3rga: Difference between revisions

Latest revision as of 17:16, 1 November 2023

Crystal structure of epoxide hydrolase for polyether lasalocid A biosynthesis

Structural highlights

3rga is a 1 chain structure with sequence from Streptomyces lasalocidi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.59Å
Ligands:	ACT, FMT, GOL, ILD, LSB, MOH, NA
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LSD19_STRLS Epoxide hydrolase responsible for the double epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A, a polyether antibiotic. In vitro, accepts various substrate analogs differing in the left segment of lasalocid and epoxide stereochemistry to afford products with excellent regioselectivity.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Polycyclic polyether natural products have fascinated chemists and biologists alike owing to their useful biological activity, highly complex structure and intriguing biosynthetic mechanisms. Following the original proposal for the polyepoxide origin of lasalocid and isolasalocid and the experimental determination of the origins of the oxygen and carbon atoms of both lasalocid and monensin, a unified stereochemical model for the biosynthesis of polyether ionophore antibiotics was proposed. The model was based on a cascade of nucleophilic ring closures of postulated polyepoxide substrates generated by stereospecific oxidation of all-trans polyene polyketide intermediates. Shortly thereafter, a related model was proposed for the biogenesis of marine ladder toxins, involving a series of nominally disfavoured anti-Baldwin, endo-tet epoxide-ring-opening reactions. Recently, we identified Lsd19 from the Streptomyces lasaliensis gene cluster as the epoxide hydrolase responsible for the epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A. Here we report the X-ray crystal structure of Lsd19 in complex with its substrate and product analogue to provide the first atomic structure-to our knowledge-of a natural enzyme capable of catalysing the disfavoured epoxide-opening cyclic ether formation. On the basis of our structural and computational studies, we propose a general mechanism for the enzymatic catalysis of polyether natural product biosynthesis.

Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis.,Hotta K, Chen X, Paton RS, Minami A, Li H, Swaminathan K, Mathews II, Watanabe K, Oikawa H, Houk KN, Kim CY Nature. 2012 Mar 4;483(7389):355-8. doi: 10.1038/nature10865. PMID:22388816^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Shichijo Y, Migita A, Oguri H, Watanabe M, Tokiwano T, Watanabe K, Oikawa H. Epoxide hydrolase Lsd19 for polyether formation in the biosynthesis of lasalocid A: direct experimental evidence on polyene-polyepoxide hypothesis in polyether biosynthesis. J Am Chem Soc. 2008 Sep 17;130(37):12230-1. doi: 10.1021/ja8040543. Epub 2008 Aug, 19. PMID:18710235 doi:https://dx.doi.org/10.1021/ja8040543
↑ Smith L, Hong H, Spencer JB, Leadlay PF. Analysis of specific mutants in the lasalocid gene cluster: evidence for enzymatic catalysis of a disfavoured polyether ring closure. Chembiochem. 2008 Dec 15;9(18):2967-75. doi: 10.1002/cbic.200800585. PMID:19025863 doi:https://dx.doi.org/10.1002/cbic.200800585
↑ Matsuura Y, Shichijo Y, Minami A, Migita A, Oguri H, Watanabe M, Tokiwano T, Watanabe K, Oikawa H. Intriguing substrate tolerance of epoxide hydrolase Lsd19 involved in biosynthesis of the ionophore antibiotic lasalocid A. Org Lett. 2010 May 21;12(10):2226-9. doi: 10.1021/ol100541e. PMID:20394359 doi:https://dx.doi.org/10.1021/ol100541e
↑ Minami A, Migita A, Inada D, Hotta K, Watanabe K, Oguri H, Oikawa H. Enzymatic epoxide-opening cascades catalyzed by a pair of epoxide hydrolases in the ionophore polyether biosynthesis. Org Lett. 2011 Apr 1;13(7):1638-41. doi: 10.1021/ol200100e. Epub 2011 Mar 4. PMID:21375229 doi:https://dx.doi.org/10.1021/ol200100e
↑ Hotta K, Chen X, Paton RS, Minami A, Li H, Swaminathan K, Mathews II, Watanabe K, Oikawa H, Houk KN, Kim CY. Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis. Nature. 2012 Mar 4;483(7389):355-8. doi: 10.1038/nature10865. PMID:22388816 doi:10.1038/nature10865

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OCA

[1] Shichijo Y, Migita A, Oguri H, Watanabe M, Tokiwano T, Watanabe K, Oikawa H. Epoxide hydrolase Lsd19 for polyether formation in the biosynthesis of lasalocid A: direct experimental evidence on polyene-polyepoxide hypothesis in polyether biosynthesis. J Am Chem Soc. 2008 Sep 17;130(37):12230-1. doi: 10.1021/ja8040543. Epub 2008 Aug, 19. PMID:18710235 doi:https://dx.doi.org/10.1021/ja8040543

[2] Smith L, Hong H, Spencer JB, Leadlay PF. Analysis of specific mutants in the lasalocid gene cluster: evidence for enzymatic catalysis of a disfavoured polyether ring closure. Chembiochem. 2008 Dec 15;9(18):2967-75. doi: 10.1002/cbic.200800585. PMID:19025863 doi:https://dx.doi.org/10.1002/cbic.200800585

[3] Matsuura Y, Shichijo Y, Minami A, Migita A, Oguri H, Watanabe M, Tokiwano T, Watanabe K, Oikawa H. Intriguing substrate tolerance of epoxide hydrolase Lsd19 involved in biosynthesis of the ionophore antibiotic lasalocid A. Org Lett. 2010 May 21;12(10):2226-9. doi: 10.1021/ol100541e. PMID:20394359 doi:https://dx.doi.org/10.1021/ol100541e

[4] Minami A, Migita A, Inada D, Hotta K, Watanabe K, Oguri H, Oikawa H. Enzymatic epoxide-opening cascades catalyzed by a pair of epoxide hydrolases in the ionophore polyether biosynthesis. Org Lett. 2011 Apr 1;13(7):1638-41. doi: 10.1021/ol200100e. Epub 2011 Mar 4. PMID:21375229 doi:https://dx.doi.org/10.1021/ol200100e

[5] Hotta K, Chen X, Paton RS, Minami A, Li H, Swaminathan K, Mathews II, Watanabe K, Oikawa H, Houk KN, Kim CY. Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis. Nature. 2012 Mar 4;483(7389):355-8. doi: 10.1038/nature10865. PMID:22388816 doi:10.1038/nature10865

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[2]

[3]

[4]

[5]

@@ Line 3: / Line 3: @@
 <StructureSection load='3rga' size='340' side='right'caption='[[3rga]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3rga]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/'streptomyces_lasaliensis' 'streptomyces lasaliensis']. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RGA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RGA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3rga]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_lasalocidi Streptomyces lasalocidi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RGA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RGA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ILD:(4R,5S)-3-[(2R)-2-{(2S,2R,4S,5S,5R)-2,5-DIETHYL-5-[(1S)-1-HYDROXYETHYL]-4-METHYLOCTAHYDRO-2,2-BIFURAN-5-YL}BUTANOYL]-4-METHYL-5-PHENYL-1,3-OXAZOLIDIN-2-ONE'>ILD</scene>, <scene name='pdbligand=LSB:(4R,5S)-3-[(2R,3S,4S)-2-ETHYL-5-[(3R)-2-ETHYL-3-[2-[(2R,3R)-2-ETHYL-3-METHYL-OXIRAN-2-YL]ETHYL]OXIRAN-2-YL]-3-HYDROXY-4-METHYL-PENTANOYL]-4-METHYL-5-PHENYL-1,3-OXAZOLIDIN-2-ONE'>LSB</scene>, <scene name='pdbligand=MOH:METHANOL'>MOH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.59&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lasB, lsd19 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=324833 'Streptomyces lasaliensis'])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ILD:(4R,5S)-3-[(2R)-2-{(2S,2R,4S,5S,5R)-2,5-DIETHYL-5-[(1S)-1-HYDROXYETHYL]-4-METHYLOCTAHYDRO-2,2-BIFURAN-5-YL}BUTANOYL]-4-METHYL-5-PHENYL-1,3-OXAZOLIDIN-2-ONE'>ILD</scene>, <scene name='pdbligand=LSB:(4R,5S)-3-[(2R,3S,4S)-2-ETHYL-5-[(3R)-2-ETHYL-3-[2-[(2R,3R)-2-ETHYL-3-METHYL-OXIRAN-2-YL]ETHYL]OXIRAN-2-YL]-3-HYDROXY-4-METHYL-PENTANOYL]-4-METHYL-5-PHENYL-1,3-OXAZOLIDIN-2-ONE'>LSB</scene>, <scene name='pdbligand=MOH:METHANOL'>MOH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=3rga FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rga OCA], [https://pdbe.org/3rga PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rga RCSB], [https://www.ebi.ac.uk/pdbsum/3rga PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rga ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/LSD19_STRLS LSD19_STRLS]] Epoxide hydrolase responsible for the double epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A, a polyether antibiotic. In vitro, accepts various substrate analogs differing in the left segment of lasalocid and epoxide stereochemistry to afford products with excellent regioselectivity.<ref>PMID:18710235</ref> <ref>PMID:19025863</ref> <ref>PMID:20394359</ref> <ref>PMID:21375229</ref>
+[https://www.uniprot.org/uniprot/LSD19_STRLS LSD19_STRLS] Epoxide hydrolase responsible for the double epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A, a polyether antibiotic. In vitro, accepts various substrate analogs differing in the left segment of lasalocid and epoxide stereochemistry to afford products with excellent regioselectivity.<ref>PMID:18710235</ref> <ref>PMID:19025863</ref> <ref>PMID:20394359</ref> <ref>PMID:21375229</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Streptomyces lasaliensis]]
 [[Category: Large Structures]]
-[[Category: Chen, X]]
+[[Category: Streptomyces lasalocidi]]
-[[Category: Hotta, K]]
+[[Category: Chen X]]
-[[Category: Kim, C Y]]
+[[Category: Hotta K]]
-[[Category: Mathews, I I]]
+[[Category: Kim C-Y]]
-[[Category: Epoxide-opening cyclic ether formation]]
+[[Category: Mathews II]]
-[[Category: Isomerase]]
-[[Category: Ntf2-like]]

3rga: Difference between revisions

Latest revision as of 17:16, 1 November 2023

Crystal structure of epoxide hydrolase for polyether lasalocid A biosynthesis

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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