Enzyme-catalyzed Mechanism of Isoniazid Activation in Class I and Class III Peroxidases

Roberta Pierattelli, Lucia Banci, Nigel A. J. Eady, Jacques Bodiguel, Jamie N. Jones, Peter C. E. Moody, Emma Lloyd Raven, Brigitte Jamart-Grégoire, Katherine A. Brown
2004 Journal of Biological Chemistry  
There is an urgent need to understand the mechanism of activation of the frontline anti-tuberculosis drug isoniazid by the Mycobacterium tuberculosis catalase-peroxidase. To address this, a combination of NMR spectroscopic, biochemical, and computational methods have been used to obtain a model of the frontline anti-tuberculosis drug isoniazid bound to the active site of the class III peroxidase, horseradish peroxidase C. This information has been used in combination with the new crystal
more » ... re of the M. tuberculosis catalase-peroxidase to predict the mode of INH binding across the class I heme peroxidase family. An enzyme-catalyzed mechanism for INH activation is proposed that brings together structural, functional, and spectroscopic data from a variety of sources. Collectively, the information not only provides a molecular basis for understanding INH activation by the M. tuberculosis catalase-peroxidase but also establishes a new conceptual framework for testing hypotheses regarding the enzyme-catalyzed turnover of this compound in a number of heme peroxidases.
doi:10.1074/jbc.m402384200 pmid:15231844 fatcat:m2gnvnbb3vh33ap3gsp7r2v5ni