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Understanding the mechanism of H2S oxidation by flavin-dependent sulfide oxidases: a DFT/IEF-PCM study

  • Jenner BonanataEmail author
  • E. Laura CoitiñoEmail author
Original Paper
  • 35 Downloads
Part of the following topical collections:
  1. QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)

Abstract

In the last years, H2S has been recognized as a signaling molecule in mammals, which can synthesize and catabolize (by oxidation) such species. The latter process is accelerated by a sulfide:quinone oxidoreductase (SQR, E.C. 1.8.5.4), a flavin-dependent sulfide oxidase (FDSO). FDSOs catalyze electron transfer from H2S to an acceptor in catalytic cycles involving two phases: (I) reduction of FAD by H2S (SH) and (II) electron transfer from FADH to the electron acceptor. The first step of FAD reduction consists on the reaction of SH with a catalytic disulfide at the active site of the enzyme, to yield a thiolate and a persulfide in the protein. This step is ca. 106 times faster than the analogous reaction with low-molecular-weight disulfides (LMWDs) and the causes of such extraordinary acceleration remain unknown. Using the IEF-PCM(ε ≈ 10)/M06-2X-D3/6-31+G(d,p) level of theory, we have modeled the reaction of SH with a disulfide as located in a representative model of the active site extracted from a prokaryotic SQR, assessing the effects of partial covalent interactions (PCIs) between the leaving sulfur atom and flavin ring on the activation Gibbs free-energy barrier at 298 K (G298K). To also evaluate the importance of entropic penalties on the first step, we have modeled at the same level of theory the reaction of (bis)hydroxyethyl disulfide in aqueous solution, a LMWD for which experimental data is available. Our results show that PCIs between the leaving sulfur atom and the flavin group only have a minor effect (G298K reduced by 1.6 kcal mol−1) while compensating entropic penalties could have a much larger effect (up to 8.3 kcal mol−1). Finally, we also present here a first model of some of further steps in the phase I of the catalytic cycle as in mammalian FDSOs, providing some light about their detailed mechanism.

Graphical abstract

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Keywords

Hydrogen sulfide Flavoenzyme Sulfide oxidase Sulfide:quinone oxidoreductase Partial covalent interactions Entropic effects 

Abbreviations

AfSQR

SQR of A. ferroxidans

DFT

density functional theory

ESM

Electronic Supporting Material

FAD

flavin adenine dinucleotide in its oxidized form

FADH

flavin adenine dinucleotide in its reduced form

FDSO

flavin-dependent sulfide oxidase

HED

(bis)hydroxyethyl disulfide

LMWD

low-molecular-weight disulfide

MD

molecular dynamics

PCI

partial covalent interaction

PCM

polarizable continuum model

SQR

sulfide:quinone oxidoreductase

WBI

Wiberg bond index

Notes

Acknowledgments

The authors want to thank Prof. Beatriz Álvarez (Universidad de la República, Uruguay) for pointing-out the interest of addressing SQR mechanisms by computational modeling. JB and ELC are active members of the National System of Researchers (SNI-ANII, Uruguay) and of the Program of Development of the Basic Sciences (PEDECIBA).

Funding information

This research was funded by ANII under grant FCE_3_2016_1_125514.

Supplementary material

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References

  1. 1.
    Gadalla MM, Snyder SH (2010) Hydrogen sulfide as a gasotransmitter. J Neurochem 113(1):14–26.  https://doi.org/10.1111/j.1471-4159.2010.06580.x CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Filipovic MR (2015) Persulfidation (S-sulfhydration) and H2S. Handb Exp Pharmacol 230:29–59.  https://doi.org/10.1007/978-3-319-18144-8_2 CrossRefPubMedGoogle Scholar
  3. 3.
    Paul BD, Snyder SH (2015) H2S: a novel gasotransmitter that signals by sulfhydration. Trends Biochem Sci 40(11):687–700.  https://doi.org/10.1016/j.tibs.2015.08.007 CrossRefGoogle Scholar
  4. 4.
    Chen X, Jhee KH, Kruger WD (2004) Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem 279(50):52082–52086.  https://doi.org/10.1074/jbc.C400481200 CrossRefPubMedGoogle Scholar
  5. 5.
    Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J (2009) Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H2S. J Biol Chem 284(5):3076–3085.  https://doi.org/10.1074/jbc.M805459200 CrossRefPubMedGoogle Scholar
  6. 6.
    Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H (2009) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11(4):703–714.  https://doi.org/10.1089/ARS.2008.2253 CrossRefPubMedGoogle Scholar
  7. 7.
    Jackson MR, Melideo SL, Jorns MS (2015) Role of human sulfide: quinone oxidoreductase in H2S metabolism. Methods Enzymol 554:255–270.  https://doi.org/10.1016/bs.mie.2014.11.037 Google Scholar
  8. 8.
    Jackson MR, Melideo SL, Jorns MS (2012) Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry 51(34):6804–6815.  https://doi.org/10.1021/bi300778t CrossRefPubMedGoogle Scholar
  9. 9.
    Mueller EG (2006) Trafficking in persulfides: delivering sulfur in biosynthetic pathways. Nat Chem Biol 2(4):185–194.  https://doi.org/10.1038/nchembio779 CrossRefPubMedGoogle Scholar
  10. 10.
    Sousa FM, Pereira JG, Marreiros BC, Pereira MM (2018) Taxonomic distribution, structure/function relationship and metabolic context of the two families of sulfide dehydrogenases: SQR and FCSD. Biochim Biophys Acta Bioenerg 1859(9):742–753.  https://doi.org/10.1016/j.bbabio.2018.04.004 CrossRefPubMedGoogle Scholar
  11. 11.
    Shahak Y, Hauska G (2008) Sulfide oxidation from cyanobacteria to humans: sulfide:quinone oxidoreductase (SQR). In: Hell R, Dahl C, Knaff D, Leustek T (eds) Sulfur metabolism in phototrophic organisms. Springer Netherlands, Dordrecht, pp 319–335.  https://doi.org/10.1007/978-1-4020-6863-8_16 CrossRefGoogle Scholar
  12. 12.
    Chen ZW, Koh M, Van Driessche G, Van Beeumen JJ, Bartsch RG, Meyer TE, Cusanovich MA, Mathews FS (1994) The structure of flavocytochrome c sulfide dehydrogenase from a purple phototrophic bacterium. Science 266(5184):430–432.  https://doi.org/10.1126/science.7939681 CrossRefPubMedGoogle Scholar
  13. 13.
    Cherney MM, Zhang Y, James MN, Weiner JH (2012) Structure-activity characterization of sulfide:quinone oxidoreductase variants. J Struct Biol 178(3):319–328.  https://doi.org/10.1016/j.jsb.2012.04.007 CrossRefPubMedGoogle Scholar
  14. 14.
    Cherney MM, Zhang Y, Solomonson M, Weiner JH, James MN (2010) Crystal structure of sulfide:quinone oxidoreductase from Acidithiobacillus ferrooxidans: insights into sulfidotrophic respiration and detoxification. J Mol Biol 398(2):292–305.  https://doi.org/10.1016/j.jmb.2010.03.018 CrossRefPubMedGoogle Scholar
  15. 15.
    Brito JA, Sousa FL, Stelter M, Bandeiras TM, Vonrhein C, Teixeira M, Pereira MM, Archer M (2009) Structural and functional insights into sulfide:quinone oxidoreductase. Biochemistry 48(24):5613–5622.  https://doi.org/10.1021/bi9003827 CrossRefPubMedGoogle Scholar
  16. 16.
    Marcia M, Ermler U, Peng G, Michel H (2009) The structure of Aquifex aeolicus sulfide:quinone oxidoreductase, a basis to understand sulfide detoxification and respiration. Proc Natl Acad Sci USA 106(24):9625–9630.  https://doi.org/10.1073/pnas.0904165106 CrossRefGoogle Scholar
  17. 17.
    Jackson MR, Loll PJ, Jorns MS (2019) X-ray structure of human sulfide:quinone oxidoreductase: insights into the mechanism of mitochondrial hydrogen sulfide oxidation. Structure 27(5):794–805 e794.  https://doi.org/10.1016/j.str.2019.03.002 CrossRefPubMedGoogle Scholar
  18. 18.
    Li Q, Lancaster Jr JR (2013) Chemical foundations of hydrogen sulfide biology. Nitric Oxide 35:21–34.  https://doi.org/10.1016/j.niox.2013.07.001 CrossRefPubMedGoogle Scholar
  19. 19.
    Mishanina TV, Yadav PK, Ballou DP, Banerjee R (2015) Transient kinetic analysis of hydrogen sulfide oxidation catalyzed by human sulfide:quinone oxidoreductase. J Biol Chem. 290(41):25072–25080.  https://doi.org/10.1074/jbc.M115.682369 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Landry AP, Ballou DP, Banerjee R (2017) H2S oxidation by nanodisc-embedded human sulfide quinone oxidoreductase. J Biol Chem 292(28):11641–11649.  https://doi.org/10.1074/jbc.M117.788547 CrossRefGoogle Scholar
  21. 21.
    Zhang Y, Qadri A, Weiner JH (2016) The quinone-binding site of Acidithiobacillus ferrooxidans sulfide:quinone oxidoreductase controls both sulfide oxidation and quinone reduction. Biochem Cell Biol 94(2):159–166.  https://doi.org/10.1139/bcb-2015-0097 CrossRefGoogle Scholar
  22. 22.
    Cuevasanta E, Lange M, Bonanata J, Coitiño EL, Ferrer-Sueta G, Filipovic MR, Alvarez B (2015) Reaction of hydrogen sulfide with disulfide and sulfenic acid to form the strongly nucleophilic persulfide. J Biol Chem 290(45):26866–26880.  https://doi.org/10.1074/jbc.M115.672816 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bauza A, Quinonero D, Deya PM, Frontera A (2013) On the importance of anion-π interactions in the mechanism of sulfide:quinone oxidoreductase. Chem Asian J 8(11):2708–2713.  https://doi.org/10.1002/asia.201300786 CrossRefPubMedGoogle Scholar
  24. 24.
    Olsson MH, Sondergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pK a predictions. J Chem Theory Comput 7(2):525–537.  https://doi.org/10.1021/ct100578z CrossRefGoogle Scholar
  25. 25.
    D.A. Case DSC, T. E. Cheatham, III, T. A. Darden, R. E. Duke, T. J. Giese, H. Gohlke, A. W. Goetz, D. Greene, N. Homeyer, S. Izadi, A. Kovalenko, T. S. Lee, S. LeGrand, P. Li, C. Lin, J. Liu, T. Luchko, R. Luo, D. Mermelstein, K. M. Merz, G. Monard, H. Nguyen, I. Omelyan, A. Onufriev, F. Pan, R. Qi, D. R. Roe, A. Roitberg, C. Sagui, C. L. Simmerling, W. M. Botello-Smith, J. Swails, R. C. Walker, J. Wang, R. M. Wolf, X. Wu, L. Xiao, D.M. York and P.A. Kollman (2017) AMBER 2017. University of California, San Francisco, San Francisco, CAGoogle Scholar
  26. 26.
    Loncharich RJ, Brooks BR, Pastor RW (1992) Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N'-methylamide. Biopolymers 32(5):523–535.  https://doi.org/10.1002/bip.360320508 CrossRefPubMedGoogle Scholar
  27. 27.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103(19):8577–8593.  https://doi.org/10.1063/1.470117 CrossRefGoogle Scholar
  28. 28.
    Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341.  https://doi.org/10.1016/0021-9991(77)90098-5 CrossRefGoogle Scholar
  29. 29.
    Zhao Y, Truhlar DG (2007) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theoret Chem Acc 120(1–3):215–241.  https://doi.org/10.1007/s00214-007-0310-x CrossRefGoogle Scholar
  30. 30.
    Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys 132(15):154104.  https://doi.org/10.1063/1.3382344 CrossRefPubMedGoogle Scholar
  31. 31.
    Ditchfield R, Hehre WJ, Pople JA (1971) Self-consistent molecular-orbital methods. IX. An extended Gaussian-type basis for molecular-orbital studies of organic molecules. J Chem Phys 54(2):724–728.  https://doi.org/10.1063/1.1674902 CrossRefGoogle Scholar
  32. 32.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2013) Gaussian 09, Revision D.01, Gaussian Inc., Wallingford CTGoogle Scholar
  33. 33.
    Fukui K (1981) The path of chemical reactions - the IRC approach. Acc Chem Res 14(12):363–368.  https://doi.org/10.1021/ar00072a001 CrossRefGoogle Scholar
  34. 34.
    Neves RP, Fernandes PA, Varandas AJ, Ramos MJ (2014) Benchmarking of density functionals for the accurate description of thiol-disulfide exchange. J Chem Theory Comput 10(11):4842–4856.  https://doi.org/10.1021/ct500840f CrossRefPubMedGoogle Scholar
  35. 35.
    Reed AE, Weinstock RB, Weinhold F (1985) Natural population analysis. J Chem Phys 83(2):735–746.  https://doi.org/10.1063/1.449486 CrossRefGoogle Scholar
  36. 36.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105(8):2999–3093.  https://doi.org/10.1021/cr9904009 CrossRefPubMedGoogle Scholar
  37. 37.
    Li L, Li C, Zhang Z, Alexov E (2013) On the dielectric "constant" of proteins: smooth dielectric function for macromolecular modeling and its implementation in DelPhi. J Chem Theory Comput 9(4):2126–2136.  https://doi.org/10.1021/ct400065j CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Voges D, Karshikoff A (1998) A model of a local dielectric constant in proteins. J Chem Phys 108(5):2219–2227.  https://doi.org/10.1063/1.475602 CrossRefGoogle Scholar
  39. 39.
    Bonanata JN, Signorelli S, Coitiño EL (2011) Increasing complexity models for describing the generation of substrate radicals at the active site of ethanolamine ammonia-lyase/B12. Comput Theoret Chem 975(1–3):52–60.  https://doi.org/10.1016/j.comptc.2011.07.029 CrossRefGoogle Scholar
  40. 40.
    Portillo-Ledesma S, Sardi F, Manta B, Tourn MV, Clippe A, Knoops B, Alvarez B, Coitiño EL, Ferrer-Sueta G (2014) Deconstructing the catalytic efficiency of peroxiredoxin-5 peroxidatic cysteine. Biochemistry 53(38):6113–6125.  https://doi.org/10.1021/bi500389m CrossRefGoogle Scholar
  41. 41.
    Bondi A (1964) Van der Waals volumes and radii. J Phys Chem 68(3):441–451.  https://doi.org/10.1021/j100785a001 CrossRefGoogle Scholar
  42. 42.
    Zhao Y, Truhlar DG (2004) Hybrid meta density functional theory methods for thermochemistry, thermochemical kinetics, and noncovalent interactions: the MPW1B95 and MPWB1K models and comparative assessments for hydrogen bonding and van der Waals interactions. J Phys Chem A 108(33):6908–6918.  https://doi.org/10.1021/jp048147q CrossRefGoogle Scholar
  43. 43.
    Wheeler SE, Houk KN (2010) Integration grid errors for meta-GGA-predicted reaction energies: origin of grid errors for the M06 suite of functionals. J Chem Theory Comput 6(2):395–404.  https://doi.org/10.1021/ct900639j CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias and Centro de Investigaciones Biomédicas (CEINBIO)Universidad de la RepúblicaMontevideoUruguay

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