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| | ==THE MOLECULAR MECHANISM OF SUBSTRATE RECOGNITION AND CATALYSIS OF THE MEMBRANE ACYLTRANSFERASE PatA -- Complex of PatA with palmitate, mannose, and palmitoyl-6-mannose== | | ==THE MOLECULAR MECHANISM OF SUBSTRATE RECOGNITION AND CATALYSIS OF THE MEMBRANE ACYLTRANSFERASE PatA -- Complex of PatA with palmitate, mannose, and palmitoyl-6-mannose== |
| - | <StructureSection load='5oce' size='340' side='right' caption='[[5oce]], [[Resolution|resolution]] 2.41Å' scene=''> | + | <StructureSection load='5oce' size='340' side='right'caption='[[5oce]], [[Resolution|resolution]] 2.41Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5oce]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycs2 Mycs2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OCE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5oce]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OCE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9R2:[(2~{R},3~{S},4~{S},5~{S},6~{S})-3,4,5,6-tetrakis(oxidanyl)oxan-2-yl]methyl+hexadecanoate'>9R2</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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]] 2.41Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MSMEG_2934, MSMEI_2860 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=246196 MYCS2])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9R2:[(2~{R},3~{S},4~{S},5~{S},6~{S})-3,4,5,6-tetrakis(oxidanyl)oxan-2-yl]methyl+hexadecanoate'>9R2</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene></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=5oce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oce OCA], [http://pdbe.org/5oce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oce RCSB], [http://www.ebi.ac.uk/pdbsum/5oce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oce ProSAT]</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=5oce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oce OCA], [https://pdbe.org/5oce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oce RCSB], [https://www.ebi.ac.uk/pdbsum/5oce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oce ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACYLT_MYCS2 ACYLT_MYCS2]] Catalyzes the acylation to the position 6 of the alpha-1,2-linked mannose residue of the phosphatidyl-myo-inositol dimannoside (PIM2) or monomannoside (PIM1).<ref>PMID:12851411</ref> | + | [https://www.uniprot.org/uniprot/ACYLT_MYCS2 ACYLT_MYCS2] Catalyzes the acylation to the position 6 of the alpha-1,2-linked mannose residue of the phosphatidyl-myo-inositol dimannoside (PIM2) or monomannoside (PIM1).<ref>PMID:12851411</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Mycs2]] | + | [[Category: Large Structures]] |
| - | [[Category: Albesa-Jove, D]] | + | [[Category: Mycolicibacterium smegmatis MC2 155]] |
| - | [[Category: Guerin, M E]] | + | [[Category: Albesa-Jove D]] |
| - | [[Category: Tersa, M]] | + | [[Category: Guerin ME]] |
| - | [[Category: Acyltransferase]]
| + | [[Category: Tersa M]] |
| - | [[Category: Glycolipid biosynthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
ACYLT_MYCS2 Catalyzes the acylation to the position 6 of the alpha-1,2-linked mannose residue of the phosphatidyl-myo-inositol dimannoside (PIM2) or monomannoside (PIM1).[1]
Publication Abstract from PubMed
Glycolipids play a central role in a variety of important biological processes in all living organisms. PatA is a membrane acyltransferase involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements, and virulence factors of Mycobacterium tuberculosis. PatA catalyzes the transfer of a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to the 2-position of inositol in PIM1/PIM2. We report here the crystal structure of PatA in the presence of 6-O-palmitoyl-alpha-d-mannopyranoside, unraveling the acceptor binding mechanism. The acceptor mannose ring localizes in a cavity at the end of a surface-exposed long groove where the active site is located, whereas the palmitate moiety accommodates into a hydrophobic pocket deeply buried in the alpha/beta core of the protein. Both fatty acyl chains of the PIM2 acceptor are essential for the reaction to take place, highlighting their critical role in the generation of a competent active site. By the use of combined structural and quantum-mechanics/molecular-mechanics (QM/MM) metadynamics, we unravel the catalytic mechanism of PatA at the atomic-electronic level. Our study provides a detailed structural rationale for a stepwise reaction, with the generation of a tetrahedral transition state for the rate-determining step. Finally, the crystal structure of PatA in the presence of beta-d-mannopyranose and palmitate suggests an inhibitory mechanism for the enzyme, providing exciting possibilities for inhibitor design and the discovery of chemotherapeutic agents against this major human pathogen.
The Molecular Mechanism of Substrate Recognition and Catalysis of the Membrane Acyltransferase PatA from Mycobacteria.,Tersa M, Raich L, Albesa-Jove D, Trastoy B, Prandi J, Gilleron M, Rovira C, Guerin ME ACS Chem Biol. 2017 Dec 11. doi: 10.1021/acschembio.7b00578. PMID:29185694[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kordulakova J, Gilleron M, Puzo G, Brennan PJ, Gicquel B, Mikusova K, Jackson M. Identification of the required acyltransferase step in the biosynthesis of the phosphatidylinositol mannosides of mycobacterium species. J Biol Chem. 2003 Sep 19;278(38):36285-95. Epub 2003 Jul 8. PMID:12851411 doi:http://dx.doi.org/10.1074/jbc.M303639200
- ↑ Tersa M, Raich L, Albesa-Jove D, Trastoy B, Prandi J, Gilleron M, Rovira C, Guerin ME. The Molecular Mechanism of Substrate Recognition and Catalysis of the Membrane Acyltransferase PatA from Mycobacteria. ACS Chem Biol. 2017 Dec 11. doi: 10.1021/acschembio.7b00578. PMID:29185694 doi:http://dx.doi.org/10.1021/acschembio.7b00578
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