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| | ==Crystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acid== | | ==Crystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acid== |
| - | <StructureSection load='5j5d' size='340' side='right' caption='[[5j5d]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='5j5d' size='340' side='right'caption='[[5j5d]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j5d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J5D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j5d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J5D FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GT:2-OXOHEPTANEDIOIC+ACID'>6GT</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]] 2.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dapA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6GT:2-OXOHEPTANEDIOIC+ACID'>6GT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/4-hydroxy-tetrahydrodipicolinate_synthase 4-hydroxy-tetrahydrodipicolinate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.3.3.7 4.3.3.7] </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=5j5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5d OCA], [https://pdbe.org/5j5d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j5d RCSB], [https://www.ebi.ac.uk/pdbsum/5j5d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5d 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=5j5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5d OCA], [http://pdbe.org/5j5d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j5d RCSB], [http://www.ebi.ac.uk/pdbsum/5j5d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5d ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DAPA_MYCTU DAPA_MYCTU]] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).<ref>PMID:18062777</ref> | + | [https://www.uniprot.org/uniprot/DAPA_MYCTU DAPA_MYCTU] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).<ref>PMID:18062777</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5j5d" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5j5d" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dihydrodipicolinate synthase|Dihydrodipicolinate synthase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 4-hydroxy-tetrahydrodipicolinate synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Gopal, B]] | + | [[Category: Gopal B]] |
| - | [[Category: Navratna, V]] | + | [[Category: Navratna V]] |
| - | [[Category: Alpha-ketopimelic acid]]
| + | |
| - | [[Category: Dap pathway]]
| + | |
| - | [[Category: L-lysine]]
| + | |
| - | [[Category: Lyase]]
| + | |
| Structural highlights
Function
DAPA_MYCTU Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).[1]
Publication Abstract from PubMed
The Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L-aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB). Alpha-ketopimelic acid (alpha-KPA) showed maximum inhibition of 88% and IC50 of 21 muM in the presence of pyruvate (500 muM) and ASA (400 muM). Competition experiments with pyruvate and ASA revealed competition of alpha-KPA with pyruvate. Liquid chromatography-mass spectrometry (LC-MS) data with multiple reaction monitoring (MRM) showed that the relative abundance peak of final product, 2,3,4,5-tetrahydrodipicolinate, was decreased by 50%. Thermal shift assays showed 1 degrees C Tm shift of Mtb-rDapA upon binding alpha-KPA. The 2.4 A crystal structure of Mtb-rDapA-alpha-KPA complex showed the interaction of critical residues at the active site with alpha-KPA. Molecular dynamics simulations over 500 ns of pyruvate docked to Mtb-DapA and of alpha-KPA-bound Mtb-rDapA revealed formation of hydrogen bonds with pyruvate throughout in contrast to alpha-KPA. Molecular descriptors analysis showed that ligands with polar surface area of 91.7 A(2) are likely inhibitors. In summary, alpha-hydroxypimelic acid and other analogues could be explored further as inhibitors of Mtb-DapA.
Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues.,Shrivastava P, Navratna V, Silla Y, Dewangan RP, Pramanik A, Chaudhary S, Rayasam G, Kumar A, Gopal B, Ramachandran S Sci Rep. 2016 Aug 9;6:30827. doi: 10.1038/srep30827. PMID:27501775[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kefala G, Evans GL, Griffin MD, Devenish SR, Pearce FG, Perugini MA, Gerrard JA, Weiss MS, Dobson RC. Crystal structure and kinetic study of dihydrodipicolinate synthase from Mycobacterium tuberculosis. Biochem J. 2008 Apr 15;411(2):351-60. PMID:18062777 doi:10.1042/BJ20071360
- ↑ Shrivastava P, Navratna V, Silla Y, Dewangan RP, Pramanik A, Chaudhary S, Rayasam G, Kumar A, Gopal B, Ramachandran S. Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues. Sci Rep. 2016 Aug 9;6:30827. doi: 10.1038/srep30827. PMID:27501775 doi:http://dx.doi.org/10.1038/srep30827
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