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==Thioesterase Domain of Picromycin Polyketide Synthase (PICS TE), pH 8.4==
==Thioesterase Domain of Picromycin Polyketide Synthase (PICS TE), pH 8.4==
<StructureSection load='1mnq' size='340' side='right' caption='[[1mnq]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='1mnq' size='340' side='right'caption='[[1mnq]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1mnq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Streptomyces_venezuelae Streptomyces venezuelae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MNQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MNQ FirstGlance]. <br>
<table><tr><td colspan='2'>[[1mnq]] 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=1MNQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MNQ FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1kez|1kez]], [[1mn6|1mn6]], [[1mna|1mna]], [[1mo0|1mo0]]</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]] 2.2&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">picAIV ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=54571 Streptomyces venezuelae])</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=1mnq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mnq OCA], [https://pdbe.org/1mnq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mnq RCSB], [https://www.ebi.ac.uk/pdbsum/1mnq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mnq 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=1mnq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mnq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1mnq RCSB], [http://www.ebi.ac.uk/pdbsum/1mnq PDBsum]</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]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mn/1mnq_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mn/1mnq_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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=1mnq ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.
Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases.,Tsai SC, Lu H, Cane DE, Khosla C, Stroud RM Biochemistry. 2002 Oct 22;41(42):12598-606. PMID:12379102<ref>PMID:12379102</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Streptomyces venezuelae]]
[[Category: Streptomyces venezuelae]]
[[Category: Cane, D E]]
[[Category: Cane DE]]
[[Category: Khosla, C]]
[[Category: Khosla C]]
[[Category: Lu, H]]
[[Category: Lu H]]
[[Category: Stroud, R M]]
[[Category: Stroud RM]]
[[Category: Tsai, S C]]
[[Category: Tsai S-C]]
[[Category: Alpha-beta hydrolase]]
[[Category: Open substrate channel]]
[[Category: Polyketide synthase]]
[[Category: Thioesterase]]
[[Category: Transferase]]

Latest revision as of 10:46, 14 February 2024

Thioesterase Domain of Picromycin Polyketide Synthase (PICS TE), pH 8.4Thioesterase Domain of Picromycin Polyketide Synthase (PICS TE), pH 8.4

Structural highlights

1mnq 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 2.2Å
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.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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

1mnq, resolution 2.20Å

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