Skip to main content
SpringerLink
Log in

The effect of neighboring amino acid residues and solution environment on the oxidative stability of tyrosine in small peptides

  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The effects of neighboring residues and formulation variables on tyrosine oxidation were investigated in model dipeptides (glysyl tyrosine, N-acetyl tyrosine, glutamyl tyrosine, and tyrosyl arginine) and tripeptide (lysyl tyrosyl lysine). The tyrosyl peptides were oxidized by light under alkaline conditions by a zero-order reaction. The rate of the photoreaction was dependent on tyrosyl pKa, which was perturbed by the presence of neighboring charged amino acid residues. The strength of light exposure, oxygen headspace, and the presence of cationic surfactant, cetyltrimethylammonia chloride had a significant effect on the kinetics of tyrosyl photooxidation. Tyrosine and model tyrosyl peptides were also oxidized by hydrogen peroxide/metal ions at neutral pH. Metal-catalyzed oxidation followed first-order kinetics. Adjacent negatively charged amino acids accelerated tyrosine oxidation owing to affinity of the negative charges to metalions, whereas positively charged amino acid residues disfavored the reaction. The oxidation of tyrosine in peptides was greatly affected by the presence of adjacent charged residues, and the extent of the effect depended on the solution environment.

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

Similar content being viewed by others

References

  1. Pharmaceutical Manufacturers Association.Survey Report. Washington, DC: PhRMA; 1998–2002.

    Google Scholar 

  2. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals.Int J Pharm. 1999;185:129–188.

    Article  PubMed  CAS  Google Scholar 

  3. Penner MH, Yamasaki RB, Osuga DT, Babin DR, Meares CF, Feeney RE. Comparative oxidations of tyrosines and methionines in transferrins: human serum transferring, human lactotransferrin, and chicken ovotransferrin.Arch Biochem Biophys. 1983;225:740–747.

    Article  PubMed  CAS  Google Scholar 

  4. Stadtman ER. Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions.Annu Rev Biochem. 1993;62:797–821.

    Article  PubMed  CAS  Google Scholar 

  5. Li S, Schoneich C, Borchardt RT. Chemical instability of protein pharmaceuticals: mechanisms of oxidation and strategies for stabilization.Biotechnol Bioeng. 1995;48:490–500.

    Article  PubMed  CAS  Google Scholar 

  6. Wang YJ, Hanson MA. Parenteral formulations of proteins and peptides: stability and stabilizers. In:Technical Report 10. Bethesda, MD: Parenteral Drug Association; 1998:3–26.

    Google Scholar 

  7. Kerwin BA Jr, Remmele RL Jr. Protect from light: photodegradation and protein biologics.J Pharm Sci. 2007;96:1468–1479.

    Article  PubMed  CAS  Google Scholar 

  8. Creed D. The photophysics and photochemistry of the near-UV absorbing amino acids. II. Tyrosine and its simple derivatives.Photochem Photobiol. 1984;39:563–575.

    CAS  Google Scholar 

  9. Joshi P, Carraro C, Pathak M. Involvement of reactive oxygen species in the oxidation of tyrosine and dopa to melanin and in skin tanning.Biochem Biophys Res Commun. 1987;142:265–274.

    Article  PubMed  CAS  Google Scholar 

  10. Huggins TG, Wells-Knecht MC, Detorie NA, Baynes JW, Thorpe SR. Formation of o-tyrosine and dityrosine in protein during radiolytic and metal-catalyzed oxidation.J Biol Chem. 1993;268:12341–12347.

    PubMed  CAS  Google Scholar 

  11. Aeschbach R, Amado R, Neukom H. Formation of dityrosine cross-links in protein by oxidation of tyrosine residues.Biochim Biophys Acta. 1976;439:292–301.

    PubMed  CAS  Google Scholar 

  12. Bertolotti SG, Garcia NA. Effect of the peptide bond on the singlet-molecular-oxygen-mediated sensitized photo-oxidation of tyrosine and tryptophan dipeptides.J Photochem Photobiol. 1991;10:57–70.

    Article  CAS  Google Scholar 

  13. Nema S, Washkuhn RJ, Beussink DR. Photostability testing: an overview.Pharm Technol. 1996;19:170–185.

    Google Scholar 

  14. Fransson J, Florin-Robertsson E, Axelsson K, Nyhlen C. Oxidation of human insulin-like growth factor I in formulation studies: kinetics of methionine oxidation in aqueous solution and in solid state.Pharm Res. 1996;13:1252–1257.

    Article  PubMed  CAS  Google Scholar 

  15. Gu L, Chiang H-S, Johnson D. Light degradation of ketorolac tromethamine.Int J Pharm. 1988;41:105–113.

    Article  CAS  Google Scholar 

  16. Mendenhall D. Stability of parenterals.Drug Dev Ind Pharm. 1984;10:1297–1342.

    Article  CAS  Google Scholar 

  17. Tanford C, Hauenstein JD, Rands DG. Phenolic hydroxyl ionization in proteins. II. Ribonuclease.J Am Chem Soc. 1955;77:6409–6413.

    Article  CAS  Google Scholar 

  18. Weil L. On the mechanism of the photo-oxidation of amino acids sensitized by methylene blue.Arch Biochim Biophys. 1965;110:57–68.

    Article  CAS  Google Scholar 

  19. Scotchler AB, Robinson AB. Deamidation of glutaminyl residues: dependence on pH, temperature and ionic strength.Anal Biochem. 1974;59:319–322.

    Article  PubMed  CAS  Google Scholar 

  20. Flatmark T. On the heterogeneity of beef heart cytochrome C. III. A kinetic study of the nonenzymatic deamidation of the main subfraction.Acta Chem Scand A. 1966;20:1487–1496.

    Article  CAS  Google Scholar 

  21. Donbrow M, Azaz E, Pillersdorf A. Autoxidation of polysorbates.J Pharm Sci. 1978;67:1676–1681.

    Article  PubMed  CAS  Google Scholar 

  22. Hora MS, Rana RK, Wilcox CL, et al. Development of a lyophilized formulation of interleukin-2.Dev Biol Stand. 1991;74:295–306.

    Google Scholar 

  23. Kumar V, Kalonia D. Removal of peroxides of polyethylene glycols by vacuum drying: implications in the stability of biotech and pharmaceutical formulations.AAPS PharmSciTech. 2006;7:E62.

    Google Scholar 

  24. Steinhardt J, Stocker N. Effects of high pH and sodium dodecyl sulfate on the hidden tyrosines of human serum albumin.Biochemistry. 1973;12:1789–1797.

    Article  PubMed  CAS  Google Scholar 

  25. Blount BC, Duncan MW. Trace quantification of oxidative damage products, meta- and ortho-tyrosine, in biological samples by gas chromatography-electron capture negative ionization mass spectrometry.Anal Biochem. 1997;244:270–276.

    Article  PubMed  CAS  Google Scholar 

  26. Zhao F, Ghezzo-Schoneich E, Aced G, Hong J, Milby T, Schoneich C. Metal-catalyzed oxidation of histidine in human growth hormone.J Biol Chem. 1997;272:9019–9029.

    Article  PubMed  CAS  Google Scholar 

  27. Frank MJ, Johnson JB, Rubin SH. Spectrophotometeric determination of sodium nitroprusside and its photodegradation products.J Pharm Sci. 1976;65:44–48.

    Article  PubMed  CAS  Google Scholar 

  28. Chatterji DC, Gallelli JF. Thermal and photolytic decomposition of methotrexate in aqueous solutions.J Pharm Sci. 1978;67:526–531.

    Article  PubMed  CAS  Google Scholar 

  29. Jamil N, Afrozrizvi H, Ahmed I, Ejazbeg A. Studies on the photostability of reserpine in parenterals solutions.Pharmazie. 1983;38:467–469.

    PubMed  CAS  Google Scholar 

  30. Feitelson J, Havon E, Treinin A. Photoionization of phenols in water: effects of light intensity, oxygen, pH, and temperature.J Am Chem Soc. 1973;95:1025–1029.

    Article  CAS  Google Scholar 

  31. Shimizu O. Excited states in photodimerization of aqueous tyrosine at room temperature.Photochem Photobiol. 1973;18:25–133.

    Article  Google Scholar 

  32. Matheson IBC, Lee J. Chemical reaction rates of amino acids with singlet oxygen.Photochem Photobiol. 1979;29:879–881.

    Article  CAS  Google Scholar 

  33. Galand D Jr, Zigler JS Jr, Kinoshita J. Structural changes in bovine lens crystalline induced by ascorbate, metal, and oxygen.Arch Biochim Biophys. 1986;251:771–776.

    Article  Google Scholar 

  34. Kanazawa H, Fujimoto S, Ohara A. Effect of radical scavengers on the inactivation of papain by ascorbic acid in the presence of cupric ions.Biol Pharm Bull. 1994;17:476–481.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 06269, Storrs, CT

    Jian Zhang & Devendra S. Kalonia

Authors
  1. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Devendra S. Kalonia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Devendra S. Kalonia.

Additional information

Published: December 7, 2007

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Kalonia, D.S. The effect of neighboring amino acid residues and solution environment on the oxidative stability of tyrosine in small peptides. AAPS PharmSciTech 8, 102 (2007). https://doi.org/10.1208/pt0804102

Download citation

  • Received:

  • Revised:

  • Accepted:

  • DOI: https://doi.org/10.1208/pt0804102

Keywords

Search

Navigation