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Catalytic mechanism of type C sialidase from Streptococcus pneumoniae: from covalent intermediate to final product

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Abstract

Streptococcus pneumoniae is a Gram-positive human pathogenic bacterium, which is the main cause of pneumonia and meningitis in children and the elderly. Three sialidases (or neuraminidases) encoded from Streptococcus pneumoniae could catalyze the cleavage of sialic acid linkages. This mechanism is directly connected with infection, apoptosis, and signaling, and usually considered to be one of the critical virulence factors. Type C neuraminidase (NanC) is unique because its primary product of Neu5Ac2en is considered to be an inhibitor to the other two sialidases. Experimentally, there are two different pathways for the formation mechanism of Neu5Ac2en catalyzed by NanC. In this work, a combined quantum mechanical and molecular mechanical approach was employed in all calculations. Starting from the covalent sialylated intermediate, we first examined the reaction to Neu5Ac2en and found the reaction prefers a direct proton abstraction mechanism rather than the water mediated proton abstraction mechanism. Free energy profiles can confirm that Neu5Ac2en is the major product of NanC. Functional roles of some important residues were also investigated, e.g., D315 acts as the proton acceptor during the formation of Neu5Ac2en, while the general base for the hydrolytic reaction to Neu5Ac. This study can facilitate the understanding of the catalytic mechanism of NanC and has the potential to aid in future inhibitor design studies.

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References

  1. Kiefel MJ, von Itzstein M (2002) Chem Rev 102:471

  2. Taylor G (1996) Curr Opin Struct Biol 6:830

    Article  CAS  Google Scholar 

  3. Li N, Ren A, Wang X, Fan X, Zhao Y, Gao GF, Cleary P, Wang B (2015) Proc Natl Acad Sci U S A 112:238

    Article  CAS  Google Scholar 

  4. King SJ (2010) Mol Oral Microbiol 25:15

    Article  CAS  Google Scholar 

  5. King SJ, Hippe KR, Weiser JN (2006) Mol Microbiol 59:961

    Article  CAS  Google Scholar 

  6. Bridy-Pappas AE, Margolis MB, Center KJ, Isaacman DJ (2005) Pharmacotherapy 25:1193

    Article  Google Scholar 

  7. Manco S, Hernon F, Yesilkaya H, Paton JC, Andrew PW, Kadioglu A (2006) Infect Immun 74:4014

    Article  CAS  Google Scholar 

  8. Parker D, Soong G, Planet P, Brower J, Ratner AJ, Prince A (2009) Infect Immun 77:3722

    Article  CAS  Google Scholar 

  9. Pettigrew MM, Fennie KP, York MP, Daniels J, Ghaffar F (2006) Infect Immun 74:3360

    Article  CAS  Google Scholar 

  10. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Phan TV, Smythe ML, White HF, Oliver SW, Colman PM, Varghese JN, Ryan DM, Woods JM, Bethell RC, Hotham VJ, Cameron JM, Penn CR (1993) Nature 363:418

  11. Taylor NR, von Itzstein M (1994) J Med Chem 37:616

  12. Chokhawala HA, Yu H, Chen X (2007) ChemBioChem 8:194

    Article  CAS  Google Scholar 

  13. Mitchell FL, Neres J, Ramraj A, Raju RK, Hillier IH, Vincent MA, Bryce RA (2013) Biochem 52:3740

    Article  CAS  Google Scholar 

  14. Pierdominici-Sottile G, Horenstein NA, Roitberg AE (2011) Biochem 50:10150

    Article  CAS  Google Scholar 

  15. Frasch ACC (2000) Parasitol Today 16:282

    Article  CAS  Google Scholar 

  16. Watts AG, Damager I, Amaya ML, Buschiazzo A, Alzari P, Frasch AC, Withers SG (2003) J Am Chem Soc 125:7532

    Article  CAS  Google Scholar 

  17. Rogers IL, Naidoo KJ (2016) ACS Catal 6:6384

    Article  CAS  Google Scholar 

  18. Gut H, King SJ, Walsh MA (2008) FEBS Lett 582:3348

    Article  CAS  Google Scholar 

  19. Xu G, Li X, Andrew PW, Taylor GL (2008) Acta Crystallogr Sect F Struct Biol Cryst Commun 64:772

    Article  CAS  Google Scholar 

  20. Xu G, Potter JA, Russell RJM, Oggioni MR, Andrew PW, Taylor GL (2008) J Mol Biol 384:436

    Article  CAS  Google Scholar 

  21. Xu G, Kiefel MJ, Wilson JC, Andrew PW, Oggioni MR, Taylor GL (2011) J Am Chem Soc 133:1718

    Article  CAS  Google Scholar 

  22. Owen CD, Lukacik P, Potter JA, Sleator O, Taylor GL, Walsh MA (2015) J Biol Chem 290:27736

    Article  CAS  Google Scholar 

  23. Newstead SL, Potter JA, Wilson JC, Xu G, Chien C-H, Watts AG, Withers SG, Taylor GL (2008) J Biol Chem 283:9080

    Article  CAS  Google Scholar 

  24. Warshel A, Levitt M (1976) J Mol Biol 103:227

    Article  CAS  Google Scholar 

  25. Elstner M, Porezag D, Jungnickel G, Elsner J, Haugk M, Frauenheim T, Suhai S, Seigert G (1998) Phys Rev B58:7260

    Article  Google Scholar 

  26. Elstner M, Frauenheim T, Kaxiras E, Seifert G, Suhai S (2000) Phys Status Solidi B217:357

    Article  Google Scholar 

  27. Elstner M (2006) Theor Chem Accounts 116:316

    Article  CAS  Google Scholar 

  28. Elstner M, Cui Q, Munih P, Kaxiras E, Frauenheim T, Karplus M (2003) J Comput Chem 24:565

    Article  CAS  Google Scholar 

  29. Niehaus TA, Elstner M, Frauenheim T, Suhai S (2001) J Mol Struct (THEOCHEM) 541:185

    Article  CAS  Google Scholar 

  30. Cui Q, Elstner M, Kaxiras E, Frauenheim T, Karplus M (2001) J Phys Chem B 105:569

    Article  CAS  Google Scholar 

  31. MacKerell Jr AD, Bashford D, Bellott M, Dunbrack Jr RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher III WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) J Phys Chem B 102:3586

    Article  CAS  Google Scholar 

  32. Field MJ, Bash PA, Karplus M (1990) J Comput Chem 11:700

    Article  CAS  Google Scholar 

  33. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926

    Article  CAS  Google Scholar 

  34. Brooks III CL, Karplus M (1983) J Chem Phys 79:6312

    Article  CAS  Google Scholar 

  35. Brooks III CL, Brunger A, Karplus M (1985) Biopoly 24:843

    Article  CAS  Google Scholar 

  36. Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327

    Article  CAS  Google Scholar 

  37. Steinbach PJ, Brooks BR (1994) J Comput Chem 15:667

    Article  CAS  Google Scholar 

  38. Torrie GM, Valleau JP (1977) J Comput Phys 23:187

    Article  Google Scholar 

  39. Kumar S, Bouzida D, Swendsen RH, Kollman PA, Rosenberg JM (1992) J Comput Chem 13:1011

    Article  CAS  Google Scholar 

  40. Roux B (1995) Comput Phys Commun 91:275

    Article  CAS  Google Scholar 

  41. 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 J, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann E, Yazyev O, Austin J, Cammi R, Pomelli C, Ochterski W, Martin RL, Morokuma K, Zakrzewski VG, Voth A, Salvador P, Dannenberg JJ, Dapprich S, Daniels D, Farkas O, Foresman JB, Ortiz JV, Cioslowski, Fox J (2009) Gaussian 09, revision a.01. Gaussian, Inc, Wallingford

  42. Lee AC, Crippen GM (2009) J Chem Inf Modl 49:2013

    Article  CAS  Google Scholar 

  43. Davies MN, Toseland CP, Moss DS, Flower DR (2006) BMC Biochem 7:18

    Article  Google Scholar 

  44. Olsson MHM, Sondergaard CR, Rostkowski M, Jensen JH (2011) J Chem Theo Comput 7:525

    Article  CAS  Google Scholar 

  45. Sondergaard CR, Olsson MHM, Rostkowski M, Jensen JH (2011) J Chem Theo Comput 7:2284

    Article  CAS  Google Scholar 

  46. Callegari D, Ranaghan KE, Woods CJ, Minari R, Tiseo M, Mor M, Mulholland AJ, Lodola A (2018) Chem Sci 9:2740

    Article  CAS  Google Scholar 

  47. Berces A, Whitfield DM, Nukada T (2001) Tetrahedron 57:477

    Article  CAS  Google Scholar 

  48. Liu J, Zhang C, Xu D (2012) J Mol Graph Model 37:67

    Article  Google Scholar 

  49. Elstner M, Jalkanen KJ, Knapp-Mohammady M, Frauenheim T, Suhai S (2001) Chem Phys 263:203

    Article  CAS  Google Scholar 

  50. Zhou H, Tajkhorshid E, Frauenheim T, Suhai S, Elstner M (2002) Chem Phys 277:91

    Article  CAS  Google Scholar 

  51. Range K, Riccardi D, Cui Q, Elstner M, York DM (2005) Phys Chem Chem Phys 7:3070

    Article  CAS  Google Scholar 

  52. Cui Q, Elstner M, Karplus M (2002) J Phys Chem B 106:2721

    Article  CAS  Google Scholar 

  53. Liu J, Wang X, Xu D (2010) J Phys Chem B 114:1462

    Article  CAS  Google Scholar 

  54. Liu J, Zheng M, Zhang C, Xu D (2013) J Phys Chem B 117:10080

    Article  CAS  Google Scholar 

  55. Xiong J, Xu D (2017) J Phys Chem B 121:931

    Article  CAS  Google Scholar 

  56. Sherwoord 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, Sc r, Casci J, Watson M, King F, Karlsen E, Sjøvoll M, Fahmi A, Schäfer A, Lennartz C (2003) J Mol Struct (THEOCHEM) 632:1

    Article  Google Scholar 

  57. Metz S, Kästner J, Sokol AA, Keal TW, Sherwood P (2014) WIREs Comput Mol Sci 4:101

    Article  CAS  Google Scholar 

  58. Bruice TC (2002) Acc Chem Res 35:139

    Article  CAS  Google Scholar 

  59. Sadiq SK, Coveney PV (2015) J Chem Theory Comput 11:316

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by the National Key Research and Development Program (No. 2016YFB0700801) and the National Natural Science Foundation of China (No. 21473117). Some of the results described in this work were obtained on the Supercomputing Center of Chinese Academy of Science.

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Authors and Affiliations

  1. MOE Key Laboratory of Green Chemistry & Technology, College of Chemistry, Sichuan University, Chengdu, Sichuan, 610064, People’s Republic of China

    Jing Xiong & Dingguo Xu

  2. School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China

    Jing Xiong

  3. Analytical&Testing Center, Sichuan University, Chengdu, Sichuan, 610064, People’s Republic of China

    Chunchun Zhang

Authors
  1. Jing Xiong
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  2. Chunchun Zhang
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  3. Dingguo Xu
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Correspondence to Chunchun Zhang or Dingguo Xu.

Electronic supplementary material

Supporting information 1

Distances between C3 of Neu5Ac unit and the carboxylate group of D315 in the CI complex (covalently sialylated enzyme intermediate); The endocyclic torsion angles for Neu5Ac unit of the CI and two products of Neu5Ac2en and Neu5Ac. B3LYP/MM single point free energy correction strategy. RMSD for the backbone atoms of the CI complex in classical MD simulation. Distance between the oxygen atom of this water molecule and C3 along the simulation time. (DOCX 1270 kb)

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Xiong, J., Zhang, C. & Xu, D. Catalytic mechanism of type C sialidase from Streptococcus pneumoniae: from covalent intermediate to final product. J Mol Model 24, 297 (2018). https://doi.org/10.1007/s00894-018-3822-5

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  • DOI: https://doi.org/10.1007/s00894-018-3822-5

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