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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 1569-76 (2010)
Cited: 23 times
EuropePMC logo PMID: 19907057

Abstract

Isoniazid (INH) is an anti-tuberculosis prodrug that is activated by mammalian lactoperoxidase and Mycobacterium tuberculosis catalase peroxidase (MtCP). We report here binding studies, an enzyme assay involving INH, and the crystal structure of the complex of bovine lactoperoxidase (LPO) with INH to illuminate binding properties and INH activation as well as the mode of diffusion and interactions together with a detailed structural and functional comparison with MtCP. The structure determination shows that isoniazid binds to LPO at the substrate binding site on the distal heme side. The substrate binding site is connected to the protein surface through a long hydrophobic channel. The acyl hydrazide moiety of isoniazid interacts with Phe(422) O, Gln(423) O(epsilon1), and Phe(254) O. In this arrangement, pyridinyl nitrogen forms a hydrogen bond with a water molecule, W-1, which in turn forms three hydrogen bonds with Fe(3+), His(109) N(epsilon2), and Gln(105) N(epsilon2). The remaining two sides of isoniazid form hydrophobic interactions with the atoms of heme pyrrole ring A, C(beta) and C(gamma) atoms of Glu(258), and C(gamma) and C(delta) atoms of Arg(255). The binding studies indicate that INH binds to LPO with a value of 0.9 x 10(-6) m for the dissociation constant. The nitro blue tetrazolium reduction assay shows that INH is activated by the reaction of LPO-H(2)O(2) with INH. This suggests that LPO can be used for INH activation. It also indicates that the conversion of INH into isonicotinoyl radical by LPO may be the cause of INH toxicity.

Articles - 3i6n mentioned but not cited (4)

  1. 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)
  2. 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)
  3. CO binding and ligand discrimination in human myeloperoxidase. Murphy EJ, Maréchal A, Segal AW, Rich PR. Biochemistry 49 2150-2158 (2010)
  4. Withdrawn Infect Disord Drug Targets (2012)


Reviews citing this publication (2)

  1. Lactoperoxidase: structural insights into the function,ligand binding and inhibition. Sharma S, Singh AK, Kaushik S, Sinha M, Singh RP, Sharma P, Sirohi H, Kaur P, Singh TP. Int J Biochem Mol Biol 4 108-128 (2013)
  2. Lactoperoxidase as a potential drug target. Flemmig J, Gau J, Schlorke D, Arnhold J. Expert Opin Ther Targets 20 447-461 (2016)

Articles citing this publication (17)

  1. Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: an in silico analysis. Purohit R, Rajendran V, Sethumadhavan R. J Mol Model 17 869-877 (2011)
  2. 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)
  3. A novel metabolite of antituberculosis therapy demonstrates host activation of isoniazid and formation of the isoniazid-NAD+ adduct. Mahapatra S, Woolhiser LK, Lenaerts AJ, Johnson JL, Eisenach KD, Joloba ML, Boom WH, Belisle JT. Antimicrob Agents Chemother 56 28-35 (2012)
  4. 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)
  5. Crystal structure of halogenase PltA from the pyoluteorin biosynthetic pathway. Pang AH, Garneau-Tsodikova S, Tsodikov OV. J Struct Biol 192 349-357 (2015)
  6. First structural evidence for the mode of diffusion of aromatic ligands and ligand-induced closure of the hydrophobic channel in heme peroxidases. Singh AK, Singh N, Tiwari A, Sinha M, Kushwaha GS, Kaur P, Srinivasan A, Sharma S, Singh TP. J Biol Inorg Chem 15 1099-1107 (2010)
  7. Structural evidence for the order of preference of inorganic substrates in mammalian heme peroxidases: crystal structure of the complex of lactoperoxidase with four inorganic substrates, SCN, I, Br and Cl. Singh AK, Pandey N, Sinha M, Kaur P, Sharma S, Singh TP. Int J Biochem Mol Biol 2 328-339 (2011)
  8. Bovine carbonyl lactoperoxidase structure at 2.0Å resolution and infrared spectra as a function of pH. Singh AK, Smith ML, Yamini S, Ohlsson PI, Sinha M, Kaur P, Sharma S, Paul JA, Singh TP, Paul KG. Protein J 31 598-608 (2012)
  9. Bovine lactoperoxidase - a versatile one- and two-electron catalyst of high structural and thermal stability. Banerjee S, Furtmüller PG, Obinger C. Biotechnol J 6 231-243 (2011)
  10. Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution. Singh RP, Singh A, Sirohi HV, Singh AK, Kaur P, Sharma S, Singh TP. FEBS Open Bio 6 640-650 (2016)
  11. Mode of binding of the antithyroid drug propylthiouracil to mammalian haem peroxidases. Singh RP, Singh A, Kushwaha GS, Singh AK, Kaur P, Sharma S, Singh TP. Acta Crystallogr F Struct Biol Commun 71 304-310 (2015)
  12. Rapid in vivo detection of isoniazid-sensitive Mycobacterium tuberculosis by breath test. Choi SW, Maiga M, Maiga MC, Atudorei V, Sharp ZD, Bishai WR, Timmins GS. Nat Commun 5 4989 (2014)
  13. Enhanced Antibacterial Activity of Lactoperoxidase-Thiocyanate-Hydrogen Peroxide System in Reduced-Lactose Milk Whey. Al-Baarri AN, Damayanti NT, Legowo AM, Tekiner İH, Hayakawa S. Int J Food Sci 2019 8013402 (2019)
  14. Structural evidence of the oxidation of iodide ion into hyper-reactive hypoiodite ion by mammalian heme lactoperoxidase. Singh PK, Ahmad N, Yamini S, Singh RP, Singh AK, Sharma P, Smith ML, Sharma S, Singh TP. Protein Sci 31 384-395 (2022)
  15. Structure of Yak Lactoperoxidase at 1.55 Å Resolution. Viswanathan V, Rani C, Ahmad N, Singh PK, Sharma P, Kaur P, Sharma S, Singh TP. Protein J 40 8-18 (2021)
  16. Design of anti-thyroid drugs: Binding studies and structure determination of the complex of lactoperoxidase with 2-mercaptoimidazole at 2.30 Å resolution. Sirohi HV, Singh PK, Iqbal N, Sharma P, Singh AK, Kaur P, Sharma S, Singh TP. Proteins 85 1882-1890 (2017)
  17. Isoniazid and thioacetazone may exhibit antitubercular activity by binding directly with the active site of mycolic acid cyclopropane synthase: Hypothesis based on computational analysis. Banerjee D, Bhattacharyya R. Bioinformation 8 787-789 (2012)


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