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| | ==Structure of Mycobacterium tuberculosis IlvE, a branched-chain amino acid transaminase, in complex with D-cycloserine derivative== | | ==Structure of Mycobacterium tuberculosis IlvE, a branched-chain amino acid transaminase, in complex with D-cycloserine derivative== |
| - | <StructureSection load='5u3f' size='340' side='right' caption='[[5u3f]], [[Resolution|resolution]] 1.69Å' scene=''> | + | <StructureSection load='5u3f' size='340' side='right'caption='[[5u3f]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5u3f]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U3F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U3F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5u3f]] is a 2 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=5U3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U3F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7TS:(5-HYDROXY-6-METHYL-4-{[(3-OXO-2,3-DIHYDRO-1,2-OXAZOL-4-YL)AMINO]METHYL}PYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>7TS</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]] 1.695Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Branched-chain-amino-acid_transaminase Branched-chain-amino-acid transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.42 2.6.1.42] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7TS:(5-HYDROXY-6-METHYL-4-{[(3-OXO-2,3-DIHYDRO-1,2-OXAZOL-4-YL)AMINO]METHYL}PYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>7TS</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=5u3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u3f OCA], [http://pdbe.org/5u3f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u3f RCSB], [http://www.ebi.ac.uk/pdbsum/5u3f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u3f 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=5u3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u3f OCA], [https://pdbe.org/5u3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u3f RCSB], [https://www.ebi.ac.uk/pdbsum/5u3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u3f ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ILVE_MYCTU ILVE_MYCTU]] Catalyzes the reversible transfers of an amino group from glutamate to the alpha-ketoacid of the respective amino acid in the final step in the biosynthesis of branchedchain amino acids. The amino acids can be ranked in the following order with respect to their efficiency as amino donor: Leu > Ile > Val.<ref>PMID:20445230</ref> | + | [https://www.uniprot.org/uniprot/ILVE_MYCTU ILVE_MYCTU] Catalyzes the reversible transfers of an amino group from glutamate to the alpha-ketoacid of the respective amino acid in the final step in the biosynthesis of branchedchain amino acids. The amino acids can be ranked in the following order with respect to their efficiency as amino donor: Leu > Ile > Val.<ref>PMID:20445230</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 5u3f" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5u3f" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aminotransferase 3D structures|Aminotransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Branched-chain-amino-acid transaminase]] | + | [[Category: Large Structures]] |
| - | [[Category: Blanchard, J S]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Favrot, L]]
| + | [[Category: Amorim Franco TM]] |
| - | [[Category: Franco, T M.Amorim]] | + | [[Category: Blanchard JS]] |
| - | [[Category: Amino acid biosynthesis]] | + | [[Category: Favrot L]] |
| - | [[Category: Branched-chain amino acid transaminase]] | + | |
| - | [[Category: D-cycloserine]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Pyridoxal phosphate]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
ILVE_MYCTU Catalyzes the reversible transfers of an amino group from glutamate to the alpha-ketoacid of the respective amino acid in the final step in the biosynthesis of branchedchain amino acids. The amino acids can be ranked in the following order with respect to their efficiency as amino donor: Leu > Ile > Val.[1]
Publication Abstract from PubMed
The branched-chain aminotransferase is a pyridoxal 5'-phosphate (PLP)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, l-leucine, l-isoleucine, and l-valine, in bacteria. We have investigated the mechanism of inactivation of the branched-chain aminotransferase from Mycobacterium tuberculosis (MtIlvE) by d- and l-cycloserine. d-Cycloserine is currently used only in the treatment of multidrug-drug-resistant tuberculosis. Our results show a time- and concentration-dependent inactivation of MtIlvE by both isomers, with l-cycloserine being a 40-fold better inhibitor of the enzyme. Minimum inhibitory concentration (MIC) studies revealed that l-cycloserine is a 10-fold better inhibitor of Mycobacterium tuberculosis growth than d-cycloserine. In addition, we have crystallized the MtIlvE-d-cycloserine inhibited enzyme, determining the structure to 1.7 A. The structure of the covalent d-cycloserine-PMP adduct bound to MtIlvE reveals that the d-cycloserine ring is planar and aromatic, as previously observed for other enzyme systems. Mass spectrometry reveals that both the d-cycloserine- and l-cycloserine-PMP complexes have the same mass, and are likely to be the same aromatized, isoxazole product. However, the kinetics of formation of the MtIlvE d-cycloserine-PMP and MtIlvE l-cycloserine-PMP adducts are quite different. While the kinetics of the formation of the MtIlvE d-cycloserine-PMP complex can be fit to a single exponential, the formation of the MtIlvE l-cycloserine-PMP complex occurs in two steps. We propose a chemical mechanism for the inactivation of d- and l-cycloserine which suggests a stereochemically determined structural role for the differing kinetics of inactivation. These results demonstrate that the mechanism of action of d-cycloserine's activity against M. tuberculosis may be more complicated than previously thought and that d-cycloserine may compromise the in vivo activity of multiple PLP-dependent enzymes, including MtIlvE.
Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine.,Amorim Franco TM, Favrot L, Vergnolle O, Blanchard JS ACS Chem Biol. 2017 Mar 16. doi: 10.1021/acschembio.7b00142. PMID:28272868[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Castell A, Mille C, Unge T. Structural analysis of mycobacterial branched-chain aminotransferase: implications for inhibitor design. Acta Crystallogr D Biol Crystallogr. 2010 May;66(Pt 5):549-57. Epub 2010 Apr 21. PMID:20445230 doi:10.1107/S0907444910004877
- ↑ Amorim Franco TM, Favrot L, Vergnolle O, Blanchard JS. Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine. ACS Chem Biol. 2017 Mar 16. doi: 10.1021/acschembio.7b00142. PMID:28272868 doi:http://dx.doi.org/10.1021/acschembio.7b00142
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