KatG catalase-peroxidase enzyme

Fig. 5.7 Mechanism proposed for autocatalytic formation of the Met-Tyr-Trp crosslinked tripeptide found in all KatG catalase-peroxidases based on experimental observations with the enzyme from M. tuberculosis. The iron between two bars represents the prosthetic heme group...

Isoniazid interferes with mycolic acid synthesis by inhibiting an enoyl reductase (InhA) which forms part of the fatty acid synthase system in mycobacteria. Mycolic acids are produced by a diversion of the normal fatty acid synthetic pathway in which short-chain (16 carbon) and long-chain (24 carbon) fatty acids are produced by addition of 7 or 11 malonate extension units from malonyl coenzyme A to acetyl coenzyme A. InhA inserts a double bond into the extending fatty acid chain at the 24 carbon stage. The long-chain fatty acids are further extended and condensed to produce the 60-90 carbon (3-hydroxymycolic acids which are important components of the mycobacterial cell wall. Isoniazid is converted inside the mycobacteria to a free radical species by a catalase peroxidase enzyme, KatG. The active free radicals then attack and inhibit the enoyl reductase, InhA, by covalent attachment to the active site. 

The most common mechanism of isoniazid resistance is the mycobacteria s formation of mutations in catalase-peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mechanism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis. 

Ghiladi RA, Rnudsen GM, Medzihradszky KF et al (2005) The Met-Tyr-Trp crosslink in Mycobacterium tuberculosis catalase-peroxidase (KatG) Autocatalytic formation and effect on enzyme catalysis and spectroscopic properties. J Biol Chem 280 22651-22663... 

Given that INH is a prodrug that requires intracellular activation for anti-TB activity, a logical site for drug resistance would be a mutation of the KatG protein. A correlation between INH activation and peroxidase enzyme dates back to the 1960s, when it was reported that INH resistant M tuberculae also lacked peroxi-dase/catalase activity. 

One striking example is the Mycobacterium tuberculosis enoyl-acyl carrier protein (AGP) reductase (InhA), which catalyzes the last reaction in fatty acid elongation. This enzyme is the target of isoniazid, one of the major drugs used for treatment of tuberculosis. Isoniazid is activated by KatG, a mycobacterial catalase—peroxidase, to a species that reacts with the NAD coenzyme of InhA. The resulting adduct is a potent inhibitor of InhA. Efforts are under way to make more potent inhibitors that do not require KatG activation. 

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