Catalase-peroxidase (KatG) is found in eubacteria, archaea, and lower eukaryotae. The enzyme from Mycobacterium tuberculosis has received the greatest attention because of its role in activation of the antitubercular pro-drug isoniazid, and the high frequency with which drug resistance stems from mutations to the katG gene. Generally, the catalase activity of KatGs is striking. It rivals that of typical catalases, enzymes with which KatGs share no structural similarity. Instead, catalatic turnover is accomplished with an active site that bears a strong resemblance to a typical peroxidase (e.g., cytochrome c peroxidase). Yet, KatG is the only member of its superfamily with such capability. It does so using two mutually dependent cofactors: a heme and an entirely unique Met-Tyr-Trp (MYW) covalent adduct. Heme is required to generate the MYW cofactor. The MYW cofactor allows KatG to leverage heme intermediates toward a unique mechanism for H2O2 oxidation. This review evaluates the range of intermediates identified and their connection to the diverse catalytic processes KatG facilitates, including mechanisms of isoniazid activation.
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Indole N-Linked Hydroperoxyl Adduct of Protein-Derived Cofactor Modulating Catalase-Peroxidase Functions.
Angew Chem Int Ed Engl
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Department of Chemistry, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA.
Bifunctional catalase-peroxidase (KatG) features a posttranslational methionine-tyrosine-tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen-linked hydroperoxyl adduct (MYW-OOH) in Mycobacterium tuberculosis KatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW-OOH-containing KatG protein, we investigated the chemical stability and functional impact of MYW-OOH.
View Article and Find Full Text PDFMutual synergy between catalase and peroxidase activities of the bifunctional enzyme KatG is facilitated by electron hole-hopping within the enzyme.
J Biol Chem
November 2017
From the Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849-5312,
KatG is a bifunctional, heme-dependent enzyme in the front-line defense of numerous bacterial and fungal pathogens against HO-induced oxidative damage from host immune responses. Contrary to the expectation that catalase and peroxidase activities should be mutually antagonistic, peroxidatic electron donors (PxEDs) enhance KatG catalase activity. Here, we establish the mechanism of synergistic cooperation between these activities.
View Article and Find Full Text PDFInteraction with the Redox Cofactor MYW and Functional Role of a Mobile Arginine in Eukaryotic Catalase-Peroxidase.
Biochemistry
June 2016
Department of Chemistry, Division of Biochemistry, BOKU-University of Natural Resources and Life Sciences, Muthgasse 18, A-1190 Vienna, Austria.
Catalase-peroxidases (KatGs) are unique bifunctional heme peroxidases with an additional posttranslationally formed redox-active Met-Tyr-Trp cofactor that is essential for catalase activity. On the basis of studies of bacterial KatGs, controversial mechanisms of hydrogen peroxide oxidation were proposed. The recent discovery of eukaryotic KatGs with differing pH optima of catalase activity now allows us to scrutinize those postulated reaction mechanisms.
View Article and Find Full Text PDFDensity Functional Theory Insights into the Role of the Methionine-Tyrosine-Tryptophan Adduct Radical in the KatG Catalase Reaction: O2 Release from the Oxyheme Intermediate.
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Department of Chemistry, Brooklyn College, Brooklyn, New York 11210, United States.
Density functional theory was employed for a comprehensive study that provided electronic and structural insights into the KatG catalase reaction that involves oxyheme. The catalytic role of a unique amino acid cofactor Met-Tyr-Trp (MYW) in its radical form found in KatG was thereby elucidated. It was established that the MYW-radical is flexible such that a "hinge-like opening" rotation of the Trp-107 ring with respect to the Tyr-229 ring along their covalent C-C bond is an inherent feature of its catalytic properties.
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Arch Biochem Biophys
February 2014
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA. Electronic address:
Catalase-peroxidase (KatG) is found in eubacteria, archaea, and lower eukaryotae. The enzyme from Mycobacterium tuberculosis has received the greatest attention because of its role in activation of the antitubercular pro-drug isoniazid, and the high frequency with which drug resistance stems from mutations to the katG gene. Generally, the catalase activity of KatGs is striking.
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