Skip to main content
SpringerLink
Log in

Contemporary Approaches to α,β-Dehydroamino Acid Chemical Modifications

  • Review
  • Published:
Chemical Research in Chinese Universities Aims and scope

Abstract

As one of the most common unnatural amino acids(uAAs), α,β-dehydroamino acids(α,β-dhAAs) can be found in various ribosomally synthesized and post-translationally modified peptides(RiPPs) and other naturally occurring peptides. In recent years, novel reactions for α,β-dhAA modification continue to emerge. Due to their unique electrophilicity different from 20 natural amino acids, α,β-dhAAs, especially dehydroalanine(Dha), have become powerful tools for site-selective protein modification. In this review, we mainly focus on the latest research progress of C—C and C-heteroatom(C—X, X=S, N, Se, Si, P, B) bond formation methods based on α,β-dhAAs in the past five years. Particularly, we pay much attention to the α,β-dhAA derivatization methodologies used in the late-stage modification for natural peptides and proteins. In addition, we also focus on the downstream functionalization and therapeutic biologic applications of these modifications.

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. Siodlak D., Amino Acids, 2015, 47, 1

    Article  CAS  PubMed  Google Scholar 

  2. Arnison P. G., Bibb M. J., Bierbaum G., Bowers A. A., Bugni T. S., Bulaj G., Camarero J. A., Campopiano D. J., Challis G. L., Clardy J., Cotter P. D., Craik D. J., Dawson M., Dittmann E., Donadio S., Dorrestein P. C., Entian K. D., Fischbach M. A., Garavelli J. S., Goransson U., Gruber C. W., Haft D. H., Hemscheidt T. K., Hertweck C., Hill C., Horswill A. R., Jaspars M., Kelly W. L., Klinman J. P., Kuipers O. P., Link A. J., Liu W., Marahiel M. A., Mitchell D. A., Moll G. N., Moore B. S., Muller R., Nair S. K., Nes I. F., Norris G. E., Olivera B. M., Onaka H., Patchett M. L., Piel J., Reaney M. J. T., Rebuffat S., Ross R. P., Sahl H. G., Schmidt E. W., Selsted M. E., Severinov K., Shen B., Sivonen K., Smith L., Stein T., Sussmuth R. D., Tagg J. R., Tang G. L., Truman A. W., Vederas J. C., Walsh C. T., Walton J. D., Wenzel S. C., Willey J. M., van der Donk W. A., Nat. Prod. Rep., 2013, 30, 1568

    Article  CAS  Google Scholar 

  3. Ortega Manuel A., van der Donk Wilfred A., Cell Chem. Biol., 2016, 23, 31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Knerr P. J., van der Donk W. A., Annu. Rev. Biochem., 2012, 81, 479

    Article  CAS  PubMed  Google Scholar 

  5. Repka L. M., Chekan J. R., Nair S. K., van der Donk W. A., Chem. Rev., 2017, 117, 5457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bagley M. C., Dale J. W., Merritt E. A., Xiong X., Chem. Rev., 2005, 105, 685

    Article  CAS  PubMed  Google Scholar 

  7. Edler M. C., Fernandez A. M., Lassota P., Ireland C. M., Barrows L. R., Biochem. Pharmacol., 2002, 63, 707

    Article  CAS  PubMed  Google Scholar 

  8. Gavaret J. M., Nunez J., Cahnmann H. J., J. Biol. Chem., 1980, 255, 5281

    Article  CAS  PubMed  Google Scholar 

  9. Li H., Xu H., Zhou Y., Zhang J., Long C., Li S., Chen S., Zhou J. M., Shao F., Science, 2007, 315, 1000

    Article  CAS  PubMed  Google Scholar 

  10. Wang Z., Lyons B., Truscott R. J. W., Schey K. L., Aging Cell, 2014, 13, 226

    Article  CAS  PubMed  Google Scholar 

  11. Krall N., da Cruz F. P., Boutureira O., Bernardes G. J. L., Nat. Chem., 2016, 8, 102

    Article  CAS  Google Scholar 

  12. Boutureira O., Bernardes G. J. L., Chem. Rev., 2015, 115, 2174

    Article  CAS  PubMed  Google Scholar 

  13. Hu J. J., He P. Y., Li Y. M., J. Pept. Sci., 2021, 27, e3286

    Article  CAS  PubMed  Google Scholar 

  14. Li Q. Q., Chen P. G., Hu Z. W., Cao Y., Chen L. X., Chen Y. X., Zhao Y. F., Li Y. M., Chem. Sci., 2017, 8, 7675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liang F., Sun H., Zhao C. G., Cui T., Hong S. S., Chen J., Liu L. Y., Chem. Res. Chinese Universities, 2003, 19(3), 317

    CAS  Google Scholar 

  16. Chalker J. M., Gunnoo S. B., Boutureira O., Gerstberger S. C., Fernandez-Gonzalez M., Bernardes G. J. L., Griffin L., Hailu H., Schofield C. J., Davis B. G., Chem. Sci., 2011, 2, 1666

    Article  CAS  Google Scholar 

  17. Gunnoo S. B., Madder A., ChemBioChem, 2016, 17, 529

    Article  CAS  PubMed  Google Scholar 

  18. Humphrey J. M., Chamberlin A. R., Chem. Rev., 1997, 97, 2243

    Article  CAS  PubMed  Google Scholar 

  19. Yamaguchi J., Yamaguchi A. D., Itami K., Angew. Chem. Int. Ed., 2012, 51, 8960

    Article  CAS  Google Scholar 

  20. Shin J. A., Kim J., Lee H., Ha S., Lee H. Y., J. Org. Chem., 2019, 84, 4558

    Article  CAS  PubMed  Google Scholar 

  21. Prier C. K., Rankic D. A., MacMillan D. W. C., Chem. Rev., 2013, 113, 5322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bottecchia C., Noël T., Chem. Eur. J., 2019, 25, 26

    Article  CAS  PubMed  Google Scholar 

  23. Aycock R. A., Vogt D. B., Jui N. T., Chem. Sci., 2017, 8, 7998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Medrano-Uribe K., Miranda L. D., Tetrahedron Lett., 2019, 60, 151152

    Article  CAS  Google Scholar 

  25. Rossolini T., Ferko B., Dixon D. J., Org. Lett., 2019, 21, 6668

    Article  CAS  PubMed  Google Scholar 

  26. Chu L. L., Ohta C., Zuo Z. W., MacMillan D. W. C., J. Am. Chem. Soc., 2014, 136, 10886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shah A. A., Kelly M. J., Perkins J. J., Org. Lett., 2020, 22, 2196

    Article  CAS  Google Scholar 

  28. Zhang O., Schubert J. W., J. Org. Chem., 2020, 85, 6225

    Article  CAS  PubMed  Google Scholar 

  29. Wang X., Chen Y., Song H., Liu Y., Wang Q., Org. Lett., 2021, 23, 2199

    Article  CAS  PubMed  Google Scholar 

  30. Aycock R. A., Pratt C. J., Jui N. T., ACS Catal., 2018, 8, 9115

    Article  CAS  Google Scholar 

  31. Yang J., Sun W., He Z., Yu C., Bao G., Li Y., Liu Y., Hong L., Wang R., Org. Lett., 2018, 20, 7080

    Article  CAS  PubMed  Google Scholar 

  32. Funk M. A., van der Donk W. A., Acc. Chem. Res., 2017, 50, 1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Key H. M., Miller S. J., J. Am. Chem. Soc., 2017, 139, 15460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Bruijn A. D., Roelfes G., Chem. Eur. J., 2018, 24, 12728

    Article  CAS  PubMed  Google Scholar 

  35. de Vries R. H., Viel J. H., Oudshoorn R., Kuipers O. P., Roelfes G., Chem. Eur. J., 2019, 25, 12698

    Article  CAS  PubMed  Google Scholar 

  36. Gober J. G., Ghodge S. V., Bogart J. W., Wever W. J., Watkins R. R., Brustad E. M., Bowers A. A., ACS Chem. Biol., 2017, 12, 1726

    Article  CAS  PubMed  Google Scholar 

  37. Walsh C. T., Garneau-Tsodikova S., Gatto Jr G. J., Angew. Chem. Int. Ed., 2005, 44, 7342

    Article  CAS  Google Scholar 

  38. Yu C. H., Si T., Wu W. H., Hu J., Du J. T., Zhao Y. F., Li Y. M., Biochem. Biophys. Res. Commun., 2008, 375, 59

    Article  CAS  PubMed  Google Scholar 

  39. Zhang S. Y., Sperlich B., Li F. Y., Al-Ayoubi S., Chen H. X., Zhao Y. F., Li Y. M., ACS Chem. Biol., 2017, 12, 1703

    Article  CAS  PubMed  Google Scholar 

  40. Wright T. H., Bower B. J., Chalker J. M., Bernardes G. J. L., Wiewiora R., Ng W. L., Raj R., Faulkner S., Vallee M. R. J., Phanumartwiwath A., Coleman O. D., Thezenas M. L., Khan M., Galan S. R. G., Lercher L., Schombs M. W., Gerstberger S., Palm-Espling M. E., Baldwin A. J., Kessler B. M., Claridge T. D. W., Mohammed S., Davis B. G., Science, 2016, 354, 597

    Article  CAS  Google Scholar 

  41. Wright T. H., Davis B. G., Nat. Protoc., 2017, 12, 2243

    Article  PubMed  Google Scholar 

  42. Josephson B., Fehl C., Isenegger P. G., Nadal S., Wright T. H., Poh A. W. J., Bower B. J., Giltrap A. M., Chen L., Batchelor-McAuley C., Roper G., Arisa O., Sap J. B. I., Kawamura A., Baldwin A. J., Mohammed S., Compton R. G., Gouverneur V., Davis B. G., Nature, 2020, 585, 530

    Article  CAS  PubMed  Google Scholar 

  43. Yang A., Ha S., Ahn J., Kim R., Kim S., Lee Y., Kim J., Soell D., Lee H. Y., Park H. S., Science, 2016, 354, 623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. van Lier R. C. W., de Bruijn A. D., Roelfes G., Chem. Eur. J., 2021, 27, 1430

    Article  CAS  PubMed  Google Scholar 

  45. Zhu Y., van der Donk W. A., Org. Lett., 2001, 3, 1189

    Article  CAS  PubMed  Google Scholar 

  46. Okuda T., Zahn H., Chem. Ber., 1965, 98, 1164

    Article  CAS  Google Scholar 

  47. Aimoto S., Teruya K., Hasegawa K., Sato T., Akaji K., Kawakami T., Chem. Res. Chinese Universities, 2006, 22(2), 253

    Article  CAS  Google Scholar 

  48. Gutiérrez-Jiménez M. I., Aydillo C., Navo C. D., Avenoza A., Corzana F., Jiménez-Osés G., Zurbano M. M., Busto J. H., Peregrina J. M., Org. Lett., 2016, 18, 2796

    Article  PubMed  CAS  Google Scholar 

  49. Petracca R., Bowen K. A., McSweeney L., O’Flaherty S., Genna V., Twamley B., Devocelle M., Scanlan E. M., Org. Lett., 2019, 21, 3281

    Article  CAS  PubMed  Google Scholar 

  50. Meledin R., Mali S. M., Singh S. K., Brik A., Org. Biomol. Chem., 2016, 14, 4817

    Article  CAS  PubMed  Google Scholar 

  51. Jiang H. K., Kurkute P., Li C. L., Wang Y. H., Chen P. J., Lin S. Y., Wang Y. S., Biochemistry, 2020, 59, 3796

    Article  CAS  PubMed  Google Scholar 

  52. Galan S. R. G., Wickens J. R., Dadova J., Ng W. L., Zhang X., Simion R. A., Quinlan R., Pires E., Paton R. S., Caddick S., Chudasama V., Davis B. G., Nat. Chem. Biol., 2018, 14, 955

    Article  CAS  PubMed  Google Scholar 

  53. Chen H., Zhang Y., Li Q. Q., Zhao Y. F., Chen Y. X., Li Y. M., J. Org. Chem., 2018, 83, 7528

    Article  CAS  PubMed  Google Scholar 

  54. Dadová J., Wu K. J., Isenegger P. G., Errey J. C., Bernardes G. J. L., Chalker J. M., Raich L., Rovira C., Davis B. G., ACS Cent. Sci., 2017, 3, 1168

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Freedy A. M., Matos M. J., Boutureira O., Corzana F., Guerreiro A., Akkapeddi P., Somovilla V. J., Rodrigues T., Nicholls K., Xie B., Jimenez-Oses G., Brindle K. M., Neves A. A., Bernardes G. J. L., J. Am. Chem. Soc., 2017, 139, 18365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scamp R. J., DeRamon E., Paulson E. K., Miller S. J., Ellman J. A., Angew. Chem. Int. Ed., 2020, 59, 890

    Article  CAS  Google Scholar 

  57. Lin Y. A., Boutureira O., Lercher L., Bhushan B., Paton R. S., Davis B. G., J. Am. Chem. Soc., 2013, 135, 12156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Reddy K. M., Mugesh G., RSC Adv., 2019, 9, 34

    Article  CAS  Google Scholar 

  59. Oroz P., Navo C. D., Avenoza A., Busto J. H., Corzana F., Jiménez-Osés G., Peregrina J. M., Org. Lett., 2021, 23, 1955

    Article  CAS  PubMed  Google Scholar 

  60. Mortensen M., Husmann R., Veri E., Bolm C., Chem. Soc. Rev., 2009, 38, 1002

    Article  CAS  PubMed  Google Scholar 

  61. Pan J. L., Li Q. Z., Zhang T. Y., Hou S. H., Kang J. C., Zhang S. Y., Chem. Commun., 2016, 52, 13151

    Article  CAS  Google Scholar 

  62. Bartoccini F., Bartolucci S., Lucarini S., Piersanti G., Eur. J. Org. Chem., 2015, 2015, 3352

    Article  CAS  Google Scholar 

  63. Chung J. Y. L., Shevlin M., Klapars A., Journet M., Org. Lett., 2016, 18, 1812

    Article  CAS  PubMed  Google Scholar 

  64. Wan Y., Zhu J., Yuan Q., Wang W., Zhang Y., Org. Lett., 2021, 23, 1406

    Article  CAS  PubMed  Google Scholar 

  65. de Vries R. H., Roelfes G., Chem. Commun., 2020, 56, 11058

    Article  CAS  Google Scholar 

  66. He P. Y., Chen H., Hu H. G., Hu J. J., Lim Y. J., Li Y. M., Chem. Commun., 2020, 56, 12632

    Article  CAS  Google Scholar 

  67. Gillaizeau I., Tokairin Y., Konno H., Noireau A., West C., Moriwaki H., Soloshonok V., Nicolas C., Org. Chem. Front., 2021, 8, 2190

    Article  Google Scholar 

  68. de Vries R. H., Viel J. H., Kuipers O. P., Roelfes G., Angew. Chem. Int. Ed., 2021, 60, 3946

    Article  CAS  Google Scholar 

  69. Ballio A., Bossa F., Camoni L., DiGiorgio D., Flamand M. C., Maraite H., Nitti G., Pucci P., Scaloni A., FEBS Lett., 1996, 381, 213

    Article  CAS  PubMed  Google Scholar 

  70. Ballio A., Barra D., Bossa F., Collina A., Grgurina I., Marino G., Moneti G., Paci M., Pucci P., Segre A., Simmaco M., FEBS Lett., 1991, 291, 109

    Article  CAS  PubMed  Google Scholar 

  71. Chambers K. A., Abularrage N. S., Hill C. J., Khan I. H., Scheck R. A., Angew. Chem. Int. Ed., 2020, 59, 7350

    Article  CAS  Google Scholar 

  72. Cao H. Q., Liu H. N., Liu Z. Y., Qiao B. K., Zhang F. G., Ma J. A., Org. Lett., 2020, 22, 6414

    Article  CAS  PubMed  Google Scholar 

  73. de Bruijn A. D., Roelfes G., Chem. Eur. J., 2018, 24, 11314

    Article  CAS  PubMed  Google Scholar 

  74. Brandhofer T., Mancheño O. G., Chemcatchem, 2019, 11, 3797

    Article  CAS  Google Scholar 

  75. Lai K. Y., Galan S. R. G., Zeng Y., Zhou T. H., He C., Raj R., Riedl J., Liu S., Chooi K. P., Garg N., Zeng M., Jones L. H., Hutchings G. J., Mohammed S., Nair S. K., Chen J., Davis B. G., van der Donk W. A., Cell, 2021, 184, 2680

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (Nos.2018YFA0507600, 2019YFA0904200) and the National Natural Science Foundation of China(No.92053108).

Author information

Authors and Affiliations

  1. Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China

    Mengqian Zhang, Peiyang He & Yanmei Li

  2. Beijing Institute for Brain Disorders, Beijing, 100069, P. R. China

    Yanmei Li

  3. Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, P. R. China

    Yanmei Li

Authors
  1. Mengqian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peiyang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanmei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanmei Li.

Ethics declarations

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, M., He, P. & Li, Y. Contemporary Approaches to α,β-Dehydroamino Acid Chemical Modifications. Chem. Res. Chin. Univ. 37, 1044–1054 (2021). https://doi.org/10.1007/s40242-021-1307-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40242-021-1307-z

Keywords

Search

Navigation