6vo2

Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex with Mg, NADPH and inhibitor.

spinqualitylabelsall models 6vo2, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vo2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, NDP, R67 Activity: Ketol-acid reductoisomerase, with EC number 1.1.1.86 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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] 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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