Skip to main content

Advertisement

SpringerLink
Log in

Structural significance of modified nucleoside 5-taurinomethyl-2-thiouridine, τm5s2U, found at ‘wobble’ position in anticodon loop of human mitochondrial tRNALys

  • Original Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

The myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial encephalomyopathic disease caused due to the lack of hypermodified nucleoside 5-taurinomethyl-2-thiouridine at ‘wobble’ 34th position in the anticodon loop of human mitochondrial tRNALys. Understanding the structural significance of τm5s2U might be helpful to get more information about the MERRF disease in detail at the atomic level. Hence, conformational preferences of hypermodified nucleoside 5-taurinomethyl-2-thiouridine 5′-monophosphate, ‘p-τm5s2U,’ have been studied using semiempirical quantum chemical RM1 method. Full geometry optimization using ab initio molecular orbital HF-SCF (6-31G**) and DFT (B3LYP/6-31G**) methods has also been used to compare the salient features. The RM1 preferred most stable conformation of ‘p-τm5s2U’ has been stabilized by hydrogen bonding interactions between O(11a)…HN(8), O1P(34)…HN(8), O1P(34)…HC(10), O4′(34)…HC(6), S(2)…HC1′(34), O5′(34)…HC(6), and O(4)…HC(7). Another conformational study of 5-taurinomethyl-2-thiouridine side chain in the presence of anticodon loop bases of human mitochondrial tRNALys showed similar conformation as found in RM1 preferred most stable conformation of ‘p-τm5s2U.’ The glycosyl torsion angle of τm5s2U retains ‘anti’ conformation. Similarly, MD simulation results are also found in accordance with RM1 preferred stable structure. The solvent-accessible surface area calculations revealed surface accessibility of τm5s2U in human mt tRNALys anticodon loop. The MEPs calculations of codon–anticodon models of τm5s2U(34):G3 and τm5s2U(34):A3 showed unique potential tunnels between the hydrogen bond donor and acceptor atoms. These results might be useful to understand the exact role of τm5s2U(34) to recognize AAG/AAA codons and to design new strategies to prevent mitochondrial disease, MERRF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. McCloskey J, Graham D, Zhou S, Crain P, Ibba M, Konisky J, Soll D, Olsen G (2001) Post-transcriptional modification in archaeal tRNAs: identities and phylogenetic relations of nucleotides from mesophilic and hyperthermophilic Methanococcales. Nucleic Acids Res 29:4699–4706

    Article  CAS  Google Scholar 

  2. Limbach P, Crain P, McCloskey J (1994) Summary: the modified nucleosides of RNA. Nucleic Acids Res 22:2183–2196

    Article  CAS  Google Scholar 

  3. Curran J (1998) In: Grosjean H, Renne R (eds) Modification and editing of RNA. ASM Press, Washington, DC

    Google Scholar 

  4. Suzuki T (2005) Biosynthesis and function of tRNA wobble modifications. Top Curr Gen 12:23–69

    CAS  Google Scholar 

  5. Bjork G (1995) In: Soll DR, RajBhandary UL (eds) tRNA: structure, biosynthesis and function. ASM press, Washington, DC

    Google Scholar 

  6. Juhling F, Morl M, Hartmann R, Sprinzl M, Stadler P, Putz J (2009) tRNAdb 2009: compilation of tRNA sequences and tRNA genes. Nucleic Acids Res 37:D159–D162

    Article  Google Scholar 

  7. Yokoyama S, Nishimura S (1995) In: Soll DR, RajBhandary UL (ed) tRNA: structure, biosynthesis and function. ASM press, Washington

  8. Suzuki T, Suzuki T, Wada T, Saigo K, Watanabe K (2002) Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases. EMBO J 21:6581–6589

    Article  CAS  Google Scholar 

  9. Yasukawa T, Suzuki T, Suzuki T, Ueda T, Ohta S, Watanabe K (2000) Modification defect at anticodon wobble nucleotide of mitochondrial tRNAsLeu(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. J Biol Chem 275:4251–4257

    Article  CAS  Google Scholar 

  10. Sturman J (1993) Taurine in development. Phys Rev 73:119–147

    CAS  Google Scholar 

  11. Huxtable R (1992) Physiological actions of taurine. Phys Rev 72:101–163

    CAS  Google Scholar 

  12. Mankovskaya I, Serebrovskaya T, Swanson R, Vavilova G, Kharlamova O (2000) Mechanisms of taurine antihypoxic and antioxidant action. High Alt Med Biol 1:105–110

    Article  CAS  Google Scholar 

  13. Pokhrel P, Lau-Cam C (2000) Protection by taurine and structurally related sulfur-containing compounds against erythrocyte membrane damage by hydrogen peroxide. Adv Exp Med Biol 483:411–429

    Article  CAS  Google Scholar 

  14. Del Olmo N, Galarreta M, Bustamante J, Del Rio R, Solis J (2000) Taurine-induced synaptic potentiation: role of calcium and interaction with LTP. Neuropharmacology 39:40–54

    Article  Google Scholar 

  15. Bureau M, Olsen R (1991) Taurine acts on a subclass of GABAA receptors in mammalian brain in vitro. Eur J Pharmacol 207:9–16

    Article  CAS  Google Scholar 

  16. Yasukawa T, Suzuki T, Ishii N, Ohta S, Watanabe K (2001) Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. EMBO J 20:4794–4802

    Article  CAS  Google Scholar 

  17. Watanabe K (2007) Role of modified nucleosides in the translation function of tRNAs from extreme thermophilic bacteria and animal mitochondria. Bull Chem Soc Jpn 80:1253–1267

    Article  CAS  Google Scholar 

  18. Larsson N, Tulinius M, Holme E, Oldfors A, Andersen O, Wahlström J, Aasly J (1992) Segregation and manifestations of the mtDNA tRNA (Lys) A–>G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet 51:1201–1212

    CAS  Google Scholar 

  19. Larsson N, Tulinius M, Holme E, Oldfors A (1995) Pathogenetic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas. Muscle Nerve Suppl 3:102–106

    Article  Google Scholar 

  20. Howell N (1999) Human mitochondrial diseases: answering questions and questioning answers. Int Rev Cytol 186:49–116

    Article  CAS  Google Scholar 

  21. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T (1980) Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J Neurol Sci 47:117–133

    Article  CAS  Google Scholar 

  22. Jacobs H (2003) Disorders of mitochondrial protein synthesis. Hum Mol Genet 12:R293–R301

    Article  CAS  Google Scholar 

  23. Florentz C, Sohm B, Tryoen-Toth P, Putz J, Sissler M (2003) Human mitochondrial tRNAs in health and disease. Cell Mol Life Sci 60:1356–1375

    Article  CAS  Google Scholar 

  24. Enriquez J, Chomyn A, Attardi G (1995) MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination. Nat Genet 10:47–55

    Article  CAS  Google Scholar 

  25. Oldfors A, Holme E, Tulinius M, Larsson N (1995) Tissue distribution and disease manifestations of the tRNA(Lys) A–>G(8344) mitochondrial DNA mutation in a case of myoclonus epilepsy and ragged red fibres. Acta Neuropathol 90:328–333

    Article  CAS  Google Scholar 

  26. Mancuso M, Filosto M, Mootha V, Rocchi A, Pistolesi S, Murri L, DiMauro S, Siciliano G (2004) A novel mitochondrial tRNAPhe mutation causes MERRF syndrome. Neurology 62:2119–2121

    Article  CAS  Google Scholar 

  27. Pfeffer G, Majamaa K, Turnbull M, Thorburn D, Chinnery F (2012) Treatment for mitochondrial disorders. Cochrane Database Syst Rev. doi:10.1002/14651858.CD004426.pub3

    Google Scholar 

  28. James A, Wei Y, Pang C-Y, Murphy M (1996) Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem J 318:401–407

    Article  CAS  Google Scholar 

  29. De la Mata M, Garrido-Maraver J, Cotán D, Cordero M, Oropesa-Ávila M, Izquierdo G, De Miguel M, Lorite B, Infante R, Ybot P, Jackson S, Sánchez-Alcázar (2012) A recovery of MERRF fibroblasts and cybrids pathophysiology by coenzyme Q10. Neurotherapeutics 9:446–463

    Article  CAS  Google Scholar 

  30. Yokoyama S, Watanabe T, Murao K, Ishikura H, Yamaizumi Z, Nishimura S, Miyazawa T (1985) Molecular mechanism of codon recognition by tRNA species with modified uridine in the first position of the anticodon. PNAS 82:4905–4909

    Article  CAS  Google Scholar 

  31. Ashraf S, Sochacka E, Cain R, Guenther R, Malkiewicz A, Agris P (1999) Single atom modification (O–>S) of tRNA confers ribosome binding. RNA 5:188–194

    Article  CAS  Google Scholar 

  32. Kamble A, Kumbhar B, Sambhare S, Bavi R, Sonawane K (2014) Conformational preferences of modified nucleoside 5-taurinomethyluridine, τm5U occur at ‘wobble’ 34th position in the anticodon loop of tRNA. Cell Biochem Biophys Cell Biochem Biophys 71:1589–1603

    Article  Google Scholar 

  33. Kurata S, Weixlbaumer A, Ohtsuki T, Shimazaki T, Wada T, Kirino Y, Takai K, Watanabe K, Ramakrishnan V, Suzuki T (2008) Modified uridines with C5-methylene substituents at the first position of the tRNA anticodon stabilize U.G wobble pairing during decoding. J Biol Chem 283:18801–18811

    Article  CAS  Google Scholar 

  34. Sonavane U, Sonawane K, Tewari R (2002) Conformational preferences of base substituent in hypermodified nucleotide queuosine 5’ monophosphate pQ and protonated variant pQH+. J Biomol Struct Dyn 20:473–485

    Article  CAS  Google Scholar 

  35. Hehre J, Radom W, Schleyer P, Pople J (1986) ab initio molecular orbital theory. Wiley, New York

    Google Scholar 

  36. Rocha G, Freire R, Simas A, Stewart J (2006) RM1: a reparameterization of AM1 for H, C, N, O, P, P, F, Cl, Br and I. J Comp Chem 27:1101–1111

    Article  CAS  Google Scholar 

  37. Ferreira D, Machado A, Tiago F, Madurro J, Madurro A, Odonirio A (2012) Molecular modeling study on the possible polymers formed during the electropolymerization of 3-hydroxyphenylacetic acid. J Mol Graph Model 34:18–27

    Article  CAS  Google Scholar 

  38. Labidi N (2012) Comparative study of kinetics isomerization of substituted polyacetylene (Cl, F, Br and I): semi empirical RM1 study. JSCS 19:163–171

    Google Scholar 

  39. Pol-Fachin L, Fraga C, Barreiro E, Verli H (2010) A Characterization of the conformational ensemble from bioactive N-acylhydrazone derivatives. J Mol Graph Model 28:446–454

    Article  CAS  Google Scholar 

  40. Kerber V, Passos C, Verli H, Fett-Neto A, Quirion J, Henriques A (2008) Psychollatine, a glucosidic monoterpene indole alkaloid from Psychotria umbellate. J Nat Prod 71:697–700

    Article  CAS  Google Scholar 

  41. Goncalves A, Franca T, Figueroa-Villar J, Pascutti P (2010) Conformational analysis of toxogonine, TMB-4 and HI-6 using PM6 and RM1 Methods. J Brazil Chem Soc 21:179–184

    Article  CAS  Google Scholar 

  42. Kumbhar N, Sonawane K (2011) Iso-energetic multiple conformations of hypermodified nucleic acid base wybutine (yW) which occur at 37th position in anticodon loop of tRNAPhe. J Mol Graph Model 29:935–946

    Article  CAS  Google Scholar 

  43. Bavi R, Kamble A, Kumbhar N, Kumbhar B, Sonawane K (2011) Conformational preferences of modified nucleoside N2-methylguanosine (m2G) and its derivative N2, N2-dimethylguanosine (m2 2G) occur at 26th position (Hinge Region) in tRNA. Cell Biochem Biophys 61:507–521

    Article  CAS  Google Scholar 

  44. Kumbhar N, Kumbhar B, Sonawane K (2012) Structural significance of hypermodified nucleic acid base hydroxywybutine (OHyW) which occur at 37th position in the anticodon loop of tRNAPhe. J Mol Graph Model 38:174–185

    Article  CAS  Google Scholar 

  45. Anisimov V, Cavasotto C (2011) Hydration free energies using semiempirical quantum mechanical Hamiltonians and a continuum solvent model with multiple atomic-type parameters. J Phys Chem B 115:7896–7905

    Article  CAS  Google Scholar 

  46. Slater J (1951) A simplification of the Hartree–Fock method. Phys Rev 81:385–390

    Article  CAS  Google Scholar 

  47. Becke A (1993) Density functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  48. Francl M, Pietro W, Hehre W, Binkley J, Gordon M, Defrees D, Pople J (1982) Self-consistent molecular orbital methods. XXIII. A polarization-type basis set for second-row elements. J Chem Phys 77:3654–3665

    Article  CAS  Google Scholar 

  49. Yurenko Y, Zhurakivsky R, Ghomi M, Samijlenko S, Hovorun D (2008) Ab initio comprehensive conformational analysis of 2′-deoxyuridine, the biologically significant DNA minor nucleoside, and reconstruction of its low-temperature matrix infrared spectrum. J Phys Chem B. 112:1240–1250

    Article  CAS  Google Scholar 

  50. Kosenkov D, Kholod Y, Gorb L, Shishkin O, Hovorun D, Mons M, Leszczynski J (2009) Ab initio kinetic simulation of gas-phase experiments: tautomerization of cytosine and guanine. J Phys Chem B 113:6140–6150

    Article  CAS  Google Scholar 

  51. Hovorun D (2014) Why the tautomerization of the G C Watson-Crick base pair via the DPT does not cause point mutations during DNA replication? QM and QTAIM comprehensive analysis. J Biomol Struct Dynam 32:1474–1499

    Article  Google Scholar 

  52. Samijlenko S, Yurenko Y, Stepanyugin A, Hovorun D (2010) Tautomeric equilibrium of uracil and thymine in model protein-nucleic acid contacts. spectroscopic and quantum chemical approach. J Phys Chem B 114:1454–1461

    Article  CAS  Google Scholar 

  53. Furmanchuk A, Isayev O, Gorb L, Shishkin O, Hovorunce D, Leszczynski J (2011) Novel view on the mechanism of water-assisted proton transfer in the DNA bases: bulk water hydration. Phys Chem Chem Phys 13:4311–4317

    Article  CAS  Google Scholar 

  54. Brovarets O, Zhurakivsky R, Hovorun D (2014) Does the tautomeric status of the adenine bases change upon the dissociation of the A*·Asyn Topal-Fresco DNA mismatch? A combined QM and QTAIM atomistic insight. Phys Chem Chem Phys 16:3715–3725

    Article  CAS  Google Scholar 

  55. Sonawane K, Tewari R (2008) Conformational preferences of hypermodified nucleoside lysidine (k2C) occurring at wobble position in anticodon loop of tRNAIle. Nucleos Nucleot Nucl 27:1158–1174

    Article  CAS  Google Scholar 

  56. Kumbhar B, Kamble A, Sonawane K (2013) Conformational preferences of modified nucleoside N(4)-acetylcytidine, ac4C Occur at “Wobble” 34th position in the anticodon loop of tRNA. Cell Biochem Biophys 66:797–816

    Article  CAS  Google Scholar 

  57. Tewari R (1987) Theoretical studies on conformational preferences of modified nucleic acid base N6-(N-threonylcarbonyl) Adenine. Ind J Biochem Biophys 24:170–176

    CAS  Google Scholar 

  58. Tewari R (1987) Theoretical studies on conformational preferences of modified nucleic acid base N6-(N-glycylcarbonyl) Adenine. Intl J Quant Chem 31:611–624

    Article  CAS  Google Scholar 

  59. Tewari R (1988) Conformational preferences of modified nucleic acid bases N6-(∆2-isopentenyl) adenine and 2-methylthio-N6-(∆2-isopentenyl) adenine by the quantum chemical PCILO calculations. Intl J Quant Chem 34:133–142

    Article  CAS  Google Scholar 

  60. Sonawane K, Sonavane U, Tewari R (2002) Conformational preferences of anticodon 3’-adjacent hypermodified nucleic acid base cis- or trans-zeatin and its 2- methylthio derivatives cis- or trans-ms2zeatin. J Biomol Struct Dyn 19:637–648

    Article  CAS  Google Scholar 

  61. Sonawane K, Sonavane U, Tewari R (2000) Conformational flipping of the N(6) substituent in diprotonated N6-(N-glycylcarbonyl) adenines: the role of N(6) H in purine ring protonated ureido adenines. Intl J Quant Chem 78:398–405

    Article  CAS  Google Scholar 

  62. Sonavane U, Sonawane K, Morin A, Grosjean H, Tewari R (1999) N(7)-protonation induced conformational flipping in hypermodified nucleic acid bases N6-(N-threonylcarbonyl) adenine and its 2-methylthio- or N(6)-methyl-derivatives. Intl J Quant Chem 75:223–229

    Article  CAS  Google Scholar 

  63. SYBYL 7.3. (2006) Tripos International, South Hanley Rd., St. Louis, Missouri, USA

  64. Cornell W, Cieplak P, Bayly C, Gould I, Merz K, Ferguson D, Spellmeyer D, Fox T, Caldwell J, Kollman P (1995) A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 117:5179–5197

    Article  CAS  Google Scholar 

  65. Holbrook S, Sussman J, Warrant R, Kim S (1978) Crystal structure of yeast phenylalanine transfer RNA II. Structural feature and functional implications. J Mol Biol 123:631–660

    Article  CAS  Google Scholar 

  66. Takai K, Yokoyama S (2003) Roles of 5-substituents of tRNA wobble uridines in the recognition of purine-ending codons. Nucleic Acids Res 31:6383–6391

    Article  CAS  Google Scholar 

  67. Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E, Ferrin T (2004) UCSF Chimera- a visualization system for exploratory research and analysis. J Comp Chem 25:1605–1612

    Article  CAS  Google Scholar 

  68. Cortijo V, Sanz M, Lopez J, Alonso J (2009) Conformational study of taurine in the gas phase. J Phys Chem A 113:14681–14683

    Article  CAS  Google Scholar 

  69. Yurenko Y, Zhurakivsky R, Samijlenko S, Ghomi M, Hovorun D (2007) The whole of intramolecular H-bonding in the isolated DNA nucleoside thymidine. AIM electron density topological study. Chem Phys Lett 447:140–146

    Article  CAS  Google Scholar 

  70. Bavi R, Sambhare S, Sonawane K (2013) MD simulation studies to investigate iso-energetic conformational behavior of modified nucleosides m2G and m2 2G present in the tRNA. Comput Struct Biotechnol J 5:e201302015

    Article  Google Scholar 

  71. Ghosh A, Bansal M (1999) C-H···O hydrogen bonds in minor groove of A-tracts in DNA double helices. J Mol Biol 294:1149–1158

    Article  CAS  Google Scholar 

  72. Bella J, Humphries M (2005) Cα-H···O = C hydrogen bonds contribute to the specificity of RGD cell-adhesion interactions. BMC Struct Biol 5:4

    Article  Google Scholar 

  73. Brovarets O, Yurenko Y, Hovorun D (2015) Intermolecular CH···O/N H-bonds in the biologically important pairs of natural nucleobases: a thorough quantum-chemical study. J Biomol Struct Dyn 32:993–1022

    Article  Google Scholar 

  74. Brovarets O, Yurenko Y, Hovorun D (2014) The significant role of the intermolecular CH···O/N hydrogen bonds in governing the biologically important pairs of the DNA and RNA modified bases: a comprehensive theoretical investigation. J Biomol Struct Dyn. doi:10.1080/07391102.2014.968623

    Google Scholar 

  75. Brovarets O, Hovorun D (2014) Can tautomerization of the A·T Watson-Crick base pair via double proton transfer provoke point mutations during DNA replication? A comprehensive QM and QTAIM analysis. J Biomol Struct Dyn 32:127–154

    Article  CAS  Google Scholar 

  76. Brovarets O, Hovorun D (2015) The physicochemical essence of the purine pyrimidine transition mismatches with Watson–Crick geometry in DNA: a C* versa A*C. A QM and QTAIM atomistic understanding. J Biomol Struct Dyn 33:28–55

    Article  CAS  Google Scholar 

  77. Murphy F, Ramakrishnan V, Malkiewicz A, Agris P (2004) The role of modifications in codon discrimination by tRNALys UUU. Nat Struct Mol Biol 11:1186–1191

    Article  CAS  Google Scholar 

  78. Crick F (1966) Codon-anticodon pairing: the wobble hypothesis. J Mol Biol 19:548–555

    Article  CAS  Google Scholar 

  79. Otero-Navas I, Seminario J (2012) Molecular electrostatic potential of DNA base-base pairing and mispairing. J Mol Model 18:91–101

    Article  CAS  Google Scholar 

  80. Sambhare S, Kumbhar B, Kamble D, Bavi R, Kumbhar N, Sonawane K (2014) Structural significance of modified nucleosides k2C and t6A present in the anticodon loop of tRNAIle. RSC Adv. 4:14176–14188

    Article  CAS  Google Scholar 

Download references

Acknowledgments

KDS is gratefully acknowledged to University Grants Commission (UGC), New Delhi, for financial support under the major research project, vide UGC Letter No. F. 40-204/2011 (SR) dated June 29, 2011. ASK and PMF are thankful to UGC for providing project fellowship. Authors are thankful to Department of Biochemistry and Computer Centre, Shivaji University, Kolhapur, for providing computational facilities.

Author information

Authors and Affiliations

  1. Structural Bioinformatics Unit, Department of Biochemistry, Shivaji University, Kolhapur, MS, 416 004, India

    Asmita S. Kamble, Susmit B. Sambhare, Prayagraj M. Fandilolu & Kailas D. Sonawane

  2. Department of Microbiology, Shivaji University, Kolhapur, MS, 416 004, India

    Kailas D. Sonawane

Authors
  1. Asmita S. Kamble
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susmit B. Sambhare
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prayagraj M. Fandilolu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kailas D. Sonawane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kailas D. Sonawane.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamble, A.S., Sambhare, S.B., Fandilolu, P.M. et al. Structural significance of modified nucleoside 5-taurinomethyl-2-thiouridine, τm5s2U, found at ‘wobble’ position in anticodon loop of human mitochondrial tRNALys . Struct Chem 27, 839–854 (2016). https://doi.org/10.1007/s11224-015-0642-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-015-0642-4

Keywords

Search

Navigation