6bon: Difference between revisions
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==Crystal structure of 2-methylcitrate synthase from Aspergillus fumigatus with oxaloacetate and coenzyme-A.== | ==Crystal structure of 2-methylcitrate synthase from Aspergillus fumigatus with oxaloacetate and coenzyme-A.== | ||
<StructureSection load='6bon' size='340' side='right' caption='[[6bon]], [[Resolution|resolution]] 2.35Å' scene=''> | <StructureSection load='6bon' size='340' side='right'caption='[[6bon]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6bon]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfc Aspfc]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BON OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[6bon]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfc Aspfc]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BON OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6BON FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=OAA:OXALOACETATE+ION'>OAA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=OAA:OXALOACETATE+ION'>OAA</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mcsA, AFUB_094700 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=451804 ASPFC])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mcsA, AFUB_094700 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=451804 ASPFC])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6bon FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bon OCA], [http://pdbe.org/6bon PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bon RCSB], [http://www.ebi.ac.uk/pdbsum/6bon PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bon ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/PRPC_ASPFC PRPC_ASPFC]] Component of the methylcitrate cycle that catalyzes the synthesis of (2S,3S)-2-methylcitrate from propionyl-CoA and oxaloacetate. Plays an important role in detoxification of propionyl-CoA, an inhibitor of both primary and secondary metabolism. Has also citrate synthase activity using as substrates acetyl-CoA and oxaloacetate. Plays a key role in the estabishment of invasive pulmonary aspergillosis.<ref>PMID:17973657</ref> | [[http://www.uniprot.org/uniprot/PRPC_ASPFC PRPC_ASPFC]] Component of the methylcitrate cycle that catalyzes the synthesis of (2S,3S)-2-methylcitrate from propionyl-CoA and oxaloacetate. Plays an important role in detoxification of propionyl-CoA, an inhibitor of both primary and secondary metabolism. Has also citrate synthase activity using as substrates acetyl-CoA and oxaloacetate. Plays a key role in the estabishment of invasive pulmonary aspergillosis.<ref>PMID:17973657</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Aspergillus fumigatus is a ubiquitous fungus that is not only a problem in agriculture, but also in healthcare. Aspergillus fumigatus drug resistance is becoming more prominent which is mainly attributed to the widespread use of fungicides in agriculture. The fungi-specific 2-methylcitrate cycle is responsible for detoxifying propionyl-CoA, a toxic metabolite produced as the fungus breaks down proteins and amino acids. The enzyme responsible for this detoxification is 2-methylcitrate synthase (mcsA) and is a potential candidate for the design of new anti-fungals. However, mcsA is very similar in structure to human citrate synthase (hCS) and catalyzes the same reaction. Therefore, both enzymes were studied in parallel to provide foundations for design of mcsA-specific inhibitors. The first crystal structures of citrate synthase from humans and 2-methylcitrate synthase from A. fumigatus are reported. The determined structures capture various conformational states of the enzymes and several inhibitors were identified and characterized. Despite a significant homology, mcsA and hCS display pronounced differences in substrate specificity and cooperativity. Considering that the active sites of the enzymes are almost identical, the differences in reactions catalyzed by enzymes are caused by residues that are in the vicinity of the active site and influence conformational changes of the enzymes. | |||
Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase.,Schlachter CR, Klapper V, Radford T, Chruszcz M Biol Chem. 2019 Nov 26;400(12):1567-1581. doi: 10.1515/hsz-2019-0106. PMID:31141475<ref>PMID:31141475</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6bon" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Citrate Synthase 3D structures|Citrate Synthase 3D structures]] | |||
*[[Methylcitrate synthase|Methylcitrate synthase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Aspfc]] | [[Category: Aspfc]] | ||
[[Category: Large Structures]] | |||
[[Category: Chruszcz, M]] | [[Category: Chruszcz, M]] | ||
[[Category: Schlachter, C]] | [[Category: Schlachter, C]] | ||
Revision as of 13:31, 17 June 2020
Crystal structure of 2-methylcitrate synthase from Aspergillus fumigatus with oxaloacetate and coenzyme-A.Crystal structure of 2-methylcitrate synthase from Aspergillus fumigatus with oxaloacetate and coenzyme-A.
Structural highlights
Function[PRPC_ASPFC] Component of the methylcitrate cycle that catalyzes the synthesis of (2S,3S)-2-methylcitrate from propionyl-CoA and oxaloacetate. Plays an important role in detoxification of propionyl-CoA, an inhibitor of both primary and secondary metabolism. Has also citrate synthase activity using as substrates acetyl-CoA and oxaloacetate. Plays a key role in the estabishment of invasive pulmonary aspergillosis.[1] Publication Abstract from PubMedAspergillus fumigatus is a ubiquitous fungus that is not only a problem in agriculture, but also in healthcare. Aspergillus fumigatus drug resistance is becoming more prominent which is mainly attributed to the widespread use of fungicides in agriculture. The fungi-specific 2-methylcitrate cycle is responsible for detoxifying propionyl-CoA, a toxic metabolite produced as the fungus breaks down proteins and amino acids. The enzyme responsible for this detoxification is 2-methylcitrate synthase (mcsA) and is a potential candidate for the design of new anti-fungals. However, mcsA is very similar in structure to human citrate synthase (hCS) and catalyzes the same reaction. Therefore, both enzymes were studied in parallel to provide foundations for design of mcsA-specific inhibitors. The first crystal structures of citrate synthase from humans and 2-methylcitrate synthase from A. fumigatus are reported. The determined structures capture various conformational states of the enzymes and several inhibitors were identified and characterized. Despite a significant homology, mcsA and hCS display pronounced differences in substrate specificity and cooperativity. Considering that the active sites of the enzymes are almost identical, the differences in reactions catalyzed by enzymes are caused by residues that are in the vicinity of the active site and influence conformational changes of the enzymes. Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase.,Schlachter CR, Klapper V, Radford T, Chruszcz M Biol Chem. 2019 Nov 26;400(12):1567-1581. doi: 10.1515/hsz-2019-0106. PMID:31141475[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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