A mechanistic study on the oxidation of hydrazides: application to the tuberculosis drug isoniazid

Amos, Ruth; Gourlay, Brendon S.; Schiesser, Carl H.; Smith, Jason A.; Yates, Brian F.

doi:10.1039/b719570b

Cited by 38 publications

(44 citation statements)

References 17 publications

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“…1). The formation of IN ⅐ in solutions lacking NAD ϩ has been confirmed both using the radical trap TEMPO (42) (41). To identify radicals formed in the presence of INH and NAD ϩ , TEMPO was included and the reaction mixture analyzed by MALDI MS (Fig.…”

Section: Definition Of the Minimal Components For In⅐nad Synthesis-mentioning

confidence: 92%

Isonicotinic Acid Hydrazide Conversion to Isonicotinyl-NAD by Catalase-peroxidases

Wiseman

Carpena

Feliz

et al. 2010

Journal of Biological Chemistry

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Activation of the pro-drug isoniazid (INH) as an anti-tubercular drug in Mycobacterium tuberculosis Isonicotinic acid hydrazide (isoniazid or INH)3 is a widely used anti-tubercular pro-drug that requires activation in a reaction involving the catalase-peroxidase KatG of Mycobacterium tuberculosis (MtKatG) (1) whereby the hydrazine group is removed and the isonicotinyl portion is added to NAD ϩ to generate isonicotinyl-NAD or IN⅐NAD (see Fig. 1). Once formed, IN⅐NAD inhibits the synthesis of mycolic acids, and therefore, the growth of M. tuberculosis, by binding to the longchain enoyl acyl carrier protein reductase (InhA) (2). Despite understanding the role of IN⅐NAD in the inhibition of mycolic acid synthesis and knowing that KatG is required for INH activation in vivo, uncertainties about the mechanism of its formation remain.The involvement of MtKatG in INH activation suggested that the peroxidatic process had a role, and this provided a focus for several studies employing external oxidants such as peroxyacetic acid (3), t-butyl hydroperoxide (4 -6) and low levels of H 2 O 2 (7, 6) to activate the peroxidatic pathway for INH oxidation and activation. In addition, EPR studies have demonstrated that INH can serve as an electron source to reduce peroxidatic intermediates, including specific Trp ⅐ radical species following peroxyacetic acid oxidation of MtKatG (3,8).A multiplicity of methods has been employed to directly and indirectly assay INH activation, including the determination of INH oxidation to isonicotinic acid (9, 10), the HPLC assay of INH disappearance (11), the inactivation of InhA in a mixture of InhA and KatG (7,12,13,14), the HPLC detection of IN⅐NAD (4, 15), and the direct measurement of IN⅐NAD using its characteristic absorbance at 326 nm (6,7,12,15,16). Reports of INH activation in mixtures lacking an external oxidant (4,5,6,9,12,14,15) initially suggested that the peroxidatic process may not be required, but the mixtures of INH, NADH, and KatG would have supported NADH reduction of molecular oxygen to superoxide and low levels of H 2 O 2 (15) to activate the peroxidase reaction.Despite the considerable evidence that a peroxidatic process is involved in IN⅐NAD synthesis, attempts to rationalize the reaction entirely in terms of the peroxidatic pathway generally produced models that were incomplete from the standpoint of electron balance (5,7,10) or that involved hypothetical intermediates not characterized in any other system (5, 6). For example, a common scheme shows the isonicotinyl radical, generated in a peroxidatic reaction, reacting with NAD ϩ to yield IN⅐NAD, when such a reaction would actually yield the IN⅐NAD ϩ ⅐ radical (Fig. 1). The need to reduce this radical in an oxidizing environment suggests that more than a simple peroxidatic pathway is involved in the INH activation process. This rationale leads to superoxide, O 2. , a known reducing agent with

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Section: Definition Of the Minimal Components For In⅐nad Synthesis-mentioning

confidence: 92%

Isonicotinic Acid Hydrazide Conversion to Isonicotinyl-NAD by Catalase-peroxidases

Wiseman

Carpena

Feliz

et al. 2010

Journal of Biological Chemistry

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“…This leads to the production of a key carbon-based acylpyridine radical (Scheme 1) [42]. Once formed, this radical species reacts with NAD + giving the adduct NAD-IZD, which is associated with the major pharmacological action of the drug [10,35].…”

Section: Mycobacterium Tuberculosis Either By H 2 O 2 or O 2 -Speciesmentioning

confidence: 99%

[Fe(CN)5(isoniazid)]3−: An iron isoniazid complex with redox behavior implicated in tuberculosis therapy

Sousa

Vieira

Butler

et al. 2014

Journal of Inorganic Biochemistry

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“…6 Recently we reported studies supporting the hypothesis that the reactive intermediate formed is the acyl radical produced by oxidation of 1. 10 An important step in the chemistry of isoniazid is the addition of this intermediate radical to the pyridinium ion in NAD þ to form 2 (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Acyl radical addition to pyridine: multiorbital interactions

et al. 2009

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A mechanistic study on the oxidation of hydrazides: application to the tuberculosis drug isoniazid

Abstract: Herein we report radical trapping experiments that support the formation of an acyl radical as the active species from the oxidation of isoniazid; these data provide insight into the mechanism of hydrazide oxidation.

Cited by 38 publications

References 17 publications

Isonicotinic Acid Hydrazide Conversion to Isonicotinyl-NAD by Catalase-peroxidases

Isonicotinic Acid Hydrazide Conversion to Isonicotinyl-NAD by Catalase-peroxidases

[Fe(CN)5(isoniazid)]3−: An iron isoniazid complex with redox behavior implicated in tuberculosis therapy

Acyl radical addition to pyridine: multiorbital interactions

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