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Papers In Press, published online ahead of print March 25, 2002
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143-0446
Corresponding Author: ortiz{at}cgl.ucsf.edu
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, Cys130 and Cys133, are located near a central cavity in the trimer. The structure supports a mechanism for the alkylhydroperoxidase activity in which Cys133 is deprotonated by a distant glutamic acid via the relay action of His137 and a water molecule. The cysteine then reacts with the peroxide to give a sulfenic acid that subsequently forms a disulfide bond with Cys130. 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.
J. Biol. Chem, 10.1074/jbc.M200864200
Submitted on January 28, 2002
Revised on March 15, 2002
Accepted on March 25, 2002
The crystal structure of mycobacterium tuberculosis Alkylhydroperoxidase AhpD, a potential target for antitubercular drug design
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