Relationship Between Mutation of Serine Residue at 315th Position in M. Tuberculosis Catalase-peroxidase Enzyme and Isoniazid Susceptibility: an in Silico Analysis

Overview

Journal J Mol Model

Publisher Springer

Specialty Molecular Biology

Date 2010 Jul 2

PMID 20593210

Citations 14

Authors

Rituraj Purohit

Vidya Rajendran

Rao Sethumadhavan

Affiliations

Soon will be listed here.

Abstract

Remarkable advances have been made in the drug therapy of tuberculosis. However much remains to be learned about the molecular and structural basis of drug resistance in Mycobacterium tuberculosis. It is known that, activation of Isoniazid (INH) is mediated by Mycobacterium tuberculosis catalase-peroxidase (MtBKatG) and mutation at position 315 (serine to threonine) leads to resistance. We have conducted studies on the drug resistance through docking and binding analysis supported by time-scale (∼ 1000 ps) and unrestrained all-atom molecular dynamics simulations of wild and mutant MtBKatG. The study showed conformational changes of binding residues. Mutant (S315T) showed high docking score and INH binding affinity as compared to wild enzyme. In molecular dynamics simulation, mutant enzyme exhibited less structure fluctuation at INH binding residues and more degree of fluctuation at C-terminal domain compared to wild enzyme. Our computational studies and data endorse that MtBKatG mutation (S315T) decrease the flexibility of binding residues and made them rigid by altering the conformational changes, in turn it hampers the INH activity. We ascertain from this work that, this study on structural mechanism of resistance development in Mycobacterium tuberculosis would lead to new therapeutics based on the result obtained in this study.

Citing Articles

Exploring Prediction of Antimicrobial Resistance Based on Protein Solvent Accessibility Variation.

Marini S, Oliva M, Slizovskiy I, Noyes N, Boucher C, Prosperi M Front Genet. 2021; 12:564186.

PMID: 33552147 PMC: 7862766. DOI: 10.3389/fgene.2021.564186.

Identification of Conformational B-cell Epitopes in Diphtheria Toxin at Varying Temperatures Using Molecular Dynamics Simulations.

Ghaderi S, Bozorgmehr M, Ahmadi M, Tarahomjoo S Arch Razi Inst. 2021; 75(4):427-437.

PMID: 33403838 PMC: 8410147. DOI: 10.22092/ari.2019.127251.1377.

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach.

Alzahrani F, Ahmed F, Sharma M, Rehan M, Mahfuz M, Baeshen M Sci Rep. 2020; 10(1):12377.

PMID: 32704157 PMC: 7378827. DOI: 10.1038/s41598-020-69033-8.

Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations.

Pimentel A, Scodro R, Caleffi-Ferracioli K, Dias Siqueira V, Zanetti Campanerut-Sa P, Lopes L J Mol Model. 2017; 23(4):121.

PMID: 28303436 DOI: 10.1007/s00894-017-3290-3.

Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosis pyrazinamidase enzyme and pyrazinamide susceptibility.

Vats C, Dhanjal J, Goyal S, Gupta A, Bharadvaja N, Grover A BMC Genomics. 2015; 16 Suppl 2:S14.

PMID: 25708048 PMC: 4331714. DOI: 10.1186/1471-2164-16-S2-S14.

References

Hess B, Kutzner C, van der Spoel D, Lindahl E . GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J Chem Theory Comput. 2015; 4(3):435-47. DOI: 10.1021/ct700301q. View

Marttila H, Makinen J, Marjamaki M, Soini H . Prospective evaluation of pyrosequencing for the rapid detection of isoniazid and rifampin resistance in clinical Mycobacterium tuberculosis isolates. Eur J Clin Microbiol Infect Dis. 2008; 28(1):33-8. DOI: 10.1007/s10096-008-0584-5. View

Ranguelova K, Suarez J, Metlitsky L, Yu S, Brejt S, Brejt S . Impact of distal side water and residue 315 on ligand binding to ferric Mycobacterium tuberculosis catalase-peroxidase (KatG). Biochemistry. 2008; 47(47):12583-92. DOI: 10.1021/bi801511u. View

Wengenack N, Rusnak F . Evidence for isoniazid-dependent free radical generation catalyzed by Mycobacterium tuberculosis KatG and the isoniazid-resistant mutant KatG(S315T). Biochemistry. 2001; 40(30):8990-6. DOI: 10.1021/bi002614m. View

Heym B, Zhang Y, Poulet S, Young D, Cole S . Characterization of the katG gene encoding a catalase-peroxidase required for the isoniazid susceptibility of Mycobacterium tuberculosis. J Bacteriol. 1993; 175(13):4255-9. PMC: 204858. DOI: 10.1128/jb.175.13.4255-4259.1993. View

Marttila H, Soini H, Eerola E, Vyshnevskaya E, Vyshnevskiy B, Otten T . A Ser315Thr substitution in KatG is predominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemother. 1998; 42(9):2443-5. PMC: 105851. DOI: 10.1128/AAC.42.9.2443. View

Welinder K . Bacterial catalase-peroxidases are gene duplicated members of the plant peroxidase superfamily. Biochim Biophys Acta. 1991; 1080(3):215-20. DOI: 10.1016/0167-4838(91)90004-j. View

Han L, Lin H, Li Z, Zheng C, Cao Z, Xie B . PEARLS: program for energetic analysis of receptor-ligand system. J Chem Inf Model. 2006; 46(1):445-50. DOI: 10.1021/ci0502146. View

Hazbon M, Brimacombe M, Bobadilla Del Valle M, Cavatore M, Guerrero M, Varma-Basil M . Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2640-9. PMC: 1538650. DOI: 10.1128/AAC.00112-06. View

10.

Emsley P, Cowtan K . Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2126-32. DOI: 10.1107/S0907444904019158. View

11.

Bertrand T, Eady N, Jones J, Jesmin , Nagy J, Jamart-Gregoire B . Crystal structure of Mycobacterium tuberculosis catalase-peroxidase. J Biol Chem. 2004; 279(37):38991-9. DOI: 10.1074/jbc.M402382200. View

12.

Ng V, Cox J, Sousa A, MacMicking J, McKinney J . Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol. 2004; 52(5):1291-302. DOI: 10.1111/j.1365-2958.2004.04078.x. View

13.

Feldman H, Snyder K, Ticoll A, Pintilie G, Hogue C . A complete small molecule dataset from the protein data bank. FEBS Lett. 2006; 580(6):1649-53. DOI: 10.1016/j.febslet.2006.02.003. View

14.

Shrake A, Rupley J . Environment and exposure to solvent of protein atoms. Lysozyme and insulin. J Mol Biol. 1973; 79(2):351-71. DOI: 10.1016/0022-2836(73)90011-9. View

15.

Timmins G, Deretic V . Mechanisms of action of isoniazid. Mol Microbiol. 2006; 62(5):1220-7. DOI: 10.1111/j.1365-2958.2006.05467.x. View

16.

Pym A, Saint-Joanis B, Cole S . Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect Immun. 2002; 70(9):4955-60. PMC: 128294. DOI: 10.1128/IAI.70.9.4955-4960.2002. View

17.

Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson H . PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res. 2005; 33(Web Server issue):W363-7. PMC: 1160241. DOI: 10.1093/nar/gki481. View

18.

Nagy J, Cass A, Brown K . Purification and characterization of recombinant catalase-peroxidase, which confers isoniazid sensitivity in Mycobacterium tuberculosis. J Biol Chem. 1998; 272(50):31265-71. DOI: 10.1074/jbc.272.50.31265. View

19.

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

20.

Zhang Y, Garbe T, Young D . Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Mol Microbiol. 1993; 8(3):521-4. DOI: 10.1111/j.1365-2958.1993.tb01596.x. View