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The tuberculosis prodrug isoniazid bound to activating peroxidases.

Metcalfe C, Macdonald IK, Murphy EJ, Brown KA, Raven EL, Moody PC
J Biol Chem 283 6193-200 (2008)
Related entries: 2v23, 2v2e, 2vcf, 2vcs

Cited: 36 times
EuropePMC logo PMID: 18056997

Abstract

Isoniazid (INH, isonicotinic acid hydrazine) is one of only two therapeutic agents effective in treating tuberculosis. This prodrug is activated by the heme enzyme catalase peroxidase (KatG) endogenous to Mycobacterium tuberculosis but the mechanism of activation is poorly understood, in part because the binding interaction has not been properly established. The class I peroxidases ascorbate peroxidase (APX) and cytochrome c peroxidase (CcP) have active site structures very similar to KatG and are also capable of activating isoniazid. We report here the first crystal structures of complexes of isoniazid bound to APX and CcP. These are the first structures of isoniazid bound to any activating enzymes. The structures show that isoniazid binds close to the delta-heme edge in both APX and CcP, although the precise binding orientation varies slightly in the two cases. A second binding site for INH is found in APX at the gamma-heme edge close to the established ascorbate binding site, indicating that the gamma-heme edge can also support the binding of aromatic substrates. We also show that in an active site mutant of soybean APX (W41A) INH can bind directly to the heme iron to become an inhibitor and in a different mode when the distal histidine is replaced by alanine (H42A). These structures provide the first unambiguous evidence for the location of the isoniazid binding site in the class I peroxidases and provide rationalization of isoniazid resistance in naturally occurring KatG mutant strains of M. tuberculosis.

Articles - 2vcn mentioned but not cited (1)

  1. Isoniazid inhibits the heme-based reactivity of Mycobacterium tuberculosis truncated hemoglobin N. Ascenzi P, Coletta A, Cao Y, Trezza V, Leboffe L, Fanali G, Fasano M, Pesce A, Ciaccio C, Marini S, Coletta M. PLoS One 8 e69762 (2013)


Reviews citing this publication (5)

  1. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Unissa AN, Subbian S, Hanna LE, Selvakumar N. Infect Genet Evol 45 474-492 (2016)
  2. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. Boelsterli UA, Lee KK. J Gastroenterol Hepatol 29 678-687 (2014)
  3. Neutron protein crystallography: A complementary tool for locating hydrogens in proteins. O'Dell WB, Bodenheimer AM, Meilleur F. Arch Biochem Biophys 602 48-60 (2016)
  4. Catalase in peroxidase clothing: Interdependent cooperation of two cofactors in the catalytic versatility of KatG. Njuma OJ, Ndontsa EN, Goodwin DC. Arch Biochem Biophys 544 27-39 (2014)
  5. Post-Translational Modification of Proteins Mediated by Nitro-Fatty Acids in Plants: Nitroalkylation. Aranda-Caño L, Sánchez-Calvo B, Begara-Morales JC, Chaki M, Mata-Pérez C, Padilla MN, Valderrama R, Barroso JB. Plants (Basel) 8 (2019)

Articles citing this publication (30)

  1. Heme enzymes. Neutron cryo-crystallography captures the protonation state of ferryl heme in a peroxidase. Casadei CM, Gumiero A, Metcalfe CL, Murphy EJ, Basran J, Concilio MG, Teixeira SC, Schrader TE, Fielding AJ, Ostermann A, Blakeley MP, Raven EL, Moody PC. Science 345 193-197 (2014)
  2. Nature of the ferryl heme in compounds I and II. Gumiero A, Metcalfe CL, Pearson AR, Raven EL, Moody PC. J Biol Chem 286 1260-1268 (2011)
  3. Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities. Cade CE, Dlouhy AC, Medzihradszky KF, Salas-Castillo SP, Ghiladi RA. Protein Sci 19 458-474 (2010)
  4. Inhibition of lactoperoxidase by its own catalytic product: crystal structure of the hypothiocyanate-inhibited bovine lactoperoxidase at 2.3-A resolution. Singh AK, Singh N, Sharma S, Shin K, Takase M, Kaur P, Srinivasan A, Singh TP. Biophys J 96 646-654 (2009)
  5. Isonicotinic acid hydrazide conversion to Isonicotinyl-NAD by catalase-peroxidases. Wiseman B, Carpena X, Feliz M, Donald LJ, Pons M, Fita I, Loewen PC. J Biol Chem 285 26662-26673 (2010)
  6. Proton delivery to ferryl heme in a heme peroxidase: enzymatic use of the Grotthuss mechanism. Efimov I, Badyal SK, Metcalfe CL, Macdonald I, Gumiero A, Raven EL, Moody PC. J Am Chem Soc 133 15376-15383 (2011)
  7. Mode of binding of the tuberculosis prodrug isoniazid to heme peroxidases: binding studies and crystal structure of bovine lactoperoxidase with isoniazid at 2.7 A resolution. Singh AK, Kumar RP, Pandey N, Singh N, Sinha M, Bhushan A, Kaur P, Sharma S, Singh TP. J Biol Chem 285 1569-1576 (2010)
  8. Spin trapping investigation of peroxide- and isoniazid-induced radicals in Mycobacterium tuberculosis catalase-peroxidase. Ranguelova K, Suarez J, Magliozzo RS, Mason RP. Biochemistry 47 11377-11385 (2008)
  9. Computational approach to understanding the mechanism of action of isoniazid, an anti-TB drug. Jena L, Waghmare P, Kashikar S, Kumar S, Harinath BC. Int J Mycobacteriol 3 276-282 (2014)
  10. Isoniazid and rifampicin inhibit allosterically heme binding to albumin and peroxynitrite isomerization by heme-albumin. Ascenzi P, Bolli A, di Masi A, Tundo GR, Fanali G, Coletta M, Fasano M. J Biol Inorg Chem 16 97-108 (2011)
  11. Crystal structure of guaiacol and phenol bound to a heme peroxidase. Murphy EJ, Metcalfe CL, Nnamchi C, Moody PC, Raven EL. FEBS J 279 1632-1639 (2012)
  12. Ascorbate peroxidase overexpression protects Leishmania braziliensis against trivalent antimony effects. Moreira DS, Xavier MV, Murta SMF. Mem Inst Oswaldo Cruz 113 e180377 (2018)
  13. Role of the oxyferrous heme intermediate and distal side adduct radical in the catalase activity of Mycobacterium tuberculosis KatG revealed by the W107F mutant. Zhao X, Yu S, Ranguelova K, Suarez J, Metlitsky L, Schelvis JP, Magliozzo RS. J Biol Chem 284 7030-7037 (2009)
  14. Access channel residues Ser315 and Asp137 in Mycobacterium tuberculosis catalase-peroxidase (KatG) control peroxidatic activation of the pro-drug isoniazid. Zhao X, Hersleth HP, Zhu J, Andersson KK, Magliozzo RS. Chem Commun (Camb) 49 11650-11652 (2013)
  15. Antibiotic resistance in Mycobacterium tuberculosis: peroxidase intermediate bypass causes poor isoniazid activation by the S315G mutant of M. tuberculosis catalase-peroxidase (KatG). Suarez J, Ranguelova K, Schelvis JPM, Magliozzo RS. J Biol Chem 284 16146-16155 (2009)
  16. Using cryo-EM to understand antimycobacterial resistance in the catalase-peroxidase (KatG) from Mycobacterium tuberculosis. Munir A, Wilson MT, Hardwick SW, Chirgadze DY, Worrall JAR, Blundell TL, Chaplin AK. Structure 29 899-912.e4 (2021)
  17. Isoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI. Lee MR, Huang HL, Lin SW, Cheng MH, Lin YT, Chang SY, Yan BS, Kuo CH, Lu PL, Wang JY, Chong IW. J Clin Med 8 E812 (2019)
  18. The crystal structure of isoniazid-bound KatG catalase-peroxidase from Synechococcus elongatus PCC7942. Kamachi S, Hirabayashi K, Tamoi M, Shigeoka S, Tada T, Wada K. FEBS J 282 54-64 (2015)
  19. Insights into the bonding pattern for characterizing the open and closed state of the substrate-binding loop in Mycobacterium tuberculosis InhA. Kumar V, Sobhia ME. Future Med Chem 6 605-616 (2014)
  20. Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations. Kamsri P, Koohatammakun N, Srisupan A, Meewong P, Punkvang A, Saparpakorn P, Hannongbua S, Wolschann P, Prueksaaroon S, Leartsakulpanich U, Pungpo P. SAR QSAR Environ Res 25 473-488 (2014)
  21. Crystal structure of the catalase-peroxidase KatG W78F mutant from Synechococcus elongatus PCC7942 in complex with the antitubercular pro-drug isoniazid. Kamachi S, Hirabayashi K, Tamoi M, Shigeoka S, Tada T, Wada K. FEBS Lett 589 131-137 (2015)
  22. Elucidating drug-enzyme interactions and their structural basis for improving the affinity and potency of isoniazid and its derivatives based on computer modeling approaches. Punkvang A, Saparpakorn P, Hannongbua S, Wolschann P, Pungpo P. Molecules 15 2791-2813 (2010)
  23. Molecular investigation of active binding site of isoniazid (INH) and insight into resistance mechanism of S315T-MtKatG in Mycobacterium tuberculosis. Srivastava G, Tripathi S, Kumar A, Sharma A. Tuberculosis (Edinb) 105 18-27 (2017)
  24. Novel Chemical Scaffolds for Inhibition of Rifamycin-Resistant RNA Polymerase Discovered from High-Throughput Screening. Scharf NT, Molodtsov V, Kontos A, Murakami KS, Garcia GA. SLAS Discov 22 287-297 (2017)
  25. Computational modeling and bioinformatic analyses of functional mutations in drug target genes in Mycobacterium tuberculosis. Singh P, Jamal S, Ahmed F, Saqib N, Mehra S, Ali W, Roy D, Ehtesham NZ, Hasnain SE. Comput Struct Biotechnol J 19 2423-2446 (2021)
  26. Dimensionless parameter predicts bacterial prodrug success. Holt BA, Tuttle M, Xu Y, Su M, Røise JJ, Wang X, Murthy N, Kwong GA. Mol Syst Biol 18 e10495 (2022)
  27. A model of isoniazid treatment of tuberculosis. Lemmer Y, Grobler A, Moody C, Viljoen H. J Theor Biol 363 367-373 (2014)
  28. Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study. Kamsri P, Punkvang A, Saparpakorn P, Hannongbua S, Irle S, Pungpo P. J Mol Model 20 2319 (2014)
  29. Withdrawn Infect Disord Drug Targets (2012)
  30. [RuII(NO+)]3+-core complexes with 4-methyl-pyrimidine and ethyl-isonicotinate: synthesis, X-ray structure, spectroscopy, and computational and NO-release studies upon UVA irradiation. Tamasi G, Curci M, Berrettini F, Justice N, Sega A, Chiasserini L, Cini R. J Inorg Biochem 102 1874-1884 (2008)


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