Long range effects in anion-pi interactions: their crucial role in the inhibition mechanism of Mycobacterium tuberculosis malate synthase

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dc.contributor.author Bauzá Riera, Antonio
dc.contributor.author Quiñonero Santiago, David
dc.contributor.author Deyà Serra, Pere Maria
dc.contributor.author Frontera Beccaria, Antonio
dc.date.accessioned 2018-09-24T11:24:54Z
dc.identifier.uri http://hdl.handle.net/11201/147622
dc.description.abstract [eng] The glyoxylate shunt is an anaplerotic bypass of the traditional Krebs cycle. It plays a prominent role in Mycobacterium tuberculosis virulence, so it can be exploited for the development of antitubercular therapeutics. The shunt involves two enzymes: isocitrate lyase (ICL) and malate synthase (GlcB). The shunt bypasses two steps of the tricarboxylic acid cycle, allowing the incorporation of carbon, and thus, refilling oxaloacetate under carbon-limiting conditions. The targeting of ICL is complicated; however, GlcB, which accommodates the pantothenate tail of acetyl-CoA in the active site, is easier to target. A catalytic Mg2+ unit is located at the bottom of the cavity, and plays a very important role. Recently, the development of effective antituberculosis drugs based on phenyldiketo acids (PDKAs) has been reported. Interestingly, all the crystal structures of GlcB-inhibitor complexes exhibit close contact between the carboxylate of Asp633 and the face of the aromatic ring of the inhibitor. Remarkably, the replacement of the phenyl ring in PDKA by aliphatic moieties yields inactive inhibitors, suggesting that the aromatic moiety is crucial for inhibition. However, the aromatic ring of PDKA is not electron-deficient, and consequently, the anion-p interaction is expected to be very weak (dominated only by polarization effects). Herein, through a combination analysis of the recent X-ray structures of GlcB-PDKA complexes retrieved from the protein data bank (PDB) and computational ab initio studies (RI-MP2/def2-TZVP level of theory), we demonstrate the prominent role of the Mg2+ ion in the active site, which promotes long-range enhancement of the anion-p interaction.
dc.format application/pdf
dc.relation.isformatof Versió postprint del document publicat a: https://doi.org/10.1002/chem.201304995
dc.relation.ispartof Chemistry-A European Journal, 2014, vol. 20, p. 6985-6990
dc.rights (c) Wiley-VHC Verlag GmbH & Co., 2014
dc.subject.classification 54 - Química
dc.subject.other 54 - Chemistry. Crystallography. Mineralogy
dc.title Long range effects in anion-pi interactions: their crucial role in the inhibition mechanism of Mycobacterium tuberculosis malate synthase
dc.type info:eu-repo/semantics/article
dc.type info:eu-repo/semantics/acceptedVersion
dc.date.updated 2018-09-24T11:24:55Z
dc.date.embargoEndDate info:eu-repo/date/embargoEnd/2075-01-01
dc.embargo 2075-01-01
dc.rights.accessRights info:eu-repo/semantics/embargoedAccess
dc.identifier.doi https://doi.org/10.1002/chem.201304995

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