Catalase in peroxidase clothing: Interdependent cooperation of two cofactors in the catalytic versatility of KatG

• KatG has catalase activity that far exceeds all other members of its superfamily.
• KatG uses its heme to post-translationally generate a unique Met-Tyr-Trp cofactor.
• The mutual cooperation of both cofactors allows for novel modes of H2O2 oxidation.
• Intramolecular electron transfer is a prominent feature of KatG catalytic mechanisms.
• The versatility of KatG permits multiple potential pathways for isoniazid activation.

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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