Catalase-peroxidase KatG

Zhao X, S Girotto, S Yu, RS Magliozzo (2004) Evidence for radical formation at Tyr-353 in Mycobacterium tuberculosis catalase-peroxidase (KatG) J Biol Chem 279 7606-7612. 

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. 

Smulevich G, Jakopitsch C, Droghetti E et al (2006) Probing the structure and bifunctionality of catalase-peroxidase (KatG). J Inorg Biochem 100 568-585... 

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... 

Suarez J, Ranguelova K, Jarzecki AA et al (2009) An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG). J Biol Chem 284 7017-7029... 

Scheme 3 Mycobacterial catalase-peroxidase (KatG)-catalyzed reaction of isoniazid (2) and NADH.

Wei, C.J., Lei, B., Musser, J.M., and Tu, S.C. (2003) Isoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production. Antimicrob. Agents. Chemother. 47, 670-675. 

Catalase HPII Catalase-1 Catalase-peroxidase (KatG)... 

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...

Musser JM, Kapur V, Wilhams DL, Kreiswirth BN, van Soolingen D, van Embden JD. Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing restricted array of mutatins associated with drag re- 45. sistance. J. Infect. Dis. 1996 173 196-202. 

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. 

KatG bifunctional catalase-peroxidase LTQ lysine tyrosylquinone... 

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. 

CcP = Cytochrome c Peroxidase BCCP = Bacterial Cytochrome c Peroxidases APX = Soybean or pea or Tobacco Ascorbate Peroxidase MNP = Manganese Peroxidase LIP = Lignin Peroxidase EPO = Eosinophil Peroxidase LPO = Lactoperoxidase MPO = Myeloperoxidase TPO = Thyroid Peroxidase ARP = Arthomyces Ramos us Peroxidase SPO = Salivary Peroxidase PGHsynthase = Prostaglandin Hsynthase KatG = Catalase-peroxidase EPR = Electron Paramagnetic Resonance RR = Resonance Raman BHA = Benzhydroxamic Acid FA = Ferulic Acid DBNBS = 3,5-dibromo-4-nitrosobenzenesulfonic acid ABTS = 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) MNPr = Methylnitrosopropane INH = Isoniazid. 

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