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QM/MM Study of the Mechanism of the Noncanonical S-Cγ Bond Scission in S-Adenosylmethionine Catalyzed by the CmnDph2 Radical Enzyme

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Abstract

In nature, the radical SAM enzyme family plays a fascinating role in the radical chemistry, and the majority of them catalyze the cleavage of the S-C5′ bond to initiate the radical-based catalysis. Diphthamide biosynthesis protein 2 is a notable member of this superfamily, which cleaves the inert S-Cγ bond of SAM, leading to a new organometallic [4Fe-4S]-alkyl complex, expanding the mechanisms of radical SAM enzymes. In this work, we performed QM/MM calculations to elucidate the mechanism for the formation of the organometallic [4Fe-4S]-alkyl complex by the S-Cγ bond cleavage. All six possible antiferromagnetically-coupled spin states (ααββ, αβαβ, αββα, ββαα, βαβα, βααβ) were considered, the calculations showed that the reactant is at the αβαβ state, while the transition state is at the βααβ state, the product is the ααββ state. The most favorable pathway was found to be concerted, namely S-Cγ bond cleavage coupled with the Fe-Cγ bond formation, which is associated with a barrier of 25.7 kcal/mol. During the reaction, one electron is transferred from the two beta spin ferrous ions to the S-Cγ σ* orbital, which triggers the S-C bond cleavage. Importantly, the substrate coordinated iron ion prefers to be a ferrous ion and have a beta spin to facilitate the substrate activation. The present results should be helpful for the understanding of related [4Fe-4S] cluster dependent enzymatic reactions.

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References

  1. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE (2001) Nucleic Acids Res 29:1097–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Akiva E, Brown S, Almonacid DE, Barber AE 2nd, Custer AF, Hicks MA, Huang CC, Lauck F, Mashiyama ST, Meng EC, Mischel D, Morris JH, Ojha S, Schnoes AM, Stryke D, Yunes JM, Ferrin TE, Holliday GL, Babbitt PC (2014) Nucleic Acids Res 42:D521-530

    Article  CAS  PubMed  Google Scholar 

  3. Broderick JB, Duffus BR, Duschene KS, Shepard EM (2014) Chem Rev 114:4229–4317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nicolet Y (2020) Nat Catal 3:337–350

    Article  CAS  Google Scholar 

  5. Benjdia A, Heil K, Barends TR, Carell T, Schlichting I (2012) Nucleic Acids Res 40:9308–9318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Berteau O, Benjdia A (2017) Photochem Photobiol 93:67–77

    Article  CAS  PubMed  Google Scholar 

  7. Benjdia A, Balty C, Berteau O (2017) Front Chem 5:87

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fajardo AS, Legrand P, Paya-Tormo LA, Martin L, Pellicer Marti Nez MT, Echavarri-Erasun C, Vernede X, Rubio LM, Nicolet Y (2020) J Am Chem Soc 142:11006–11012

    Article  CAS  PubMed  Google Scholar 

  9. Vey JL, Yang J, Li M, Broderick WE, Broderick JB, Drennan CL (2008) Proc Natl Acad Sci USA 105:16137–16141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nicolet Y, Zeppieri L, Amara P, Fontecilla-Camps JC (2014) Angew Chem Int Ed 53:11840–11844

    Article  CAS  Google Scholar 

  11. Dowling DP, Bruender NA, Young AP, McCarty RM, Bandarian V, Drennan CL (2014) Nat Chem Biol 10:106–112

    Article  CAS  PubMed  Google Scholar 

  12. Rohac R, Amara P, Benjdia A, Martin L, Ruffie P, Favier A, Berteau O, Mouesca JM, Fontecilla-Camps JC, Nicolet Y (2016) Nat Chem 8:491–500

    Article  CAS  PubMed  Google Scholar 

  13. Bauerle MR, Schwalm EL, Booker SJ (2015) J Biol Chem 290:3995–4002

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Y, Zhu X, Torelli AT, Lee M, Dzikovski B, Koralewski RM, Wang E, Freed J, Krebs C, Ealick SE, Lin H (2010) Nature 465:891–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dong M, Kathiresan V, Fenwick MK, Torelli AT, Zhang Y, Caranto JD, Dzikovski B, Sharma A, Lancaster KM, Freed JH, Ealick SE, Hoffman BM, Lin H (2018) Science 359:1247–1250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Broderick WE, Hoffman BM, Broderick JB (2018) Acc Chem Res 51:2611–2619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Byer AS, Yang H, McDaniel EC, Kathiresan V, Impano S, Pagnier A, Watts H, Denler C, Vagstad AL, Piel J, Duschene KS, Shepard EM, Shields TP, Scott LG, Lilla EA, Yokoyama K, Broderick WE, Hoffman BM, Broderick JB (2018) J Am Chem Soc 140:8634–8638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Horitani M, Shisler K, Broderick WE, Hutcheson RU, Duschene KS, Marts AR, Hoffman BM, Broderick JB (2016) Science 352:822–825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pagnier A, Yang H, Jodts RJ, James CD, Shepard EM, Impano S, Broderick WE, Hoffman BM, Broderick JB (2020) J Am Chem Soc 142:18652–18660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brown AC, Suess DLM (2020) J Am Chem Soc 142:14240–14248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao C, Li Y, Wang C, Chen H (2020) ACS Catal 10:13245–13250

    Article  CAS  Google Scholar 

  22. Hoffman JL (1986) Biochemistry 25:4444–4449

    Article  CAS  PubMed  Google Scholar 

  23. Creason GL, Madison JT, Thompson JF (1985) Phytochemistry 24:1151–1155

    Article  CAS  Google Scholar 

  24. Vinci CR, Clarke SG (2010) J Biol Chem 285:20526–20531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cornforth JW, Reichard SA, Talalay P, Carrell HL, Glusker JP (1977) J Am Chem Soc 99:7292–7300

    Article  CAS  PubMed  Google Scholar 

  26. Friesner RA, Guallar V (2005) Annu Rev Phys Chem 56:389–427

    Article  CAS  PubMed  Google Scholar 

  27. van der Kamp MW, Mulholland AJ (2013) Biochemistry 52:2708–2728

    Article  PubMed  Google Scholar 

  28. Warshel A (2003) Annu Rev Biophys Biomol Struct 32:425–443

    Article  CAS  PubMed  Google Scholar 

  29. Hu H, Yang W (2008) Annu Rev Phys Chem 59:573–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Senn HM, Thiel W (2009) Angew Chem Int Ed 48:1198–1229

    Article  CAS  Google Scholar 

  31. Lin H, Truhlar DG (2006) Theor Chem Acc 117:185–199

    Article  Google Scholar 

  32. Gao J, Truhlar DG (2002) Annu Rev Phys Chem 53:467–505

    Article  CAS  PubMed  Google Scholar 

  33. Sousa SF, Ribeiro AJM, Neves RPP, Brás NF, Cerqueira NMFSA, Fernandes PA, Ramos MJ (2017) WIREs Comput Mol Sci 7:1281

    Article  Google Scholar 

  34. Calixto AR, Ramos MJ, Fernandes PA (2017) J Chem Theory Comput 13:5486–5495

    Article  CAS  PubMed  Google Scholar 

  35. Nicolet Y, Amara P, Mouesca JM, Fontecilla-Camps JC (2009) Proc Natl Acad Sci USA 106(35):14867–14871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dey A, Peng Y, Broderick WE, Hedman B, Hodgson KO, Broderick JB, Solomon EI (2011) J Am Chem Soc 133:18656–18662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Greco C, Fantucci P, Ryde U, de Gioia L (2011) Int J Quantum Chem 111:3949–3960

    CAS  Google Scholar 

  38. Blachly PG, Sandala GM, Giammona DA, Bashford D, McCammon JA, Noodleman L (2015) Inorg Chem 54:6439–6461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dong G, Cao L, Ryde U (2018) J Biol Inorg Chem 23:221–229

    Article  CAS  PubMed  Google Scholar 

  40. Bhave DP, Han WG, Pazicni S, Penner-Hahn JE, Carroll KS, Noodleman L (2011) Inorg Chem 50:6610–6625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Noodleman L, Lovell T, Liu T, Himo F, Torres RA (2002) Curr Opin Chem Biol 6:259–273

    Article  CAS  PubMed  Google Scholar 

  42. Dey A, Glaser T, Couture MM-J, Eltis LD, Holm RH, Hedman B, Hodgson KO, Solomon EI (2004) J Am Chem Soc 126:8320–8328

    Article  CAS  PubMed  Google Scholar 

  43. Amitouche F, Saad F, Tazibt S, Bouarab S, Vega A (2019) J Phys Chem A 123:10919–10929

    Article  CAS  PubMed  Google Scholar 

  44. Blachly PG, Sandala GM, Giammona DA, Liu T, Bashford D, McCammon JA, Noodleman L (2014) J Chem Theory Comput 10:3871–3884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kamachi T, Kouno T, Doitomi K, Yoshizawa K (2011) J Inorg Biochem 105:850–857

    Article  CAS  PubMed  Google Scholar 

  46. Guex N, Peitsch MC (1997) Electrophoresis 18:2714–2723

    Article  CAS  PubMed  Google Scholar 

  47. Johansson MU, Zoete V, Michielin O, Guex N (2012) BMC Bioinform 13:173

    Article  Google Scholar 

  48. Olsson MHM, Søndergaard CR, Rostkowski M, Jensen JH (2011) J Chem Theory Comput 7:525–537

    Article  CAS  PubMed  Google Scholar 

  49. Brooks BR, Brooks CL III, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) J Comput Chem 30:1545–1614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Senn HM, O’Hagan D, Thiel W (2005) J Am Chem Soc 127:13643–13655

    Article  CAS  PubMed  Google Scholar 

  51. Liao RZ, Thiel W (2012) J Chem Theory Comput 8:3793–3803

    Article  CAS  PubMed  Google Scholar 

  52. Sherwood P, de Vries AH, Guest MF, Schreckenbach G, Catlow CRA, French SA, Sokol AA, Bromley ST, Thiel W, Turner AJ, Billeter S, Terstegen F, Thiel S, Kendrick J, Rogers SC, Casci J, Watson M, King F, Karlsen E, Sjøvoll M, Fahmi A, Schäfer A, Lennartz C (2003) J Mol Struct 632:1–28

    Article  CAS  Google Scholar 

  53. Ahlrichs R, Bär M, Häser M, Horn H, Kölmel C (1989) Chem Phys Lett 162:165–169

    Article  CAS  Google Scholar 

  54. Smith W, Forester TR (1996) J Mol Graph 14:136–141

    Article  CAS  PubMed  Google Scholar 

  55. Kästner J, Carr JM, Keal TW, Thiel W, Wander A, Sherwood P (2009) J Phys Chem A 113:11856–11865

    Article  PubMed  Google Scholar 

  56. Becke AD (1993) J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  57. Grimme S, Antony J, Ehrlich S, Krieg H (2010) J Chem Phys 132:154104

    Article  PubMed  Google Scholar 

  58. Schäfer A, Horn H, Ahlrichs R (1992) J Chem Phys 97:2571–2577

    Article  Google Scholar 

  59. Schäfer A, Huber C, Ahlrichs R (1994) J Chem Phys 100:5829–5835

    Article  Google Scholar 

  60. Zhao Y, Truhlar DG (2007) Theor Chem Acc 120:215–241

    Article  Google Scholar 

  61. Tao J, Perdew JP, Staroverov VN, Scuseria GE (2003) Phys Rev Lett 91:146401

    Article  PubMed  Google Scholar 

  62. Staroverov VN, Scuseria GE, Tao J, Perdew JP (2003) J Chem Phys 119:12129–12137

    Article  CAS  Google Scholar 

  63. Perdew JP (1986) Phys Rev B Condens Matter 33:8822–8824

    Article  CAS  PubMed  Google Scholar 

  64. Becke AD (1988) Phys Rev A Gen Phys 38:3098–3100

    Article  CAS  PubMed  Google Scholar 

  65. Noodleman L (1988) Inorg Chem 27:3677–3679

    Article  CAS  Google Scholar 

  66. Monesca J-M, Chen JL, Noodleman L, Bashford D, Case DA (1994) J Am Chem Soc 116:11898–11914

    Article  Google Scholar 

  67. Bergeler M, Stiebritz MT, Reiher M (2013) ChemPlusChem 78:1082–1098

    Article  CAS  PubMed  Google Scholar 

  68. Ding LP, Kuang XY, Shao P, Zhong MM (2013) J Mol Model 19:1527–1536

    Article  CAS  PubMed  Google Scholar 

  69. Blomberg MRA, Borowski T, Himo F, Liao RZ, Siegbahn PEM (2014) Chem Rev 114:3601–3658

    Article  CAS  PubMed  Google Scholar 

  70. Ryde U (2017) J Chem Theory Comput 13:5745–5752

    Article  CAS  PubMed  Google Scholar 

  71. Sousa JPM, Neves RPP, Sousa SF, Ramos MJ, Fernandes PA (2020) ACS Catal 10:9545–9554

    Article  CAS  Google Scholar 

  72. Ribeiro AJM, Santos-Martins D, Russo N, Ramos MJ, Fernandes PA (2015) ACS Catal 5:5617–5626

    Article  CAS  Google Scholar 

  73. Li Y, Zhang R, Du L, Zhang Q, Wang W (2016) Int J Mol Sci 17:1372

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Key R&D Program of China (2018YFA0903500).

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Authors and Affiliations

  1. Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Hubei Key Laboratory of Materials Chemistry and Service Failure, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China

    Shuang Zhou, Wen-Jie Wei & Rong-Zhen Liao

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  1. Shuang Zhou
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Zhou, S., Wei, WJ. & Liao, RZ. QM/MM Study of the Mechanism of the Noncanonical S-Cγ Bond Scission in S-Adenosylmethionine Catalyzed by the CmnDph2 Radical Enzyme. Top Catal 65, 517–527 (2022). https://doi.org/10.1007/s11244-021-01420-5

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