Catalase-peroxidase KatG (KatG)

Catalase-peroxidase KatG is a multifunctional heme-containing enzyme essential for the survival of Mycobacterium tuberculosis within host macrophages by neutralizing reactive oxygen species like hydrogen peroxide (UniProt P9WIE5). Beyond its protective antioxidant role, KatG is clinically significant as the primary activator of the frontline antitubercular prodrug isoniazid (PubMed: 15659514). The enzyme converts isoniazid into an active isonicotinyl-NAD adduct, which subsequently inhibits InhA, an enzyme critical for mycolic acid synthesis and cell wall integrity (PubMed: 10411891). Mutations in the katG gene, most notably the S315T substitution, are the most common cause of high-level isoniazid resistance in clinical isolates of M. tuberculosis (PubMed: 11053491). Because KatG is required for drug efficacy rather than being the direct lethal target itself, its study is vital for understanding drug resistance mechanisms and developing next-generation antibiotics that bypass the need for enzymatic activation.

Other names

KatGRv1908cCatalase-peroxidaseIsoniazid-activating enzyme

KatG acts as a prodrug activator; it catalyzes the oxidation of isoniazid to form an electrophilic isonicotinic acyl radical, which then reacts with NADH to form an isonicotinyl-NAD adduct that inhibits the enoyl-ACP reductase InhA, thereby blocking mycolic acid biosynthesis.