title: Enzyme-catalyzed mechanism of isoniazid activation in class I and class III peroxidases.
abstract: 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 structure 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.
authors.affiliation: Dipartimento di Chimica e Centro Risonanze Magnetiche, Universitá di Firenze, Polo Scientifico, Via Luigi Sacconi 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pierattelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Nigel A J
authors.initials: NA
authors.lastname: Eady
authors.forename: Jacques
authors.initials: J
authors.lastname: Bodiguel
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Jones
authors.forename: Peter C E
authors.initials: PC
authors.lastname: Moody
authors.forename: Emma Lloyd
authors.initials: EL
authors.lastname: Raven
authors.forename: Brigitte
authors.initials: B
authors.lastname: Jamart-Grégoire
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Brown
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D006418:Heme / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007538:Isoniazid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010100:Oxygen / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry; D010544:Peroxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011522:Protons; D011524:Protoporphyrins / Q000737:chemistry; D012984:Software
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011522:Protons; D011524:Protoporphyrins; C448299:iron protoporphyrin IX; D006418:Heme; D006735:Horseradish Peroxidase; D010544:Peroxidases; C081610:catalase-peroxidase, bacteria; D009195:Peroxidase; D010100:Oxygen; D007538:Isoniazid