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Role of Metal Ions on the Activity of Mycobacterium tuberculosis Pyrazinamidase
Pyrazinamidase of Mycobacterium tuberculosis catalyzes the conversion of pyrazinamide to the active molecule pyrazinoic acid. Reduction of pyrazinamidase activity results in a level of pyrazinamide resistance. Previous studies have suggested that pyrazinamidase has a metal-binding site and that a divalent metal cofactor is required for activity. To determine the effect of divalent metals on the pyrazinamidase, the recombinant wild-type pyrazinamidase corresponding to the H37Rv pyrazinamide-susceptible reference strain was expressed in Escherichia coli with and without a carboxy terminal. His-tagged pyrazinamidase was inactivated by metal depletion and reactivated by titration with divalent metals. Although Co2+, Mn2+, and Zn2+ restored pyrazinamidase activity, only Co2+ enhanced the enzymatic activity to levels higher than the wild-type pyrazinamidase. Cu2+, Fe2+, Fe3+, and Mg2+ did not restore the activity under the conditions tested. Various recombinant mutated pyrazinamidases with appropriate folding but different enzymatic activities showed a differential pattern of recovered activity. X-ray fluorescence and atomic absorbance spectroscopy showed that recombinant wild-type pyrazinamidase expressed in E. coli most likely contained Zn. In conclusion, this study suggests that M. tuberculosis pyrazinamidase is a metalloenzyme that is able to coordinate several ions, but in vivo, it is more likely to coordinate Zn2+. However, in vitro, the metal-depleted enzyme could be reactivated by several divalent metals with higher efficiency than Zn.
Author Notes
Financial support: This research was funded by National Institute of Allergy and Infectious Diseases, National Institutes of Health United States Award 1R01TW008669-01, Third World Academy of Science (TWAS) Grant 08-070RG/BIO/LA-UNESCO FR:3240204464, Programme for Research and Training in Tropical Diseases (TDR)-World Health Organization Reference 2009/53662-0, and Fundación Instituto Hipólito Unanue. P.S. and M.Z. were supported by Tropical Medicine Research Centers (TMRC) New Tools to Understand and Control Endemic Parasites Grant 1 P01 AI51976 and Global Research Training Grant 3 D43 TW006581.
Authors' addresses: Patricia Sheen, Patricia Ferrer, Gina Christiansen, Paola Moreno-Román, Andrés H. Gutiérrez, Jun Sotelo, Wilfredo Evangelista, Patricia Fuentes, Daniel Rueda, Myra Flores, and Mirko Zimic, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias, Universidad Peruana Cayetano Heredia, Lima, Perú, E-mails: patricia.sheen@upch.pe, ferrerp@gmail.com, ginachristiansen1@yahoo.com, paola.moreno@upch.pe, ahgn5@hotmail.com, jihusan@gmail.com, willyef@gmail.com, pfuentesbonilla@gmail.com, ldrueda.raez@gmail.com, meff_uni@yahoo.com, and mzimic@jhsph.edu. Robert H. Gilman, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, E-mail: rgilman@jhsph.edu. Paula Olivera and José Solis, Instituto Peruano de Energía Nuclear, Lima, Perú, E-mails: polivera@IPEN.GOB.PE and jsolis@uni.edu.pe. Alessandro Pesaresi and Doriano Lamba, Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park—Basovizza, Trieste, Italy, E-mails: alessandro.pesaresi@ts.ic.cnr.it and doriano.lamba@ts.ic.cnr.it.