The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design

The Journal of Biological Chemistry
Christine M NunnPaul R Ortiz De Montellano

Abstract

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 A. 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 fa...Continue Reading

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Citations

Feb 12, 2004·Archives of Biochemistry and Biophysics·Timo JaegerRafael Radi
Jun 25, 2004·Antimicrobial Agents and Chemotherapy·Aleksey KoshkinPaul R Ortiz de Montellano
Mar 7, 2012·PloS One·Karin M VerspoorMichael E Wall
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Jan 5, 2011·Protein & Cell·Zhiyong Lou, Xiaoxue Zhang
May 23, 2003·The Journal of Biological Chemistry·Aleksey KoshkinPaul R Ortiz de Montellano
Aug 18, 2020·Applied and Environmental Microbiology·Benya NontaleerakSkorn Mongkolsuk
Apr 5, 2021·Environmental Science and Pollution Research International·Ma Laura Ortiz-HernándezPatricia Mussali-Galante
Jun 5, 2004·Archives of Biochemistry and Biophysics·Aleksey KoshkinPaul R Ortiz De Montellano

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