2hfj

From Proteopedia

(Difference between revisions)

Current revision

Pikromycin thioesterase with covalent pentaketide affinity label

Structural highlights

2hfj is a 2 chain structure with sequence from Streptomyces venezuelae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.95Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 class of biologically active microbial and plant-derived metabolites that possess a high degree of structural and functional diversity and include many human therapeutics, among them anti-infective and anti-cancer drugs, growth promoters and anti-parasitic agents. The macrolide antibiotics, characterized by a glycoside-linked macrolactone, constitute an important class of polyketides, including erythromycin and the natural ketolide anti-infective agent pikromycin. Here we describe new mechanistic details of macrolactone ring formation catalyzed by the pikromycin polyketide synthase thioesterase domain from Streptomyces venezuelae. A pentaketide phosphonate mimic of the final pikromycin linear chain-elongation intermediate was synthesized and shown to be an active site affinity label. The crystal structures of the affinity-labeled enzyme and of a 12-membered-ring macrolactone product complex suggest a mechanism for cyclization in which a hydrophilic barrier in the enzyme and structural restraints of the substrate induce a curled conformation to direct macrolactone ring formation.

Structural basis for macrolactonization by the pikromycin thioesterase.,Akey DL, Kittendorf JD, Giraldes JW, Fecik RA, Sherman DH, Smith JL Nat Chem Biol. 2006 Oct;2(10):537-42. Epub 2006 Sep 10. PMID:16969372^[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
↑ 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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2hfj"

@@ Line 1: / Line 1: @@
 ==Pikromycin thioesterase with covalent pentaketide affinity label==
-<StructureSection load='2hfj' size='340' side='right' caption='[[2hfj]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='2hfj' size='340' side='right'caption='[[2hfj]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2hfj]] is a 2 chain structure with sequence from [http://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=2HFJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2HFJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2hfj]] 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=2HFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HFJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YML:[(3R,4S,5S,7R)-4,8-DIHYDROXY-3,5,7-TRIMETHYL-2-OXOOCTYL]PHOSPHONIC+ACID'>YML</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]] 1.95&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1mna|1mna]], [[2hfk|2hfk]]</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YML:[(3R,4S,5S,7R)-4,8-DIHYDROXY-3,5,7-TRIMETHYL-2-OXOOCTYL]PHOSPHONIC+ACID'>YML</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pikAIV ([http://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=2hfj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hfj OCA], [https://pdbe.org/2hfj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hfj RCSB], [https://www.ebi.ac.uk/pdbsum/2hfj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hfj ProSAT]</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=2hfj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hfj OCA], [http://pdbe.org/2hfj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2hfj RCSB], [http://www.ebi.ac.uk/pdbsum/2hfj PDBsum]</span></td></tr>
 </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 ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hf/2hfj_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hf/2hfj_consurf.spt"</scriptWhenChecked>
-    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2hfj ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 31: / Line 33: @@
 __TOC__
 </StructureSection>
-[[Category: As 4 1526]]
+[[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 L]]
+[[Category: Sherman DH]]
-[[Category: Alpha/beta hydrolase]]
+[[Category: Smith JL]]
-[[Category: Hydrolase]]
-[[Category: Thioesterase]]

2hfj

From Proteopedia

Current revision

Pikromycin thioesterase with covalent pentaketide affinity label

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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