期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 20, 期 23, 页码 6985-6990出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201304995
关键词
ab initio calculations; anion- interactions; long-range effects; magnesium; malate synthase
资金
- CONSOLIDER-Ingenio [CSD2010-0065]
- MICINN of Spain [CTQ2011-27512 FEDER]
- Direccio General de Recerca, Desenvolupament Tecnologic i Innovacio del Govern Balear [23/2011]
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- 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 abinitio 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- interaction.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据