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| | ==Crystal structure of KasA of Mycobacterium tuberculosis with bound TLM== | | ==Crystal structure of KasA of Mycobacterium tuberculosis with bound TLM== |
| - | <StructureSection load='2wge' size='340' side='right' caption='[[2wge]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='2wge' size='340' side='right'caption='[[2wge]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2wge]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WGE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2wge]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WGE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WGE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TLM:THIOLACTOMYCIN'>TLM</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wgd|2wgd]], [[2wgg|2wgg]], [[2wgf|2wgf]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TLM:THIOLACTOMYCIN'>TLM</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-ketoacyl-[acyl-carrier-protein]_synthase_I Beta-ketoacyl-[acyl-carrier-protein] synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] </span></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=2wge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wge OCA], [https://pdbe.org/2wge PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wge RCSB], [https://www.ebi.ac.uk/pdbsum/2wge PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wge 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=2wge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wge OCA], [http://pdbe.org/2wge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2wge RCSB], [http://www.ebi.ac.uk/pdbsum/2wge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2wge ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FAB1_MYCTU FAB1_MYCTU]] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity). | + | [https://www.uniprot.org/uniprot/KASA_MYCTU KASA_MYCTU] Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12023885, PubMed:12464486, PubMed:16873379, PubMed:22017312, PubMed:24108128). Involved in the initial extension of the mycolate chain and forms monounsaturated fatty acids that averaged 40 carbons in length (PubMed:12464486).<ref>PMID:11600501</ref> <ref>PMID:12023885</ref> <ref>PMID:12464486</ref> <ref>PMID:16873379</ref> <ref>PMID:22017312</ref> <ref>PMID:24108128</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Acyl carrier protein synthase|Acyl carrier protein synthase]] | + | *[[Acyl carrier protein synthase 3D structures|Acyl carrier protein synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Kisker, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Luckner, S R]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Acyltransferase]] | + | [[Category: Kisker C]] |
| - | [[Category: Beta ketoacyl synthase i thiolactomycin]] | + | [[Category: Luckner SR]] |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Fatty acid biosynthesis]]
| + | |
| - | [[Category: Lipid synthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
KASA_MYCTU Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12023885, PubMed:12464486, PubMed:16873379, PubMed:22017312, PubMed:24108128). Involved in the initial extension of the mycolate chain and forms monounsaturated fatty acids that averaged 40 carbons in length (PubMed:12464486).[1] [2] [3] [4] [5] [6]
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
Mycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin. Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule that mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long-chain fatty acids and provide a robust platform for the development of novel thiolactomycin analogs with high affinity for KasA.
Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.,Luckner SR, Machutta CA, Tonge PJ, Kisker C Structure. 2009 Jul 15;17(7):1004-13. PMID:19604480[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schaeffer ML, Agnihotri G, Volker C, Kallender H, Brennan PJ, Lonsdale JT. Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. J Biol Chem. 2001 Dec 14;276(50):47029-37. PMID:11600501 doi:10.1074/jbc.M108903200
- ↑ Kremer L, Dover LG, Carrère S, Nampoothiri KM, Lesjean S, Brown AK, Brennan PJ, Minnikin DE, Locht C, Besra GS. Mycolic acid biosynthesis and enzymic characterization of the beta-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochem J. 2002 Jun 1;364(Pt 2):423-30. PMID:12023885 doi:10.1042/BJ20011628
- ↑ Slayden RA, Barry CE 3rd. The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2002;82(4-5):149-60. PMID:12464486 doi:10.1054/tube.2002.0333
- ↑ Molle V, Brown AK, Besra GS, Cozzone AJ, Kremer L. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem. 2006 Oct 6;281(40):30094-103. PMID:16873379 doi:10.1074/jbc.M601691200
- ↑ Borgaro JG, Chang A, Machutta CA, Zhang X, Tonge PJ. Substrate recognition by β-ketoacyl-ACP synthases. Biochemistry. 2011 Dec 13;50(49):10678-86. PMID:22017312 doi:10.1021/bi201199x
- ↑ Schiebel J, Kapilashrami K, Fekete A, Bommineni GR, Schaefer CM, Mueller MJ, Tonge PJ, Kisker C. Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis. J Biol Chem. 2013 Oct 9. PMID:24108128 doi:http://dx.doi.org/10.1074/jbc.M113.511436
- ↑ Luckner SR, Machutta CA, Tonge PJ, Kisker C. Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin. Structure. 2009 Jul 15;17(7):1004-13. PMID:19604480 doi:10.1016/j.str.2009.04.012
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