2000
DOI: 10.1021/bi001239v
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Redox Potential Measurements of the Mycobacterium tuberculosis Heme Protein KatG and the Isoniazid-Resistant Enzyme KatG(S315T):  Insights into Isoniazid Activation

Abstract: Mycobacterium tuberculosis KatG is a multifunctional heme enzyme responsible for activation of the antibiotic isoniazid. A KatG(S315T) point mutation is found in >50% of isoniazid-resistant clinical isolates. Since isoniazid activation is thought to involve an oxidation reaction, the redox potential of KatG was determined using cyclic voltammetry, square wave voltammetry, and spectroelectrochemical titrations. Isoniazid activation may proceed via a cytochrome P450-like mechanism. Therefore, the possibility tha… Show more

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Cited by 35 publications
(30 citation statements)
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References 43 publications
(58 reference statements)
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“…2, and relevant spectral features and analysis are presented in Table I. The optical purity ratio (Reinheitzahl or R z , defined as A Soret /A 280 ) for WT KatG was found to be 0.62, whereas that for KatG(Y229F) was 0.59, both being consistent with literature values (46,47). Pyridine hemochrome assays yielded 0.97-1.04 heme/monomer, indicating complete holoenzyme formation for both KatGs.…”
Section: Uv-visible Spectroscopy Of Wt Katg and Katg(y229f)-supporting
confidence: 78%
“…2, and relevant spectral features and analysis are presented in Table I. The optical purity ratio (Reinheitzahl or R z , defined as A Soret /A 280 ) for WT KatG was found to be 0.62, whereas that for KatG(Y229F) was 0.59, both being consistent with literature values (46,47). Pyridine hemochrome assays yielded 0.97-1.04 heme/monomer, indicating complete holoenzyme formation for both KatGs.…”
Section: Uv-visible Spectroscopy Of Wt Katg and Katg(y229f)-supporting
confidence: 78%
“…Ser-315 has been reported to be mutated to asparagine, isoleucine, arginine, and glycine, although the most frequently occurring mutation is to threonine. As a result, a number of in vitro studies have been undertaken to understand the origins of resistance using the S315T mutant as a model (50,(77)(78)(79)(80)(81)(82)(83)(84)(85)(86). In the absence of a structure for mtCP, it was recently postulated that Ser-315 forms hydrogen bonds to one of the heme propionate groups and that mutation to threonine would, therefore, modify the heme pocket, altering INH binding (16,50).…”
Section: An Alternative Binding Site For Inh In M Tuberculosis Cp-mentioning
confidence: 99%
“…There is a correlation between the standard reduction potential of the ferric/ferrous couple and the stability of high valent porphyrin species (25). In the case of catalase-peroxidases the standard reduction potential of the ferric/ferrous couple of M. tuberculosis KatG was determined to be Ϫ50 mV (26), which is much more positive than that of other plant-type peroxidases (27). This fits with the observation that Synechocystis KatG is able to oxidize chloride (27) a two-electron oxidation reaction, which needs a redox potential of the KatG couple compound I/native enzyme to exceed 1.1 V. But regarding the catalatic reactivity (i.e.…”
Section: Effect On the Chemical Nature Of The Radical Intermediates Imentioning
confidence: 99%