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Originally published In Press as doi:10.1074/jbc.M200864200 on March 25, 2002

J. Biol. Chem., Vol. 277, Issue 22, 20033-20040, May 31, 2002
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The Crystal Structure of Mycobacterium tuberculosis Alkylhydroperoxidase AhpD, a Potential Target for Antitubercular Drug Design*

Christine M. NunnDagger , Snezana DjordjevicDagger §, Patrick J. Hillas, Clinton R. Nishida, and Paul R. Ortiz de Montellano||

From the Dagger  Department of Biochemistry and Molecular Biology, University College, Gower Street, London WC1E 6BT, United Kingdom and the  Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-0446

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. tuberculosis biology.

* This work was supported by National Institutes of Health Grant GM56531 and the Higher Education Council for England United Kingdom.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1gu9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

§ To whom correspondence may be addressed: Dept. of Biochemistry and Molecular Biology, University College, Gower St., London WC1E 6BT, UK. Tel.: 44-020-7679-2230; Fax: 44-020-7679-7193; E-mail: snezana@biochemistry.ucl.ac.uk.

|| To whom correspondence may be addressed: School of Pharmacy, S-926, University of California, San Francisco, CA 94143-0446. Tel.: 415-476-2903; Fax: 415-502-4728; E-mail: ortiz@cgl.ucsf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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