Skip to main content

Advertisement

SpringerLink
Log in

Conformational turn triggers regio-selectivity in the bioactivation of thiophene-contained compounds mediated by cytochrome P450

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

In the present work, we performed Density Functional Theory calculations to explore the bioactivation mechanism of thiophene-containing molecules mediated by P450s. For this purpose, relatively large size compounds, 2,5-diaminothiophene derivatives were selected particularly for this investigation. Here we found the successive regio-selectivity triggered by conformational turn played a significant role in the occurrence of bioactivation. 2,5-Diaminothiophene was oxidized to a 2,5-diimine thiophene-reactive intermediate by Compound I (Cpd I) through successive activations of two N–H bonds (H3–N11 and H1–N6). This reaction exhibited three special characteristics: (1) self-controlled regio-selectivity during the oxidation process. There was a large scale of conformational turn in the abstraction of the first H atom which triggers the selection of the second H for abstraction. (2) Proton-shuttle mechanism. In high spin (HS) state, proton-shuttle mechanism was observed for the abstraction of the second H atom. (3) Spin-selective manner. In protein environment, the energy barrier in HS state was much lower than that in low spin state. The novel proposed bioactivation mechanism of 2,5-diaminothiophene compounds can help us in rational design of thiophene-contained drugs avoiding the occurrence of bioactivation.

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

Similar content being viewed by others

References

  1. Baskaran UL, Sabina EP (2017) Clinical and experimental research in antituberculosis drug-induced hepatotoxicity: a review. J Integr Med-Jim 15(1):27–36. https://doi.org/10.1016/s2095-4964(17)60319-4

    Article  Google Scholar 

  2. Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP (2017) Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 66(6):1154–1164. https://doi.org/10.1136/gutjnl-2016-313369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fontana RJ (2014) Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 146(4):914–U437. https://doi.org/10.1053/j.gastro.2013.12.032

    Article  CAS  Google Scholar 

  4. Fang Z-Z, Zhang Y-Y, Wang X-L, Cao Y-F, Huo H, Yang L (2011) Bioactivation of herbal constituents: simple alerts in the complex system. Expert Opin Drug Metab Toxicol 7(8):989–1007. https://doi.org/10.1517/17425255.2011.586335

    Article  PubMed  Google Scholar 

  5. Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409(1):59–71

    Article  PubMed  Google Scholar 

  6. Guengerich FP (2008) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21(1):70–83. https://doi.org/10.1021/tx700079z

    Article  CAS  PubMed  Google Scholar 

  7. Dekant W (2009) The role of biotransformation and bioactivation in toxicity. In: Luch A (eds) Molecular, clinical and environmental toxicology. Experientia Supplementum, vol 99. Springer, Basel, Boston, Berlin, Germany

    Google Scholar 

  8. Brewer CT, Chen TS (2017) Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. Int J Mol Sci. https://doi.org/10.3390/ijms18112353

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hollenberg PF, Kent UM, Bumpus NN (2008) Mechanism-based inactivation of human cytochromes P450s: experimental characterization, reactive intermediates, and clinical implications. Chem Res Toxicol 21(1):189–205. https://doi.org/10.1021/tx7002504

    Article  CAS  PubMed  Google Scholar 

  10. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O’Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15(3):269–299. https://doi.org/10.1021/tx015574b

    Article  CAS  PubMed  Google Scholar 

  11. Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, Aleo MD (2011) Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 24(9):1345–1410. https://doi.org/10.1021/tx200168d

    Article  CAS  PubMed  Google Scholar 

  12. Le Dang N, Hughes TB, Miller GP, Swamidass J (2017) Computational approach to structural alerts: furans, phenols, nitroaromatics, and thiophenes. Chem Res Toxicol 30(4):1046–1059. https://doi.org/10.1021/acs.chemrestox.6b00336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gramec D, Masic LP, Dolenc MS (2014) Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol 27(8):1344–1358. https://doi.org/10.1021/tx500134g

    Article  CAS  PubMed  Google Scholar 

  14. Chan GFQ, Towers GHN, Mitchell JC (1975) Ultraviolet-mediated antibiotic activity of thiophene compounds of tagetes. Phytochemistry 14(10):2295–2296. https://doi.org/10.1016/s0031-9422(00)91121-x

    Article  CAS  Google Scholar 

  15. Hudson JB, Graham EA, Miki N, Towers GHN, Hudson LL, Rossi R, Carpita A, Neri D (1989) Photoactive antiviral and cytotoxic activities of synthetic thiophenes and their acetylenic derivatives. Chemosphere 19(8–9):1329–1343. https://doi.org/10.1016/0045-6535(89)90080-5

    Article  CAS  Google Scholar 

  16. Matsuura H, Saxena G, Farmer SW, Hancock REW, Towers GHN (1996) Antibacterial and antifungal polyine compounds from Glehnia littoralis ssp leiocarpa. Planta Med 62(3):256–259. https://doi.org/10.1055/s-2006-957872

    Article  CAS  PubMed  Google Scholar 

  17. Lecoeur S, Andre C, Beaune PH (1996) Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol 50(2):326–333

    CAS  PubMed  Google Scholar 

  18. Mansuy D (1997) Molecular structure and hepatotoxicity: compared data about two closely related thiophene compounds. J Hepatol 26:22–25. https://doi.org/10.1016/s0168-8278(97)80493-x

    Article  CAS  PubMed  Google Scholar 

  19. Niemegeers CJE, Lenaerts FM, Awouters F, Janssen PAJ (1975) Gastrointestinal effects and acute toxicity of suprofen. Arzneimittel-Forsch/Drug Res 25(10):1537–1542

    CAS  Google Scholar 

  20. Castell JV, Gomezlechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P (1994) Photodynamic lipid-peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol 59(1):35–39. https://doi.org/10.1111/j.1751-1097.1994.tb04998.x

    Article  CAS  PubMed  Google Scholar 

  21. Priestley CC, Regan S, Park BK, Williams DP (2011) The genotoxic potential of methapyrilene using the alkaline Comet assay in vitro and in vivo. Toxicology 290(2–3):249–257. https://doi.org/10.1016/j.tox.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  22. Mercer AE, Regan SL, Hirst CM, Graham EE, Antoine DJ, Benson CA, Williams DP, Foster J, Kenna JG, Park BK (2009) Functional and toxicological consequences of metabolic bioactivation of methapyrilene via thiophene S-oxidation: induction of cell defence, apoptosis and hepatic necrosis. Toxicol Appl Pharmacol 239(3):297–305. https://doi.org/10.1016/j.taap.2009.05.027

    Article  CAS  PubMed  Google Scholar 

  23. Hutzler JM, Balogh LM, Zientek M, Kumar V, Tracy TS (2009) Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (±)-suprofen: a comparison of kinetics and probe substrate selection. Drug Metab Dispos 37(1):59–65. https://doi.org/10.1124/dmd.108.023358

    Article  CAS  PubMed  Google Scholar 

  24. Rademacher PM, Woods CM, Huang Q, Szklarz GD, Nelson SD (2012) Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9. Chem Res Toxicol 25(4):895–903. https://doi.org/10.1021/tx200519d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dansette PM, Bertho G, Mansuy D (2005) First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives. Biochem Biophys Res Commun 338(1):450–455. https://doi.org/10.1016/j.bbrc.2005.08.091

    Article  CAS  PubMed  Google Scholar 

  26. Mansuy D, Dansette PM (2011) Sulfenic acids as reactive intermediates in xenobiotic metabolism. Arch Biochem Biophys 507(1):174–185. https://doi.org/10.1016/j.abb.2010.09.015

    Article  CAS  PubMed  Google Scholar 

  27. Dansette PM, Thang DC, Elamri H, Mansuy D (1992) Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene invivo—formation of a dihydrothiophene sulfoxide mercapturic acid. Biochem Biophys Res Commun 186(3):1624–1630. https://doi.org/10.1016/s0006-291x(05)81594-3

    Article  CAS  PubMed  Google Scholar 

  28. Hu Y, Yang S, Shilliday FB, Heyde BR, Mandrell KM, Robins RH, Xie J, Reding MT, Lai Y, Thompson DC (2010) novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome P450 enzymes. Drug Metab Dispos 38(9):1522–1531. https://doi.org/10.1124/dmd.110.032581

    Article  CAS  PubMed  Google Scholar 

  29. Kumar D, de Visser SP, Sharma PK, Cohen S, Shaik S (2004) Radical clock substrates, their C–H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: What does theory reveal about the clocks’ behavior? J Am Chem Soc 126(6):1907–1920. https://doi.org/10.1021/ja039439s

    Article  CAS  PubMed  Google Scholar 

  30. de Visser SP, Shaik S (2003) A proton-shuttle mechanism mediated by the porphyrin in benzene hydroxylation by cytochrome P450 enzymes. J Am Chem Soc 125(24):7413–7424. https://doi.org/10.1021/ja034142f

    Article  CAS  PubMed  Google Scholar 

  31. de Visser SP, Kumar D, Cohen S, Shacham R, Shaik S (2004) A predictive pattern of computed barriers for C–H hydroxylation by compound I of cytochrome P450. J Am Chem Soc 126(27):8362–8363. https://doi.org/10.1021/ja04858h

    Article  PubMed  Google Scholar 

  32. Cohen S, Kozuch S, Hazan C, Shaik S (2006) Does substrate oxidation determine the regioselectivity of cyclohexene and propene oxidation by cytochrome P450? J Am Chem Soc 128(34):11028–11029. https://doi.org/10.1021/ja063269c

    Article  CAS  PubMed  Google Scholar 

  33. Mallick D, Shaik S (2017) Kinetic isotope effect probes the reactive Spin state, as well as the geometric feature and constitution of the transition State during H-abstraction by heme compound II complexes. J Am Chem Soc 139(33):11451–11459. https://doi.org/10.1021/jacs.7b04247

    Article  CAS  PubMed  Google Scholar 

  34. de Visser SP, Ogliaro F, Sharma PK, Shaik S (2002) What factors affect the regioselectivity of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond epoxidation in a model reaction. J Am Chem Soc 124(39):11809–11826. https://doi.org/10.1021/ja026872d

    Article  CAS  PubMed  Google Scholar 

  35. Bathelt CM, Ridder L, Mulholland AJ, Harvey JN (2003) Aromatic hydroxylation by cytochrome P450: model calculations of mechanism and substituent effects. J Am Chem Soc 125(49):15004–15005. https://doi.org/10.1021/ja035590q

    Article  CAS  PubMed  Google Scholar 

  36. Ai C-Z, Liu Y, Li W, Chen D-M, Zhu X-X, Yan Y-W, Chen D-C, Jiang Y-Z (2017) Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: a case of erlotinib. Plos One 12(6):1. https://doi.org/10.1371/journal.pone.0179333

    Article  CAS  Google Scholar 

  37. Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev 105(6):2279–2328. https://doi.org/10.1021/cr030722j

    Article  CAS  PubMed  Google Scholar 

  38. Schyman P, Lai W, Chen H, Wang Y, Shaik S (2011) The directive of the protein: how does cytochrome P450 select the mechanism of dopamine formation? J Am Chem Soc 133(20):7977–7984. https://doi.org/10.1021/ja201665x

    Article  CAS  PubMed  Google Scholar 

  39. Mulliken RS (1955) Electronic population analysis on LCAO-MO molecular wave functions. 3. Effects of hybridization on overlap and gross Ao populations. Journal of Chemical Physics 23(12):2338–2342. https://doi.org/10.1063/1.1741876

    Article  CAS  Google Scholar 

  40. de Visser SP, Ogliaro F, Harris N, Shaik S (2001) Multi-state epoxidation of ethene by cytochrome P450: a quantum chemical study. J Am Chem Soc 123(13):3037–3047

    Article  CAS  PubMed  Google Scholar 

  41. Harris DL, Loew GH (1998) Theoretical investigation of the proton assisted pathway to formation of cytochrome P450 compound I. J Am Chem Soc 120(35):8941–8948. https://doi.org/10.1021/ja981059x

    Article  CAS  Google Scholar 

  42. Schoneboom JC, Lin H, Reuter N, Thiel W, Cohen S, Ogliaro F, Shaik S (2002) The elusive oxidant species of cytochrome P450 enzymes: characterization by combined quantum mechanical/molecular mechanical (QM/MM) calculations. J Am Chem Soc 124(27):8142–8151. https://doi.org/10.1021/ja026279w

    Article  CAS  PubMed  Google Scholar 

  43. 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 JA Jr., 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 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 (2009) Gaussian 09, Revision D.01. Gaussian, Inc., Wallingford CT

    Google Scholar 

  44. Hirao H, Chuanprasit P, Cheong YY, Wang X (2013) How is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine: hydrogen abstraction or nitrogen oxidation? Chemistry-a Eur J 19(23):7361–7369. https://doi.org/10.1002/chem.201300689

    Article  CAS  Google Scholar 

  45. Sevrioukova IF, Poulos TL (2017) Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4. Proc Natl Acad Sci USA 114(3):486–491. https://doi.org/10.1073/pnas.1616198114

    Article  CAS  PubMed  Google Scholar 

  46. Ogliaro F, Cohen S, Filatov M, Harris N, Shaik S (2000) The high-valent compound of cytochrome P450: The nature of the Fe-S bond and the role of the thiolate ligand as an internal electron donor. Angew Chemie-Int Edit 39(21):3851. https://doi.org/10.1002/1521-3773(20001103)39:21%3c3851:aid-anie3851%3e3.0.co;2-9

    Article  CAS  Google Scholar 

  47. Kumar D, de Visser SP, Shaik S (2003) How does product isotope effect prove the operation of a two-state “rebound” mechanism in C–H hydroxylation by cytochrome P450? J Am Chem Soc 125(43):13024–13025. https://doi.org/10.1021/ja036906x

    Article  CAS  PubMed  Google Scholar 

  48. Ji L, Schueuermann G (2013) Model and mechanism: N-hydroxylation of primary aromatic amines by cytochrome P450. Angew Chemie-Int Edit 52(2):744–748. https://doi.org/10.1002/anie.201204116

    Article  CAS  Google Scholar 

  49. Ravula T, Barnaba C, Mahajan M, Anantharamaiah GM, Im S-C, Waskell L, Ramamoorthy A (2017) Membrane environment drives cytochrome P450’s spin transition and its interaction with cytochrome b(5). Chem Commun 53(95):12798–12801. https://doi.org/10.1039/c7cc07520k

    Article  CAS  Google Scholar 

  50. Ahuja S, Jahr N, Im SC, Vivekanandan S, Popovych N, Le Clair SV, Huang R, Soong R, Xu JD, Yamamoto K, Nanga RP, Bridges A, Waskell L, Ramamoorthy A (2013) A model of the membrane-bound cytochrome b(5)-Cytochrome P450 complex from NMR and mutagenesis data. J Biol Chem 288(30):22080–22095. https://doi.org/10.1074/jbc.M112.448225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang M, Huang R, Im SC, Waskell L, Ramamoorthy A (2015) Effects of membrane mimetics on cytochrome P450-Cytochrome b(5) interactions characterized by NMR spectroscopy. J Biol Chem 290(20):12705–12718. https://doi.org/10.1074/jbc.M114.597096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Prade E, Mahajan M, Im SC, Zhang M, Gentry KA, Anantharamaiah GM, Waskell L, Ramamoorthy A (2018) A minimal functional complex of cytochrome P450 and FBD of cytochrome P450 reductase in nanodiscs. Angew Chemie-Int Edit 57(28):8458–8462. https://doi.org/10.1002/anie.201802210

    Article  CAS  Google Scholar 

  53. Denisov IG, Sligar SG (2016) Nanodiscs for structural and functional studies of membrane proteins. Nat Struct Mol Biol 23(6):481–486. https://doi.org/10.1038/nsmb.3195

    Article  CAS  PubMed  Google Scholar 

  54. Mahajan M, Ravula T, Prade E, Anantharamaiah GM, Ramamoorthy A (2019) Probing membrane enhanced protein-protein interactions in a minimal redox complex of cytochrome-P450 and P450-reductase. Chem Commun (Camb, Engl) 55(41):1. https://doi.org/10.1039/c9cc01630a

    Article  CAS  Google Scholar 

  55. Barnaba C, Ramamoorthy A (2018) Picturing the membrane-assisted choreography of cytochrome P450 with lipid nanodiscs. Chem Phys Chem 19(20):2603–2613. https://doi.org/10.1002/cphc.201800444

    Article  CAS  PubMed  Google Scholar 

  56. Hollingsworth SA, Batabyal D, Nguyen BD, Poulos TL (2016) Conformational selectivity in cytochrome P450 redox partner interactions. Proc Natl Acad Sci USA 113(31):8723–8728. https://doi.org/10.1073/pnas.1606474113

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the China Postdoctoral Science Foundation (Grant no. 2017M622784), the National Natural Science Foundation of China (Grant no. 81173124), Shenzhen Science and Technology Innovation Commission (Grant nos. JCYJ20160308104109234 and KQJSCX20170728150303243), and the National Key Research and Development Program of China (Grant no. 2017YFC1702006).

Author information

Authors and Affiliations

  1. Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China

    Chun-Zhi Ai, Du-Chu Chen, Yasmeen Saeed & Yi-Zhou Jiang

  2. Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China

    Chun-Zhi Ai, Du-Chu Chen & Yasmeen Saeed

  3. School of Life Science and Medicine, Dalian University of Technology, Panjin, Liaoning, China

    Yong Liu

Authors
  1. Chun-Zhi Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Du-Chu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasmeen Saeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-Zhou Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-Zhou Jiang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2828 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ai, CZ., Liu, Y., Chen, DC. et al. Conformational turn triggers regio-selectivity in the bioactivation of thiophene-contained compounds mediated by cytochrome P450. J Biol Inorg Chem 24, 1023–1033 (2019). https://doi.org/10.1007/s00775-019-01699-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-019-01699-6

Keywords

Search

Navigation