3hlg

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[[Image:3hlg.png|left|200px]]
 
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{{STRUCTURE_3hlg| PDB=3hlg | SCENE= }}
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==Simvastatin Synthase (LovD), from Aspergillus terreus, S5 mutant, S76A mutant, complex with lovastatin==
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<StructureSection load='3hlg' size='340' side='right'caption='[[3hlg]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3hlg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_terreus Aspergillus terreus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HLG FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LVA:(3R,5R)-7-((1R,2R,6S,8R,8AS)-2,6-DIMETHYL-8-{[(2R)-2-METHYLBUTANOYL]OXY}-1,2,6,7,8,8A-HEXAHYDRONAPHTHALEN-1-YL)-3,5-DIHYDROXYHEPTANOIC+ACID'>LVA</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hlg OCA], [https://pdbe.org/3hlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hlg RCSB], [https://www.ebi.ac.uk/pdbsum/3hlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hlg ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/LOVD_ASPTE LOVD_ASPTE] Monacolin J acid methylbutanoyltransferase; part of the gene cluster that mediates the biosynthesis of lovastatin (also known as mevinolin, mevacor or monacolin K), a hypolipidemic inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in the biosynthesis of lovastatin is the production of dihydromonacolin L acid by the lovastatin nonaketide synthase lovB and the trans-acting enoyl reductase lovC via condensation of one acetyl-CoA unit and 8 malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898, PubMed:22733743). Dihydromonacolin L acid is released from lovB by the thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is oxidized by the dihydromonacolin L monooxygenase lovA twice to form monacolin J acid (PubMed:12929390, PubMed:21495633). The 2-methylbutyrate moiety of lovastatin is synthesized by the lovastatin diketide synthase lovF via condensation of one acetyl-CoA unit and one malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the covalent attachment of this moiety to monacolin J acid is catalyzed by the transesterase lovD to yield lovastatin (PubMed:10334994, PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900). LovD has broad substrate specificity and can also convert monacolin J to simvastatin using alpha-dimethylbutanoyl-S-methyl-3-mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can also catalyze the reverse reaction and function as hydrolase in vitro (PubMed:19875080). LovD has much higher activity with LovF-bound 2-methylbutanoate than with free diketide substrates (PubMed:21069965).<ref>PMID:10334994</ref> <ref>PMID:10381407</ref> <ref>PMID:12929390</ref> <ref>PMID:17113998</ref> <ref>PMID:18988191</ref> <ref>PMID:19530726</ref> <ref>PMID:19875080</ref> <ref>PMID:19900898</ref> <ref>PMID:21069965</ref> <ref>PMID:21495633</ref> <ref>PMID:22733743</ref> <ref>PMID:23653178</ref> <ref>PMID:24727900</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hl/3hlg_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3hlg ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Enzymes from natural product biosynthetic pathways are attractive candidates for creating tailored biocatalysts to produce semisynthetic pharmaceutical compounds. LovD is an acyltransferase that converts the inactive monacolin J acid (MJA) into the cholesterol-lowering lovastatin. LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic alpha-dimethylbutyryl thioester, albeit with suboptimal properties as a biocatalyst. Here we used directed evolution to improve the properties of LovD toward semisynthesis of simvastatin. Mutants with improved catalytic efficiency, solubility, and thermal stability were obtained, with the best mutant displaying an approximately 11-fold increase in an Escherichia coli-based biocatalytic platform. To understand the structural basis of LovD enzymology, seven X-ray crystal structures were determined, including the parent LovD, an improved mutant G5, and G5 cocrystallized with ligands. Comparisons between the structures reveal that beneficial mutations stabilize the structure of G5 in a more compact conformation that is favorable for catalysis.
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===Simvastatin Synthase (LovD), from Aspergillus terreus, S5 mutant, S76A mutant, complex with lovastatin===
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Directed evolution and structural characterization of a simvastatin synthase.,Gao X, Xie X, Pashkov I, Sawaya MR, Laidman J, Zhang W, Cacho R, Yeates TO, Tang Y Chem Biol. 2009 Oct 30;16(10):1064-74. PMID:19875080<ref>PMID:19875080</ref>
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{{ABSTRACT_PUBMED_19875080}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 3hlg" style="background-color:#fffaf0;"></div>
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[[3hlg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspergillus_terreus Aspergillus terreus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HLG OCA].
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==See Also==
==See Also==
*[[Simvastatin Synthase|Simvastatin Synthase]]
*[[Simvastatin Synthase|Simvastatin Synthase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019875080</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Aspergillus terreus]]
[[Category: Aspergillus terreus]]
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[[Category: Gao, X.]]
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[[Category: Large Structures]]
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[[Category: Pashkov, I.]]
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[[Category: Gao X]]
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[[Category: Sawaya, M R.]]
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[[Category: Pashkov I]]
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[[Category: Tang, Y.]]
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[[Category: Sawaya MR]]
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[[Category: Yeates, T O.]]
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[[Category: Tang Y]]
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[[Category: Alpha/beta hydrolase fold]]
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[[Category: Yeates TO]]
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[[Category: Transferase]]
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Current revision

Simvastatin Synthase (LovD), from Aspergillus terreus, S5 mutant, S76A mutant, complex with lovastatin

PDB ID 3hlg

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