Cysteine is the general base that serves in catalysis by isocitrate lyase and in mechanism-based inhibition by 3-nitropropionate

Biochemistry
Margaret M Moynihan, Andrew S Murkin

Abstract

Isocitrate lyase (ICL) catalyzes the reversible cleavage of isocitrate into succinate and glyoxylate. It is the first committed step in the glyoxylate cycle used by some organisms, including Mycobacterium tuberculosis, where it has been shown to be essential for cell survival during chronic infection. The pH-rate and pD-rate profiles measured in the direction of isocitrate synthesis revealed solvent kinetic isotope effects (KIEs) of 1.7 ± 0.4 for (D2O)V and 0.56 ± 0.07 for (D2O)(V/Ksuccinate). Whereas the (D2O)V is consistent with partially rate-limiting proton transfer during formation of the hydroxyl group of isocitrate, the large inverse (D2O)(V/Ksuccinate) indicates that substantially different kinetic parameters exist when the enzyme is saturated with succinate. Inhibition by 3-nitropropionate (3-NP), a succinate analogue, was found to proceed through an unusual double slow-onset process featuring formation of a complex with a Ki of 3.3 ± 0.2 μM during the first minute, followed by formation of a final complex with a Ki* of 44 ± 10 nM over the course of several minutes to hours. Stopped-flow measurements during the first minute revealed an apparent solvent KIE of 0.40 ± 0.03 for association and unity for dissociation. In c...Continue Reading

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Citations

Jan 29, 2020·Future Microbiology·Luciane S da SilvaRoosevelt A da Silva
Jul 7, 2017·Proceedings of the National Academy of Sciences of the United States of America·Truc V PhamThomas D Meek
Jul 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Hua WangLuiz Pedro Sório de Carvalho
Apr 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Patrick L Fernandez, Andrew S Murkin
May 29, 2021·RSC Medicinal Chemistry·Brooke X C KwaiIvanhoe K H Leung
May 22, 2018·ACS Chemical Biology·Sneha RayAndrew S Murkin
Aug 19, 2017·Journal of Chemical Information and Modeling·Yie-Vern LeeYee Siew Choong
Oct 20, 2021·Journal of the American Chemical Society·Drake M MellottLawrence D Harris

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