6wsi | pdb_00006wsi
Intact cis-2,3-epoxysuccinic acid bound to Isocitrate Lyase-1 from Mycobacterium tuberculosis
Structural highlights
FunctionACEA_MYCTU Catalyzes the formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle. May be involved in the assimilation of one-carbon compounds via the isocitrate lyase-positive serine pathway (By similarity). Publication Abstract from PubMedThe isocitrate lyases (ICL1/2) are essential enzymes of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. At present, no ICL1/2 inhibitors have progressed to clinical evaluation, despite extensive drug discovery efforts. Herein, we surveyed succinate analogs against ICL1 and found that dicarboxylic acids constrained in their synperiplanar conformations, such as maleic acid, comprise uncompetitive inhibitors of ICL1 and inhibit more potently than their trans-isomers. From this, we identified cis-2,3 epoxysuccinic acid (cis-EpS) as a selective, irreversible covalent inactivator of Mtb ICL1 (kinact/Kinact= (5.0 +/- 1.4) x 10(4) M(-1) s(-1); Kinact = 200 +/- 50 nM), the most potent inactivator of ICL1 yet characterized. Crystallographic and mass spectrometric analysis demonstrated that Cys191 of ICL1 was S-malylated by cis-EpS, and a crystallographic "snapshot" of inactivation lent insight into the chemical mechanism of this inactivation. Proteomic analysis of E. coli lysates showed that cis-EpS selectively labeled plasmid-expressed Mtb ICL1. Consistently, cis-EpS, but not its trans-isomer, inhibited the growth of Mtb under conditions in which ICL function is essential. These findings encourage the development of analogs of cis-2,3-epoxysuccinate as antituberculosis agents. Covalent Inactivation of Mycobacterium tuberculosis Isocitrate Lyase by cis-2,3-Epoxy-Succinic Acid.,Pham TV, Mellott DM, Moghadamchargari Z, Chen K, Krieger I, Laganowsky A, Sacchettini JC, Meek TD ACS Chem Biol. 2021 Mar 19;16(3):463-470. doi: 10.1021/acschembio.0c00740. Epub, 2021 Mar 10. PMID:33688722[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
