The Chemical Synthesis of the Collagenous Domain of the Hormone Adiponectin

  • Paul W. R. Harris
  • Margaret A. Brimble


As a first step towards the preparation of a functional biomolecule, a chemical synthesis of the collagenous domain of adiponectin is described. The 76 residue polypeptide (without post-translational modifications) could be assembled efficiently from smaller unprotected peptides using two native chemical ligation reactions followed by a reductive desulfurisation step. In turn, the polypeptides were synthesised in high purity by microwave enhanced solid phase synthesis.


Adiponectin Native chemical ligation Collagenous 



The authors wish to thank The Maurice Wilkins Centre for Molecular Biodiscovery for financial support.


  1. Allevi P, Paroni R, Ragusa A, Anastasia M (2004) Hydroxylysine containing glycoconjugates: an efficient synthesis of natural galactosylhydroxylysine (Gal-Hyl) and glucosylgalactosylhydroxylysine (Glu-Gal-Hyl) and of their (5S)-epimers. Tetrahedron Asymmetr 15:3139–3148CrossRefGoogle Scholar
  2. Blanco-Canosa JB, Dawson PE (2008) An efficient Fmoc-SPPS approach for the generation of thioester peptide precursors for use in native chemical ligation. Angew Chem Int Edit 47:6851–6855CrossRefGoogle Scholar
  3. Brik A, Harpaz Z, Siman P, Kumar KSA (2010) Protein synthesis assisted by native chemical ligation at leucine. ChemBioChem 11:1232–1235PubMedCrossRefGoogle Scholar
  4. Chen YX, Mant CT, Hodges RS (2007) Preparative reversed-phase high-performance liquid chromatography collection efficiency for an antimicrobial peptide on columns of varying diameters (1 to 9.4 mm ID). J Chromatogr A 1140:112–120PubMedCrossRefGoogle Scholar
  5. Chen J, Wan Q, Yuan Y, Zhu J, Danishefsky SJ (2008) Native chemical ligation at valine: a contribution to peptide and glycopeptide synthesis. Angew Chem Int Ed Engl 47:8521–8524PubMedCrossRefGoogle Scholar
  6. Crich D, Banerjee A (2007) Native chemical ligation at phenylalanine. J Am Chem Soc 129:10064–10065PubMedCrossRefGoogle Scholar
  7. Dawson PE, Muir TW, Lewis IC, Kent SBH (1994) Synthesis of proteins by native chemical ligation. Science 266:776–779PubMedCrossRefGoogle Scholar
  8. Diez JJ, Iglesias P (2010) The role of the novel adipocyte-derived protein adiponectin in human disease: an update. Mini Rev Med Chem 10:856–869PubMedCrossRefGoogle Scholar
  9. Haase C, Rohde H, Seitz O (2008) Native chemical ligation at valine. Angew Chem Int Edit 47:6807–6810CrossRefGoogle Scholar
  10. Hackeng TM, Griffin JH, Dawson PE (1999) Protein synthesis by native chemical ligation: expanded scope by using straightforward methodology. Proc Natl Acad Sci USA 96:10068–10073PubMedCrossRefGoogle Scholar
  11. Harris PWR, Brimble MA (2009) Synthesis of an arginine tagged [Cys(155)-Arg(180)] fragment of NY-ESO-1: elimination of an undesired by-product using ‘In House’ resins. Synth Stuttgart 20:3460–3466CrossRefGoogle Scholar
  12. Johnson ECB, Kent SBH (2006) Insights into the mechanism and catalysis of the native chemical ligation reaction. J Am Chem Soc 128:6640–6646PubMedCrossRefGoogle Scholar
  13. Kent SBH (2009) Total chemical synthesis of proteins. Chem Soc Rev 38:338–351PubMedCrossRefGoogle Scholar
  14. Kent SBH, Durek T, Torbeev VY (2007) Convergent chemical synthesis and high-resolution X-ray structure of human lysozyme. Proc Natl Acad Sci USA 104:4846–4851PubMedCrossRefGoogle Scholar
  15. Matsuzawa Y (2010) Adiponectin: a key player in obesity related disorders. Curr Pharm Design 16:1896–1901CrossRefGoogle Scholar
  16. Pasunooti KK, Yang R, Vedachalam S, Gorityala BK, Liu CF et al (2009) Synthesis of 4-mercapto-l-lysine derivatives: potential building blocks for sequential native chemical ligation. Bioorg Med Chem Lett 19:6268–6271PubMedCrossRefGoogle Scholar
  17. Pentelute BL, Kent SBH (2007) Selective desulfurization of cysteine in the presence of Cys(Acm) in polypeptides obtained by native chemical ligation. Org Lett 9:687–690PubMedCrossRefGoogle Scholar
  18. Rohde H, Seitz O (2010) Ligation-desulfurization: a powerful combination in the synthesis of peptides and glycopeptides. Biopolymers 94:551–559PubMedCrossRefGoogle Scholar
  19. Simpson F, Whitehead JP (2010) Adiponectin—it’s all about the modifications. Int J Biochem Cell Biol 42:785–788PubMedCrossRefGoogle Scholar
  20. Villain M, Vizzavona J, Rose K (2001) Covalent capture: a new tool for the purification of synthetic and recombinant polypeptides. Chem Biol 8:673–679PubMedCrossRefGoogle Scholar
  21. Wan Q, Danishefsky SJ (2007) Free-radical-based, specific desulfurization of cysteine: a powerful advance in the synthesis of polypeptides and glycopolypeptides. Angew Chem Int Ed 46:9248–9252CrossRefGoogle Scholar
  22. Wang Y, Xu AM, Knight C, Xu LY, Cooper GJS (2002) Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin—potential role in the modulation of its insulin-sensitizing activity. J Biol Chem 277:19521–19529PubMedCrossRefGoogle Scholar
  23. Wang Y, Lam KS, Yau MH, Xu A (2008) Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J 409:623–633PubMedCrossRefGoogle Scholar
  24. Yan LZ, Dawson PE (2001) Synthesis of peptides and proteins without cysteine residues by native chemical ligation combined with desulfurization. J Am Chem Soc 123:526–533PubMedCrossRefGoogle Scholar
  25. Yang R, Pasunooti KK, Li F, Liu XW, Liu CF (2009) Dual native chemical ligation at lysine. J Am Chem Soc 131:13592–13593PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.School of Chemical Sciences and Maurice Wilkins Centre for Molecular BiodiscoveryThe University of AucklandAucklandNew Zealand

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