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  • Chemical probing suggests Redox-regulation of the carbonic anhydrase activity of mycobacterial Rv1284

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    Accepted Manuscript (AM)
    Author(s)
    Nienaber, Lisa
    Cave-Freeman, Elysia
    Cross, Megan
    Mason, Lyndel
    Bailey, Ulla-Maja
    Amani, Parisa
    Davis, Rohan A
    Taylor, Paul
    Hofmann, Andreas
    Griffith University Author(s)
    Davis, Rohan A.
    Hofmann, Andreas
    Mason, Lyndel
    Nienaber, Lisa M.
    Cave-Freeman, Elysia A.
    Cross, Megan O.
    Amani, Parisa
    Bailey, Maja H.
    Year published
    2015
    Metadata
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    Abstract
    The mycobacterial enzyme Rv1284 is a member of the ߭carbonic anhydrase family that is considered essential for survival of the pathogen. The active site cavity of this dimeric protein is characterized by an exceptionally small volume and harbours a catalytic zinc ion coordinated by two cysteine and one histidine residue side chains. Using the natural products polycarpine and emodin as chemical probes in crystallographic experiments and stopped-flow enzyme assays, we report that the catalytic activity can be reversibly inhibited by oxidation. Oxidative conditions lead to the removal of one of the active site cysteine residues ...
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    The mycobacterial enzyme Rv1284 is a member of the ߭carbonic anhydrase family that is considered essential for survival of the pathogen. The active site cavity of this dimeric protein is characterized by an exceptionally small volume and harbours a catalytic zinc ion coordinated by two cysteine and one histidine residue side chains. Using the natural products polycarpine and emodin as chemical probes in crystallographic experiments and stopped-flow enzyme assays, we report that the catalytic activity can be reversibly inhibited by oxidation. Oxidative conditions lead to the removal of one of the active site cysteine residues from the coordination sphere of the catalytic metal ion by engagement in a disulfide bond with another cysteine residue close by. The subsequent loss of the metal ion, which is supported by crystallographic analysis, may thus render the protein catalytically inactive. The oxidative inhibition of Rv1284 can be reversed by exposing the protein to reducing conditions. Because the physical size of the chemical probes used in the present study substantially exceeds the active site volume, we hypothesized that these compounds exert their effects from a surface-bound location and identified Tyr120 as a critical residue for oxidative inactivation. These findings link conditions of oxidative stress to pH homeostasis of the pathogen. Because oxidative stress and acidification are defence mechanisms employed by the innate immune system of the host, we suggest that Rv1284 may be a component of the mycobacterial survival strategy.
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    Journal Title
    The FEBS Journal
    Volume
    282
    Issue
    14
    DOI
    https://doi.org/10.1111/febs.13313
    Copyright Statement
    © 2015 Federation of European Biochemical Societies. This is the peer reviewed version of the following article: Chemical probing suggests Redox-regulation of the carbonic anhydrase activity of mycobacterial Rv1284, FEBS Journal, Vol. 282 (14), pp. 2708-2721, 2015 which has been published in final form at http://dx.doi.org/10.1111/febs.13313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html)
    Subject
    Medicinal and biomolecular chemistry
    Biochemistry and cell biology
    Medical biochemistry and metabolomics
    Medical bacteriology
    Publication URI
    http://hdl.handle.net/10072/69962
    Collection
    • Journal articles

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