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Nunn, Christine M., Djordjevic, Snezana, Hillas, Patrick J., Nishida, Clinton R. and Ortiz de Montellano, Paul R. (2002) The crystal structure of Mycobacterium tuberculosis Alkylhydroperoxidase AhpD, a potential target for antitubercular drug design. Journal of Biological Chemistry, 277 (22). pp. 20033-20040. ISSN 00219258
Full text not available from this repository. (Request a copy)Abstract / Description
The resistance of Mycobacterium tuberculosis to isoniazid is commonly linked to inactivation of a catalase-peroxidase, KatG, that converts isoniazid to its biologically active form. Loss of KatG is associated with elevated expression of the alkylhydroperoxidases AhpC and AhpD. AhpD has no sequence identity with AhpC or other proteins but has alkylhydroperoxidase activity and possibly additional physiological activities. The alkylhydroperoxidase activity, in the absence of KatG, provides an important antioxidant defense. We have determined the M. tuberculosis AhpD structure to a resolution of 1.9 Å. The protein is a trimer in a symmetrical cloverleaf arrangement. Each subunit exhibits a new all-helical protein fold in which the two catalytic sulfhydryl groups, Cys-130 and Cys-133, are located near a central cavity in the trimer. The structure supports a mechanism for the alkylhydroperoxidase activity in which Cys-133 is deprotonated by a distant glutamic acid via the relay action of His-137 and a water molecule. The cysteine then reacts with the peroxide to give a sulfenic acid that subsequently forms a disulfide bond with Cys-130. The crystal structure of AhpD identifies a new protein fold relevant to members of this protein family in other organisms. The structural details constitute a potential platform for the design of inhibitors of potential utility as antitubercular agents and suggest that AhpD may have disulfide exchange properties of importance in other areas of M. tuberculosisbiology.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Mycobacterium tuberculosis Alkylhydroperoxidase AhpD |
| Subjects: | 500 Natural Sciences and Mathematics > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
| Department: | School of Human Sciences |
| Depositing User: | Christine Nunn |
| Date Deposited: | 03 Aug 2015 10:30 |
| Last Modified: | 25 Jun 2020 15:40 |
| URI: | https://repository.londonmet.ac.uk/id/eprint/733 |
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