Advertisement

Reaction pathway for cocaine hydrolase-catalyzed hydrolysis of (+)-cocaine

  • Yuan Yao
  • Junjun Liu
  • Fang Zheng
  • Chang-Guo ZhanEmail author
Regular Article

Abstract

A recently designed and discovered cocaine hydrolase (CocH), engineered from human butyrylcholinesterase, has been proven promising as a novel enzyme therapy for treatment of cocaine overdose and addiction because it is highly efficient in catalyzing hydrolysis of naturally occurring (−)-cocaine. It has been known that the CocH also has a high catalytic efficiency against (+)-cocaine, a synthetic enantiomer of cocaine. Reaction pathway and the corresponding free energy profile for the CocH-catalyzed hydrolysis of (+)-cocaine have been determined, in the present study, by performing first-principles pseudobond quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations. According to the QM/MM-FE results, the catalytic hydrolysis process is initiated by the nucleophilic attack on carbonyl carbon of (−)-cocaine benzoyl ester via hydroxyl oxygen of S198 side chain, and the second reaction step (i.e., dissociation of benzoyl ester) is rate-determining. This finding for CocH-catalyzed hydrolysis of (+)-cocaine is remarkably different from that for the (+)-cocaine hydrolysis catalyzed by bacterial cocaine esterase in which the first reaction step of the deacylation is associated with the highest free energy barrier (~17.9 kcal/mol). The overall free energy barrier (~16.0 kcal/mol) calculated for the acylation stage of CocH-catalyzed hydrolysis of (+)-cocaine is in good agreement with the experimental free energy barrier of ~14.5 kcal/mol derived from the experimental kinetic data.

Keywords

Catalytic mechanism Enzymatic hydrolysis Cocaine 

Notes

Acknowledgments

This work was supported in part by the NIH (Grants R01 DA035552, R01 DA013930, R01 DA032910, and R01 DA025100), NSF (Grant CHE-1111761), and NSFC (Grant No. 21102050). The entire research was performed at the University of Kentucky. The authors acknowledge the Center for Computational Sciences (CCS) at University of Kentucky for supercomputing time on IBM X-series Cluster with 340 nodes or 1360 processors.

References

  1. 1.
    Landry DW, Yang GXQ (1997) J Addict Dis 16:1–17CrossRefGoogle Scholar
  2. 2.
    Gorelick DA (1997) Drug Alcohol Depend 48:159CrossRefGoogle Scholar
  3. 3.
    Zheng F, Zhan C-G (2010) Future Med Chem 3:9–13CrossRefGoogle Scholar
  4. 4.
    Zheng F, Zhan C-G (2012) Future Med Chem 4:125–128CrossRefGoogle Scholar
  5. 5.
    Zhan C-G, Zheng F, Landry DW (2003) J Am Chem Soc 125:2462–2474CrossRefGoogle Scholar
  6. 6.
    Sun H, Pang Y-P, Lockridge O, Brimijoin S (2002) Mol Pharmacol 62:220–224CrossRefGoogle Scholar
  7. 7.
    Hamza A, Cho H, Tai H-H, Zhan C-G (2005) J Phys Chem B 109:4776–4782CrossRefGoogle Scholar
  8. 8.
    Zhan C-G, Gao D (2005) Biophys J 89:3863–3872CrossRefGoogle Scholar
  9. 9.
    Gao D, Zhan C-G (2005) J Phys Chem B 109:23070–23076CrossRefGoogle Scholar
  10. 10.
    Gao D, Zhan C-G (2006) Proteins: Struct, Funct, Bioinf 62:99–110CrossRefGoogle Scholar
  11. 11.
    Liu J, Zhan C-G (2012) J Chem Theory Comput 8:1426–1435CrossRefGoogle Scholar
  12. 12.
    Pan Y, Gao D, Yang W, Cho H, Yang G, Tai H-H, Zhan C-G (2005) Proc Natl Acad Sci USA 102:16656–16661CrossRefGoogle Scholar
  13. 13.
    Gao D, Cho H, Yang W, Pan Y, Yang G, Tai HH, Zhan C-G (2006) Angew Chem Int Ed 45:653–657CrossRefGoogle Scholar
  14. 14.
    Pan Y, Gao D, Yang W, Cho H, Zhan C-G (2007) J Am Chem Soc 129:13537–13543CrossRefGoogle Scholar
  15. 15.
    Zheng F, Yang WC, Ko M-C, Liu JJ, Cho H, Gao DQ, Tong M, Tai HH, Woods JH, Zhan C-G (2008) J Am Chem Soc 130:12148–12155CrossRefGoogle Scholar
  16. 16.
    Yang W, Pan Y, Zheng F, Cho H, Tai H-H, Zhan C-G (2009) Biophys J 96:1931–1938CrossRefGoogle Scholar
  17. 17.
    Yang W, Pan Y, Fang L, Gao D, Zheng F, Zhan C-G (2010) J Phys Chem B 114:10889–10896CrossRefGoogle Scholar
  18. 18.
    Zheng F, Yang W, Xue L, Hou S, Liu J, Zhan C-G (2010) Biochemistry 49:9113–9119CrossRefGoogle Scholar
  19. 19.
    Xue L, Ko M-C, Tong M, Yang W, Hou S, Fang L, Liu J, Zheng F, Woods JH, Tai H-H, Zhan C-G (2011) Mol Pharmacol 79:290–297CrossRefGoogle Scholar
  20. 20.
    Yang W, Xue L, Fang L, Chen X, Zhan C-G (2010) Chem Biol Interact 187:148–152CrossRefGoogle Scholar
  21. 21.
    Xue L, Hou S, Tong M, Fang L, Chen X, Jin Z, Tai H-H, Zheng F, Zhan C-G (2013) Biochem J 453:447–454CrossRefGoogle Scholar
  22. 22.
    Zheng F, Xue L, Hou S, Liu J, Zhan M, Yang W, Zhan C-G (2014) Nat Commun 5:3457. doi: 10.1388/ncomms4457 Google Scholar
  23. 23.
    Chen X, Huang X, Geng L, Xue L, Hou S, Zheng X, Brimijoin S, Zheng F, Zhan C-G (2015) Biochem J 466:243–251CrossRefGoogle Scholar
  24. 24.
    Gao Y, Orson FM, Kinsey B, Kosten T, Brimijoin S (2010) Chem Biol Interact 187:421–424CrossRefGoogle Scholar
  25. 25.
    Geng L, Gao Y, Chen X, Hou S, Zhan C-G, Radic Z, Parks R, Russell SJ, Pham L, Brimijoin S (2013) PLoS ONE 8:e67446CrossRefGoogle Scholar
  26. 26.
    Murthy V, Gao Y, Geng L, LeBrasseur N, White T, Brimijoin S (2014) J Mol Neurosci 53:409–416CrossRefGoogle Scholar
  27. 27.
    Zlebnik NE, Brimijoin S, Gao Y, Saykao AT, Parks RJ, Carroll ME (2014) Neuropsychopharmacology 39:1538–1546CrossRefGoogle Scholar
  28. 28.
    Murthy V, Gao Y, Geng L, LeBrasseur NK, White TA, Parks RJ, Brimijoin S (2014) Vaccine 32:4155–4162CrossRefGoogle Scholar
  29. 29.
    Xue L, Hou S, Yang W, Fang L, Zheng F, Zhan C-G (2013) Chem Biol Interact 203:57–62CrossRefGoogle Scholar
  30. 30.
    Hou S, Xue L, Yang W, Fang L, Zheng F, Zhan C-G (2013) Org Biomol Chem 11:7477–7485CrossRefGoogle Scholar
  31. 31.
    Zhang YK (2005) J Chem Phys 122:024114Google Scholar
  32. 32.
    Zhang YK (2006) Theor Chem Acc 116:43–50CrossRefGoogle Scholar
  33. 33.
    Zhang YK, Lee TS, Yang WT (1999) J Chem Phys 110:46–54CrossRefGoogle Scholar
  34. 34.
    Zhang YK, Liu HY, Yang WT (2000) J Chem Phys 112:3483–3492CrossRefGoogle Scholar
  35. 35.
    Cheng Y, Zhang Y, McCammon JA (2005) J Am Chem Soc 127:1553–1562CrossRefGoogle Scholar
  36. 36.
    Cis neros GA, Liu H, Zhang Y, Yang W (2003) J Am Chem Soc 125:10384–10393CrossRefGoogle Scholar
  37. 37.
    Corminboeuf C, Hu P, Tuckerman ME, Zhang Y (2006) J Am Chem Soc 128:4530–4531CrossRefGoogle Scholar
  38. 38.
    Hu P, Wang S, Zhang Y (2008) J Am Chem Soc 130:3806–3813CrossRefGoogle Scholar
  39. 39.
    Hu P, Zhang Y (2006) J Am Chem Soc 128:1272–1278CrossRefGoogle Scholar
  40. 40.
    Liu H, Zhang Y, Yang W (2000) J Am Chem Soc 122:6560–6570CrossRefGoogle Scholar
  41. 41.
    Liu J, Hamza A, Zhan C-G (2009) J Am Chem Soc 131:11964–11975CrossRefGoogle Scholar
  42. 42.
    Wang L, Yu X, Hu P, Broyde S, Zhang Y (2007) J Am Chem Soc 129:4731–4737CrossRefGoogle Scholar
  43. 43.
    Wang S, Hu P, Zhang Y (2007) J Phys Chem B 111:3758–3764CrossRefGoogle Scholar
  44. 44.
    Xiao C, Zhang Y (2007) J Phys Chem B 111:6229–6235CrossRefGoogle Scholar
  45. 45.
    Zhang Y, Kua J, McCammon JA (2002) J Am Chem Soc 124:10572–10577CrossRefGoogle Scholar
  46. 46.
    Zhang Y, Kua J, McCammon JA (2003) J Phys Chem B 107:4459–4463CrossRefGoogle Scholar
  47. 47.
    Zheng F, Zhan CG (2008) Org Biomol Chem 6:836–843CrossRefGoogle Scholar
  48. 48.
    Chen X, Fang L, Liu JJ, Zhan CG (2012) Biochemistry 51:1297–1305CrossRefGoogle Scholar
  49. 49.
    Chen X, Zhao XY, Xiong Y, Liu JJ, Zhan CG (2011) J Phys Chem B 115:12208–12219CrossRefGoogle Scholar
  50. 50.
    Wei DH, Lei BL, Tang MS, Zhan CG (2012) J Am Chem Soc 134:10436–10450CrossRefGoogle Scholar
  51. 51.
    Qiao Y, Han K, Zhan C-G (2013) Biochemistry 52:6467–6479CrossRefGoogle Scholar
  52. 52.
    Wei D, Fang L, Tang M, Zhan C-G (2013) J Phys Chem B 117:13418–13434CrossRefGoogle Scholar
  53. 53.
    Wei D, Huang X, Liu J, Tang M, Zhan C-G (2013) Biochemistry 52:5145–5154CrossRefGoogle Scholar
  54. 54.
    Qiao Y, Han K, Zhan C-G (2014) Org Biomol Chem 12:2214–2227 (Cover Article) CrossRefGoogle Scholar
  55. 55.
    Wei D, Tang M, Zhan C-G (2015) Org Biomol Chem 13:6857–6865CrossRefGoogle Scholar
  56. 56.
    Gao DQ, Zhan CG (2006) Proteins 62:99–110CrossRefGoogle Scholar
  57. 57.
    Hamza A, Cho H, Tai H-H, Zhan C-G (2005) J Phys Chem B 109:4776–4782CrossRefGoogle Scholar
  58. 58.
    Liu JJ, Zhao XY, Yang WC, Zhan C-G (2011) J Phys Chem B 115:5017–5025CrossRefGoogle Scholar
  59. 59.
    Zhan CG, Gao D (2005) Biophys J 89:3863–3872CrossRefGoogle Scholar
  60. 60.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935CrossRefGoogle Scholar
  61. 61.
    Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comput Chem 26:1668–1688CrossRefGoogle Scholar
  62. 62.
    Case DA, Darden TA, Cheatham TE, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker RC, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA (2006) AMBER 2009. University of California, San FranciscoGoogle Scholar
  63. 63.
    Miyamoto S, Kollman PA (1992) J Comput Chem 13:952–962CrossRefGoogle Scholar
  64. 64.
    Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327–341CrossRefGoogle Scholar
  65. 65.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, Revision C.02. Gaussian Inc., WallingfordGoogle Scholar
  66. 66.
    Case DA, Darden TA, Cheatham ITE, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Wang B, Pearlman DA, Crowley M, Brozell S, Tsui V, Gohlke H, Mongan J, Hornak V, Cui G, Beroza P, Schafmeister C, Caldwell JW, Ross WS, Kollman PA (2004) AMBER 2008. University of California, San FranciscoGoogle Scholar
  67. 67.
    Zhang Y, Liu H, Yang W (2002) In: Schlick T, Gan HH (eds) Computational methods for macromolecular modeling-challenges and applications. Springer, New York, pp 332–354Google Scholar
  68. 68.
    Liu J, Zhang Y, Zhan C-G (2009) J Phys Chem B 113:16226–16236CrossRefGoogle Scholar
  69. 69.
    Liu JJ, Hamza A, Zhan C-G (2009) J Am Chem Soc 131:11964–11975CrossRefGoogle Scholar
  70. 70.
    Truhlar DG, Garrett BC (1984) Annu Rev Phys Chem 35:159–189CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yuan Yao
    • 1
    • 2
  • Junjun Liu
    • 1
    • 3
  • Fang Zheng
    • 1
  • Chang-Guo Zhan
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, Molecular Modeling and Biopharmaceutical Center, Chemoinformatics and Drug Design Core of CPRI, College of PharmacyUniversity of KentuckyLexingtonUSA
  2. 2.The Academy of Fundamental and Interdisciplinary SciencesHarbin Institute of TechnologyHarbinPeople’s Republic of China
  3. 3.Tongji School of PharmacyHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

Personalised recommendations