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| | <StructureSection load='6vo2' size='340' side='right'caption='[[6vo2]], [[Resolution|resolution]] 1.59Å' scene=''> | | <StructureSection load='6vo2' size='340' side='right'caption='[[6vo2]], [[Resolution|resolution]] 1.59Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vo2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VO2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VO2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vo2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VO2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=R67:3-(methylsulfonyl)-2-oxopropanoic+acid'>R67</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]] 1.59Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ilvC, DB727_12700, E4U00_11130, ERS072840_02559, NCTC6133_02793, NCTC7878_02786, NCTC7988_02129 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=R67:3-(methylsulfonyl)-2-oxopropanoic+acid'>R67</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ketol-acid_reductoisomerase Ketol-acid reductoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.86 1.1.1.86] </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=6vo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vo2 OCA], [https://pdbe.org/6vo2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vo2 RCSB], [https://www.ebi.ac.uk/pdbsum/6vo2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vo2 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vo2 OCA], [http://pdbe.org/6vo2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vo2 RCSB], [http://www.ebi.ac.uk/pdbsum/6vo2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vo2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/A0A145BYP4_STAAU A0A145BYP4_STAAU]] Involved in the biosynthesis of branched-chain amino acids (BCAA). Catalyzes an alkyl-migration followed by a ketol-acid reduction of (S)-2-acetolactate (S2AL) to yield (R)-2,3-dihydroxy-isovalerate. In the isomerase reaction, S2AL is rearranged via a Mg-dependent methyl migration to produce 3-hydroxy-3-methyl-2-ketobutyrate (HMKB). In the reductase reaction, this 2-ketoacid undergoes a metal-dependent reduction by NADPH to yield (R)-2,3-dihydroxy-isovalerate.[HAMAP-Rule:MF_00435][SAAS:SAAS00826005] | + | [https://www.uniprot.org/uniprot/ILVC_STAA8 ILVC_STAA8] Involved in the biosynthesis of branched-chain amino acids (BCAA). Catalyzes an alkyl-migration followed by a ketol-acid reduction of (S)-2-acetolactate (S2AL) to yield (R)-2,3-dihydroxy-isovalerate. In the isomerase reaction, S2AL is rearranged via a Mg-dependent methyl migration to produce 3-hydroxy-3-methyl-2-ketobutyrate (HMKB). In the reductase reaction, this 2-ketoacid undergoes a metal-dependent reduction by NADPH to yield (R)-2,3-dihydroxy-isovalerate.[HAMAP-Rule:MF_00435] |
| | <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 6vo2" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6vo2" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ketol-acid reductoisomerase 3D structures|Ketol-acid reductoisomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ketol-acid reductoisomerase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bayaraa, T]] | + | [[Category: Staphylococcus aureus]] |
| - | [[Category: Guddat, L W]] | + | [[Category: Bayaraa T]] |
| - | [[Category: Patel, K M]] | + | [[Category: Guddat LW]] |
| - | [[Category: Complex]] | + | [[Category: Patel KM]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Metal binding protein]]
| + | |
| - | [[Category: Reductoisomerase]]
| + | |
| Structural highlights
Function
ILVC_STAA8 Involved in the biosynthesis of branched-chain amino acids (BCAA). Catalyzes an alkyl-migration followed by a ketol-acid reduction of (S)-2-acetolactate (S2AL) to yield (R)-2,3-dihydroxy-isovalerate. In the isomerase reaction, S2AL is rearranged via a Mg-dependent methyl migration to produce 3-hydroxy-3-methyl-2-ketobutyrate (HMKB). In the reductase reaction, this 2-ketoacid undergoes a metal-dependent reduction by NADPH to yield (R)-2,3-dihydroxy-isovalerate.[HAMAP-Rule:MF_00435]
Publication Abstract from PubMed
Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis . Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis ( Mt ) KARI and identified two compounds that have K i values below 200 nM. In Mt cell susceptibility assays one of these compounds exhibited an IC 50 value of 0.8 muM. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2 H -benzo[ b ][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56% identity with Mt KARI, NADPH and Mg 2+ yielded a structure to 1.72 A resolution. However, only a hydrolyzed product of the inhibitor ( i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, we have identified 3-(methylsulfonyl)-2-oxopropanic acid is a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.
Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor.,Bayaraa T, Kurz JL, Patel KM, Hussein WM, Bilyj JK, West NP, Schenk G, McGeary RP, Guddat LW Chemistry. 2020 Mar 21. doi: 10.1002/chem.202000899. PMID:32198779[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bayaraa T, Kurz JL, Patel KM, Hussein WM, Bilyj JK, West NP, Schenk G, McGeary RP, Guddat LW. Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor. Chemistry. 2020 Mar 21. doi: 10.1002/chem.202000899. PMID:32198779 doi:http://dx.doi.org/10.1002/chem.202000899
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