Skip to main content
SpringerLink
Log in

The conformation of biliverdin in dimethyl sulfoxide: implications for the coordination with copper

  • Original Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

Biliverdin (BV) structure was analyzed by using NMR techniques and unrestricted density function theory simulations to explain the incapacity of BV to build coordination complex(es) with Cu2+ in dimethyl sulfoxide, which was confirmed by UV-Vis, EPR and NMR spectroscopy. NMR showed that N atoms are protonated in all four pyrrole rings. The structure is stabilized by two hydrogen bonds between NH moieties and carbonyl oxygens from opposite terminal pyrrole rings, and by the bending of propionyl chain with carboxyl group out of the plain toward central position of BV. The simulations of deprotonated BV, which builds copper complexes in water and chloroform as described previously, showed a different conformation and organization of hydrogen bonds. Taking into account that deprotonation represents a critical step in coordinate bonds formation, the protonation of an additional N atom may represent a key difference between the interactions of BV with copper in different solvents.

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

Similar content being viewed by others

References

  1. Korać J, Todorović N, Zakrzewska J, Žižić M, Spasojević I (2018) The conformation of epinephrine in polar solvents: an NMR study. Struct Chem 29:1533–1541

    Article  Google Scholar 

  2. Watermann T, Elgabarty H, Sebastiani D (2014) Phycocyanobilin in solution - a solvent triggered molecular switch. Phys Chem Chem Phys 16:6146–6152

    Article  CAS  Google Scholar 

  3. Sailofsky BM, Brown GR (1987) Solvent effects on the photoisomerization of bilirubin. J Chem 65:1908–1916

    CAS  Google Scholar 

  4. Nam J, Lee Y, Yang Y, Jeong S, Kim W, Yoo JW, Moon JO, Lee C, Chung HY, Kim MS, Jon S, Jung Y (2018) Is it worth expending energy to convert biliverdin into bilirubin? Free Radic Biol Med 124:232–240

    Article  CAS  Google Scholar 

  5. Dimitrijevic MS, Bogdanović Pristov J, Žižić M, Stanković DM, Bajuk-Bogdanović D, Stanić M, Spasić S, Hagen W, Spasojević I (2019) Biliverdin-copper complex at physiological pH. Dalton Trans. https://doi.org/10.1039/c8dt04724c

    Article  Google Scholar 

  6. Krois D, Lehner H (1993) Helically fixed chiral bilirubins and biliverdins: a new insight into the conformational, associative and dynamic features of linear tetrapyrrols. J Chem Soc Perkin Trans 2:1351–1360

    Article  Google Scholar 

  7. Lightner DA, Holmes DL, McDonagh AF (1996) On the acid dissociation constants of bilirubin and biliverdin. pKa values from 13C NMR spectroscopy. J Biol Chem 271:2397–2405

    Article  CAS  Google Scholar 

  8. Lightner DA, Holmes DL, McDonagh AF (1996) Dissociation constants of water-insoluble carboxylic acids by 13C-NMR. pKas of mesobiliverdin-XIIIα and mesobilirubin-XIIIα. Experientia 52:639–642

    Article  CAS  Google Scholar 

  9. Sugishima M, Sakamoto H, Higashimoto Y, Noguchi M, Fukuyama K (2003) Crystal structure of rat heme oxygenase-1 in complex with biliverdin-iron chelate. Conformational change of the distal helix during the heme cleavage reaction. J Biol Chem 278:32352–32358

    Article  CAS  Google Scholar 

  10. Reichardt C (2003) Solvents and solvent effects in organic chemistry. Wiley-VCH Verlag GmbH & Co, Weinheim

    Google Scholar 

  11. Sóvágó I, Harman B, Kolozsvári I, Matyuska F (1985) Complex-formation and redox reactions of bilirubin and biliverdin with zinc(II), cadmium(II) and copper(II) ions. Inorg Chim Acta 106:181–186

    Article  Google Scholar 

  12. Berlec A, Štrukelj B (2014) A high-throughput biliverdin assay using infrared fluorescence. J Vet Diagn Investig 26:521–526

    Article  Google Scholar 

  13. Shang L, Rockwell NC, Martin SS, Lagarias JC (2010) Biliverdin amides reveal roles for propionate side chains in Bilin reductase recognition and in holophytochrome assembly and photoconversion. Biochemistry 49:6070–6082

    Article  CAS  Google Scholar 

  14. Mukerjee P, Ostrow JD (1998) Effects of added dimethylsulfoxide on pKa values of uncharged organic acids and pH values of aqueous buffers. Tetrahedron Lett 39:423–426

    Article  CAS  Google Scholar 

  15. McDonagh AF, Phimster A, Boiadjiev SE, Lightner DA (1999) Dissociation constants of carboxylic acids by 13C-NMR in DMSO/water. Tetrahedron Lett 40:8515–8518

    Article  CAS  Google Scholar 

  16. Rubino JT, Berryhill WS (1986) Effects of solvent polarity on the acid dissociation constants of benzoic acids. J Pharm Sci 75:182–186

    Article  CAS  Google Scholar 

  17. Kurtin WE, Enz J, Dunsmoor C, Evans N, Lightner DA (2000) Acid dissociation constants of bilirubin and related carboxylic acid compounds in bile salt solutions. Arch Biochem Biophys 381:83–91

    Article  CAS  Google Scholar 

  18. Ostrow JD, Celic L, Mukerjee P (1988) Molecular and micellar associations in the pH-dependent stable and metastable dissolution of unconjugated bilirubin by bile salts. J Lipid Res 29:335–348

    CAS  PubMed  Google Scholar 

  19. Li M, Xiao Z, Xiang H, Lu Z (1997) Unusual solvent effect on absorption spectra of nonplanar dodecaphenylporphyrins with different substituents. Spectrochim Acta A Mol Biomol Spectrosc 53:1691–1695

    Article  Google Scholar 

  20. Moussa F, Kanoute G, Herrenknecht C, Levillain P, Trivin F (1988) Electrochemical oxidation of bilirubin and biliverdin in dimethyl sulfoxide. Anal Chem 60:1179–1185

    Article  CAS  Google Scholar 

  21. Lu G, Lin W, Fang Y, Zhu W, Ji X, Ou Z (2011) Synthesis and electrochemical properties of meso-phenyl substituted copper corroles. Solvent effect on copper oxidation state. J Porphyrins Phthalocyanines 15:1265–1274

    Article  CAS  Google Scholar 

  22. Balch AL, Mazzanti M, Noll BC, Olmstead MM (1993) Geometric and electronic structure and dioxygen sensitivity of the copper complex of octaethylbilindione, a biliverdin analog. J Am Chem Soc 115:12206–12207

    Article  CAS  Google Scholar 

  23. Dorazio SJ, Halepas S, Bruhn T, Fleming KM, Zeller M, Brückner C (2015) Singlet oxygen oxidation products of biliverdin IXa dimethyl ester. Bioorg Med Chem 23:7671–7675

    Article  CAS  Google Scholar 

  24. Feliz M, Ribó JM, Salgado A, Trull FR, Vallès MA (1989) On the 1H NMR spectra of biliverdins with free propionic acid substituents. Mönatsh Chem 120:445–451

    Article  CAS  Google Scholar 

  25. Kaplan D, Navon G (1982) Studies of the conformation of bilirubin and its dimethyl ester in dimethyl sulphoxide solutions by nuclear magnetic resonance. Biochem J 201:605–613

    Article  CAS  Google Scholar 

  26. Pretsch E, Bühlmann P, Badertscher M (2009) Structure determination of organic compounds. Springer-Verlag, Berlin

    Google Scholar 

  27. Bates RG (1973) Determination of pH: theory and practice. Wiley & Sons, New York

    Google Scholar 

  28. Hathaway BJ, Billing DE (1970) The electronic properties and stereochemistry of mono-nuclear complexes of the copper(II) ion. Coord Chem Rev 5:143–207

    Article  CAS  Google Scholar 

  29. Garribba E, Micera G (2006) The determination of the geometry of Cu(II) complexes. J Chem Educ 83:1229–1232

    Article  CAS  Google Scholar 

  30. Elleb M, Meullemeestre J, Schwing-Weill MJ, Vierling F (1982) Spectrophotometric study of copper(II) chloride complexes in propylene carbonate and in dimethyl sulfoxide. Inorg Chem 21:1477–1483

    Article  CAS  Google Scholar 

  31. Willett RD, Chang K (1970) The crystal structure of copper(II) chloride bis(dimethylsulphoxide). Inorg Chim Acta 4:447–451

    Article  CAS  Google Scholar 

  32. Kozlowski H, Kowalik-Jankowska T, Jeżowska-Bojczuk M (2005) Chemical and biological aspects of Cu2+ interactions with peptides and aminoglycosides. Coord Chem Rev 249:2323–2334

    Article  CAS  Google Scholar 

  33. Meng R, Becker J, Lin FT, Saxena S, Weber SG (2005) Binding of copper(II) to thyrotropin-releasing hormone (TRH) and its analogs. Inorg Chim Acta 358:2933–2942

    Article  CAS  Google Scholar 

  34. Mukerjee P, Ostrow JD, Tiribelli C (2002) Low solubility of unconjugated bilirubin in dimethylsulfoxide--water systems: implications for pKa determinations. BMC Biochem 3:17

    Article  Google Scholar 

  35. Nogales D, Lightner DA (1995) On the structure of bilirubin in solution. J Biol Chem 270:73–77

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are thankful to Prof. Miloš Mojović at EPR Laboratory, Faculty of Physical Chemistry, University of Belgrade for recording EPR spectra and to Ljiljana Stojanović from School of Biological and Chemical Sciences, Queen Mary University of London, for her great help in calculating and discussing theoretical results obtained using the UDFT.

Funding

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (III43010). This article is based upon work from COST Action CA15133 FesBioNet, supported by COST (European Cooperation in Science and Technology).

Author information

Authors and Affiliations

  1. Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade Kneza Višeslava 1, Belgrade, 11030, Serbia

    Milena S. Dimitrijević, Milan Žižić, Jelena Bogdanović Pristov & Ivan Spasojević

  2. Center for Magnetic Resonance, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, 50019, Florence, Italy

    Mario Piccioli

Authors
  1. Milena S. Dimitrijević
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milan Žižić
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario Piccioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jelena Bogdanović Pristov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ivan Spasojević
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Milan Žižić or Ivan Spasojević.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(PDF 499 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dimitrijević, M.S., Žižić, M., Piccioli, M. et al. The conformation of biliverdin in dimethyl sulfoxide: implications for the coordination with copper. Struct Chem 30, 2159–2166 (2019). https://doi.org/10.1007/s11224-019-01354-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-019-01354-5

Keywords

Search

Navigation