Structural highlights
7rb1 is a 4 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Method: | X-ray diffraction, Resolution 1.9Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ACEA_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 PubMed
The isocitrate lyase paralogs of Mycobacterium tuberculosis (ICL1 and 2) are essential for mycobacterial persistence and constitute targets for the development of antituberculosis agents. We report that (2R,3S)-2-hydroxy-3-(nitromethyl)succinic acid (5-NIC) undergoes apparent retro-aldol cleavage as catalyzed by ICL1 to produce glyoxylate and 3-nitropropionic acid (3-NP), the latter of which is a covalent-inactivating agent of ICL1. Kinetic analysis of this reaction identified that 5-NIC serves as a robust and efficient mechanism-based inactivator of ICL1 (kinact/KI = (1.3 +/- 0.1) x 10(3) M(-1) s(-1)) with a partition ratio <1. Using enzyme kinetics, mass spectrometry, and X-ray crystallography, we identified that the reaction of the 5-NIC-derived 3-NP with the Cys191 thiolate of ICL1 results in formation of an ICL1-thiohydroxamate adduct as predicted. One aspect of the design of 5-NIC was to lower its overall charge compared to isocitrate to assist with cell permeability. Accordingly, the absence of the third carboxylate group will simplify the synthesis of pro-drug forms of 5-NIC for characterization in cell-infection models of M. tuberculosis.
Mechanism-Based Inactivation of Mycobacterium tuberculosis Isocitrate Lyase 1 by (2R,3S)-2-Hydroxy-3-(nitromethyl)succinic acid.,Mellott DM, Torres D, Krieger IV, Cameron SA, Moghadamchargari Z, Laganowsky A, Sacchettini JC, Meek TD, Harris LD J Am Chem Soc. 2021 Oct 27;143(42):17666-17676. doi: 10.1021/jacs.1c07970. Epub, 2021 Oct 19. PMID:34664502[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mellott DM, Torres D, Krieger IV, Cameron SA, Moghadamchargari Z, Laganowsky A, Sacchettini JC, Meek TD, Harris LD. Mechanism-Based Inactivation of Mycobacterium tuberculosis Isocitrate Lyase 1 by (2R,3S)-2-Hydroxy-3-(nitromethyl)succinic acid. J Am Chem Soc. 2021 Oct 27;143(42):17666-17676. PMID:34664502 doi:10.1021/jacs.1c07970
