.,Giraldes JW, Akey DL, Kittendorf JD, Sherman DH, Smith JL, Fecik RA Nat Chem Biol. 2006 Oct;2(10):531-6. Epub 2006 Sep 10. PMID:16969373[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tang L, Fu H, Betlach MC, McDaniel R. Elucidating the mechanism of chain termination switching in the picromycin/methymycin polyketide synthase. Chem Biol. 1999 Aug;6(8):553-8. doi: 10.1016/S1074-5521(99)80087-8. PMID:10421766 doi:http://dx.doi.org/10.1016/S1074-5521(99)80087-8
- ↑ Xue Y, Sherman DH. Alternative modular polyketide synthase expression controls macrolactone structure. Nature. 2000 Feb 3;403(6769):571-5. PMID:10676969 doi:10.1038/35000624
- ↑ Lu H, Tsai SC, Khosla C, Cane DE. Expression, site-directed mutagenesis, and steady state kinetic analysis of the terminal thioesterase domain of the methymycin/picromycin polyketide synthase. Biochemistry. 2002 Oct 22;41(42):12590-7. PMID:12379101 doi:10.1021/bi026006d
- ↑ Yin Y, Lu H, Khosla C, Cane DE. Expression and kinetic analysis of the substrate specificity of modules 5 and 6 of the picromycin/methymycin polyketide synthase. J Am Chem Soc. 2003 May 14;125(19):5671-6. PMID:12733905 doi:10.1021/ja034574q
- ↑ Akey DL, Kittendorf JD, Giraldes JW, Fecik RA, Sherman DH, Smith JL. Structural basis for macrolactonization by the pikromycin thioesterase. Nat Chem Biol. 2006 Oct;2(10):537-42. Epub 2006 Sep 10. PMID:16969372 doi:10.1038/nchembio824
- ↑ Kittendorf JD, Beck BJ, Buchholz TJ, Seufert W, Sherman DH. Interrogating the molecular basis for multiple macrolactone ring formation by the pikromycin polyketide synthase. Chem Biol. 2007 Aug;14(8):944-54. PMID:17719493 doi:10.1016/j.chembiol.2007.07.013
- ↑ Kittendorf JD, Sherman DH. The methymycin/pikromycin pathway: a model for metabolic diversity in natural product biosynthesis. Bioorg Med Chem. 2009 Mar 15;17(6):2137-46. doi: 10.1016/j.bmc.2008.10.082. Epub , 2008 Nov 5. PMID:19027305 doi:http://dx.doi.org/10.1016/j.bmc.2008.10.082
- ↑ Giraldes JW, Akey DL, Kittendorf JD, Sherman DH, Smith JL, Fecik RA. Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels. Nat Chem Biol. 2006 Oct;2(10):531-6. Epub 2006 Sep 10. PMID:16969373 doi:10.1038/nchembio822
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