The Nitro Group as a Masked Electrophile in Covalent Enzyme Inhibition

• Published in: ACS chemical biology Vol. 13; no. 6; pp. 1470 - 1473
• Main Authors: Ray, Sneha, Kreitler, Dale F, Gulick, Andrew M, Murkin, Andrew S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15-06-2018; American Chemical Society (ACS)
• Subjects: adducts; bacteria; BASIC BIOLOGICAL SCIENCES; Catalytic Domain - drug effects; Crystallography, X-Ray; Cysteine - chemistry; Enzyme Inhibitors - chemistry; inhibition; inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Isocitrate Lyase - antagonists & inhibitors; Isocitrate Lyase - chemistry; Kinetics; Models, Chemical; Mycobacterium tuberculosis - enzymology; Nitro Compounds - chemistry; peptides and proteins; Propionates - chemistry; Spectrometry, Mass, Electrospray Ionization
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.8b00225

We report the unprecedented reaction between a nitroalkane and an active-site cysteine residue to yield a thiohydroximate adduct. Structural and kinetic evidence suggests the nitro group is activated by conversion to its nitronic acid tautomer within the active site. The nitro group, therefore, shows promise as a masked electrophile in the design of covalent inhibitors targeting binding pockets with appropriately placed cysteine and general acid residues.