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Peptide asparaginyl ligases—renegade peptide bond makers

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Abstract

Making peptide bonds is tightly controlled by genetic code and machinery which includes cofactors, ATP, and RNAs. In this regard, the stand-alone and genetic-code-independent peptide ligases constitute a new family of renegade peptide-bond makers. A prime example is butelase-1, an Asn/Asp(Asx)-specific ligase that structurally belongs to the asparaginyl endopeptidase family. Butelase-1 specifically recognizes a C-terminal Asx-containing tripeptide motif, Asn/Asp-Xaa-Yaa (Xaa and Yaa are any amino acids), to form a site-specific Asn-Xaa peptide bond either intramolecularly as cyclic proteins or intermolecularly as modified proteins. Our work in the past five years has validated that butelase-1 is a potent and versatile ligase. Here we review the advances in ligases, with a focus on butelase-1, and their applications in engineering bioactive peptides and precision protein modifications, antibody-drug conjugates, and live-cell labeling.

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References

  1. Smith GP. Science, 1985, 228: 13154–1317

    Google Scholar 

  2. Verhoeyen M, Milstein C, Winter G. Science, 1988, 239: 15344–1536

    Google Scholar 

  3. Zhao H, Giver L, Shao Z, Affholter JA, Arnold FH. Nat Biotechnol, 1998, 16: 2584–261

    Google Scholar 

  4. Anderson JC, Wu N, Santoro SW, Lakshman V, King DS, Schultz PG. Proc Natl Acad Sci USA, 2004, 101: 7566–7571

    CAS  PubMed  Google Scholar 

  5. Kent SBH. Annu Rev Biochem, 1988, 57: 9574–989

    Google Scholar 

  6. Liu CF, Tam JP. Proc Natl Acad Sci USA, 1994, 91: 65844–6588

    Google Scholar 

  7. Liu CF, Tam JP. J Am Chem Soc, 1994, 116: 41494–4153

    Google Scholar 

  8. Muir TW. Annu Rev Biochem, 2003, 72: 2494–289

    Google Scholar 

  9. Tam JP, Lu YA, Liu CF, Shao J. Proc Natl Acad Sci USA, 1995, 92: 124854–12489

    Google Scholar 

  10. Pan M, Zheng Q, Ding S, Zhang L, Qu Q, Wang T, Hong D, Ren Y, Liang L, Chen C, Mei Z, Liu L. Angew Chem, 2019, 131: 26534–2657

    Google Scholar 

  11. Scott JK, Smith GP. Science, 1990, 249: 3864–390

    Google Scholar 

  12. Moolten FL, Cooperband SR. Science, 1970: 68–70

    Google Scholar 

  13. McCafferty J, Griffiths AD, Winter G, Chiswell DJ. Nature, 1990, 348: 5524–554

    Google Scholar 

  14. Beck A, Goetsch L, Dumontet C, Corvaïa N. Nat Rev Drug Discov, 2017, 16: 3154–337

    Google Scholar 

  15. Tam JP, Lu YA. Tetrahedron Lett, 1997, 38: 55994–5602

    Google Scholar 

  16. Tam JP, Lu YA, Yu Q. J Am Chem Soc, 1999, 121: 43164–4324

    Google Scholar 

  17. White CJ, Yudin AK. Nat Chem, 2011, 3: 5094–524

    Google Scholar 

  18. Tam JP, Wong CTT. J Biol Chem, 2012, 287: 270204–27025

    Google Scholar 

  19. Yoshihara HAI, Mahrus S, Wells JA. Bioorg Med Chem Lett, 2008, 18: 60004–6003

    Google Scholar 

  20. Rosen CB, Francis MB. Nat Chem Biol, 2017, 13: 6974–705

    Google Scholar 

  21. Mahal LK, Yarema KJ, Bertozzi CR. Science, 1997, 276: 11254–1128

    Google Scholar 

  22. Chen I, Howarth M, Lin W, Ting AY. Nat Methods, 2005, 2: 994–104

    Google Scholar 

  23. Popp MWL, Karssemeijer RA, Ploegh HL, Kawaoka Y. PLoS Pathog, 2012, 8: e1002604

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bi X, Yin J, Nguyen GKT, Rao C, Halim NBA, Hemu X, Tam JP, Liu CF. Angew Chem, 2017, 129: 79304–7933

    Google Scholar 

  25. Frank J. Nat Protoc, 2017, 12: 2094–212

    Google Scholar 

  26. Lipmann F. Adv Microb Physiol, 1981, 21: 2274–266

    Google Scholar 

  27. Kopp F, Marahiel MA. Nat Prod Rep, 2007, 24: 7354–749

    Google Scholar 

  28. Schmidt M, Toplak A, Quaedflieg PJ, Nuijens T. Curr Opin Chem Biol, 2017, 38: 14–7

    Google Scholar 

  29. Xu S, Zhao Z, Zhao J. Chin Chem Lett, 2018, 29: 10094–1016

    Google Scholar 

  30. Arnison PG, Bibb MJ, Bierbaum G, Bowers AA, Bugni TS, Bulaj G, Camarero JA, Campopiano DJ, Challis GL, Clardy J, Cotter PD, Craik DJ, Dawson M, Dittmann E, Donadio S, Dorrestein PC, Entian KD, Fischbach MA, Garavelli JS, Göransson U, Gruber CW, Haft DH, Hemscheidt TK, Hertweck C, Hill C, Horswill AR, Jaspars M, Kelly WL, Klinman JP, Kuipers OP, Link AJ, Liu W, Marahiel MA, Mitchell DA, Moll GN, Moore BS, Müller R, Nair SK, Nes IF, Norris GE, Olivera BM, Onaka H, Patchett ML, Piel J, Reaney MJT, Rebuffat S, Ross RP, Sahl HG, Schmidt EW, Selsted ME, Severinov K, Shen B, Sivonen K, Smith L, Stein T, Süssmuth RD, Tagg JR, Tang GL, Truman AW, Vederas JC, Walsh CT, Walton JD, Wenzel SC, Willey JM, van der Donk WA. Nat Prod Rep, 2013, 30: 1084–160

    Google Scholar 

  31. Schmidt EW, Sudek S, Haygood MG. J Nat Prod, 2004, 67: 13414–1345

    Google Scholar 

  32. Schmidt EW, Nelson JT, Rasko DA, Sudek S, Eisen JA, Haygood MG, Ravel J. Proc Natl Acad Sci USA, 2005, 102: 73154–7320

    Google Scholar 

  33. Abe Y, Shirane K, Yokosawa H, Matsushita H, Mitta M, Kato I, Ishii S. J Biol Chem, 1993, 268: 35254–3529

    Google Scholar 

  34. Barber CJS, Pujara PT, Reed DW, Chiwocha S, Zhang H, Covello PS. J Biol Chem, 2013, 288: 125004–12510

    Google Scholar 

  35. Nguyen GKT, Wang S, Qiu Y, Hemu X, Lian Y, Tam JP. Nat Chem Biol, 2014, 10: 7324–738

    Google Scholar 

  36. Harris KS, Durek T, Kaas Q, Poth AG, Gilding EK, Conlan BF, Saska I, Daly NL, van der Weerden NL, Craik DJ, Anderson MA. Nat Commun, 2015, 6: 101994–10208

    Google Scholar 

  37. Haywood J, Schmidberger JW, James AM, Nonis SG, Sukhoverkov KV, Elias M, Bond CS, Mylne JS. eLife, 2018, 7: e32955

    PubMed  PubMed Central  Google Scholar 

  38. Jackson MA, Gilding EK, Shafee T, Harris KS, Kaas Q, Poon S, Yap K, Jia H, Guarino R, Chan LY, Durek T, Anderson MA, Craik DJ. Nat Commun, 2018, 9: 24114–2422

    Google Scholar 

  39. Hemu X, El Sahili A, Hu S, Wong K, Chen Y, Wong YH, Zhang X, Serra A, Goh BC, Darwis DA, Chen MW, Sze SK, Liu CF, Lescar J, Tam JP. Proc Natl Acad Sci USA, 2019, 358: 201818568

    Google Scholar 

  40. Harris KS, Guarino RF, Dissanayake RS, Quimbar P, McCorkelle OC, Poon S, Kaas Q, Durek T, Gilding EK, Jackson MA, Craik DJ, van der Weerden NL, Anders RF, Anderson MA. Sci Rep, 2019, 9: 10820

    PubMed  PubMed Central  Google Scholar 

  41. Mazmanian SK, Liu G, Ton-That H, Schneewind O. Science, 1999, 285: 7604–763

    Google Scholar 

  42. Lee J, McIntosh J, Hathaway BJ, Schmidt EW. J Am Chem Soc, 2009, 131: 21224–2124

    Google Scholar 

  43. Luo H, Hong SY, Sgambelluri RM, Angelos E, Li X, Walton JD. Chem Biol, 2014, 21: 16104–1617

    Google Scholar 

  44. Craik DJ. Toxins, 2012, 4: 1394–156

    Google Scholar 

  45. Hatsugai N, Yamada K, Goto-Yamada S, Hara-Nishimura I. Front Plant Sci, 2015, 6: 2344–244

    Google Scholar 

  46. Dall E, Brandstetter H. Biochimie, 2016, 122: 1264–150

    Google Scholar 

  47. Harley SM, Michael Lord J. Plant Sci, 1985, 41: 1114–116

    Google Scholar 

  48. Hara-Nishimura I, Nishimura M. Plant Physiol, 1987, 85: 4404–445

    Google Scholar 

  49. Bowles DJ, Marcus SE, Pappin DJ, Findlay JB, Eliopoulos E, Maycox PR, Burgess J. J Cell Biol, 1986, 102: 12844–1297

    Google Scholar 

  50. Min W, Jones DH. Nat Struct Mol Biol, 1994, 1: 5024–504

    Google Scholar 

  51. James AM, Haywood J, Leroux J, Ignasiak K, Elliott AG, Schmidberger JW, Fisher MF, Nonis SG, Fenske R, Bond CS, Mylne JS. Plant J, 2019, 316: tpj.14293

    Google Scholar 

  52. Pi N, Gao M, Cheng X, Liu H, Kuang Z, Yang Z, Yang J, Zhang B, Chen Y, Liu S, Huang Y, Su Z. Biochemistry, 2019, 58: 30054–3015

    Google Scholar 

  53. Nguyen GKT, Kam A, Loo S, Jansson AE, Pan LX, Tam JP. J Am Chem Soc, 2015, 137: 153984–15401

    Google Scholar 

  54. Schechter I, Berger A. Biochem Biophys Res Commun, 1967, 27: 1574–162

    Google Scholar 

  55. Nguyen GKT, Qiu Y, Cao Y, Hemu X, Liu CF, Tam JP. Nat Protoc, 2016, 11: 19774–1988

    Google Scholar 

  56. Zauner FB, Dall E, Regl C, Grassi L, Huber CG, Cabrele C, Brandstetter H. Plant Cell, 2018, 30: 6864–699

    Google Scholar 

  57. Zhao L, Hua T, Crowley C, Ru H, Ni X, Shaw N, Jiao L, Ding W, Qu L, Hung LW, Huang W, Liu L, Ye K, Ouyang S, Cheng G, Liu ZJ. Cell Res, 2014, 24: 3444–358

    Google Scholar 

  58. Ludewig H, Czekster CM, Oueis E, Munday ES, Arshad M, Synowsky SA, Bent AF, Naismith JH. ACS Chem Biol, 2018, 13: 8014–811

    Google Scholar 

  59. Popp MWL, Ploegh HL. Angew Chem Int Ed, 2011, 50: 50244–5032

    Google Scholar 

  60. Dorr BM, Ham HO, An C, Chaikof EL, Liu DR. Proc Natl Acad Sci USA, 2014, 111: 133434–13348

    Google Scholar 

  61. Pishesha N, Ingram JR, Ploegh HL. Annu Rev Cell Dev Biol, 2018, 34: 1634–188

    Google Scholar 

  62. Zakeri B, Howarth M. J Am Chem Soc, 2010, 132: 45264–4527

    Google Scholar 

  63. Fierer JO, Veggiani G, Howarth M. Proc Natl Acad Sci USA, 2014, 111: E1176–E1181

    CAS  PubMed  Google Scholar 

  64. Neet KE, Koshland DE. Proc Natl Acad Sci USA, 1966, 56: 16064–1611

    Google Scholar 

  65. Polgar L, Bender ML. Biochemistry, 1967, 6: 6104–620

    Google Scholar 

  66. Nakatsuka T, Sasaki T, Kaiser ET. J Am Chem Soc, 1987, 109: 38084–3810

    Google Scholar 

  67. Wu ZP, Hilvert D. J Am Chem Soc, 1989, 111: 45134–4514

    Google Scholar 

  68. Abrahmsén L, Tom J, Burnier J, Butcher KA, Kossiakoff A, Wells JA. Biochemistry, 1991, 30: 41514–4159

    Google Scholar 

  69. Chang TK, Jackson DY, Burnier JP, Wells JA. Proc Natl Acad Sci USA, 1994, 91: 125444–12548

    Google Scholar 

  70. Liu CF, Tam JP. Org Lett, 2001, 3: 41574–4159

    Google Scholar 

  71. Tan XH, Wirjo A, Liu CF. ChemBioChem, 2007, 8: 15124–1515

    Google Scholar 

  72. Tan XH, Zhang X, Yang R, Liu CF. ChemBioChem, 2008, 9: 10524–1056

    Google Scholar 

  73. Tan X, Yang R, Liu CF. Org Lett, 2018, 20: 66914–6694

    Google Scholar 

  74. Weeks AM, Wells JA. Nat Chem Biol, 2018, 14: 504–57

    Google Scholar 

  75. Nguyen GKT, Hemu X, Quek JP, Tam JP. Angew Chem, 2016, 128: 129944–12998

    Google Scholar 

  76. Hemu X, Qiu Y, Nguyen GKT, Tam JP. J Am Chem Soc, 2016, 138: 69684–6971

    Google Scholar 

  77. Bi X, Yin J, Hemu X, Rao C, Tam JP, Liu CF. Bioconjugate Chem, 2018, 29: 21704–2175

    Google Scholar 

  78. Tam JP, Yu Q, Miao Z. Biopolymers, 1999, 51: 3114–332

    Google Scholar 

  79. Tam JP, Xu J, Eom KD. Biopolymers, 2001, 60: 1944–205

    Google Scholar 

  80. Nguyen GKT, Cao Y, Wang W, Liu CF, Tam JP. Angew Chem, 2015, 127: 159204–15924

    Google Scholar 

  81. Tam JP, Nguyen GKT, Kam A, Loo S. Advances in Site-specific and Linkage-specific Ligation–Precision ligation of DARPin-conjugates targeting the breast cancer HER2 receptor. In: Timmons PB, Hewage CM, Lebl M, eds. Proceedings of the 35th European Peptide Symposium. Chichester, 2018. 3–7

    Google Scholar 

  82. Cao Y, Nguyen GKT, Tam JP, Liu CF. Chem Commun, 2015, 51: 172894–17292

    Google Scholar 

  83. Cao Y, Nguyen GKT, Chuah S, Tam JP, Liu CF. Bioconjugate Chem, 2016, 27: 25924–2596

    Google Scholar 

  84. Aimoto S. Biopolymers, 1999, 51: 2474–265

    Google Scholar 

  85. Chin JW. Nature, 2017, 550: 534–60

    Google Scholar 

  86. Thompson RE, Stevens AJ, Muir TW. Nat Chem, 2019, 11: 7374–743

    Google Scholar 

  87. Harmand T, Bousbaine D, Chan AI, Zhang X, Liu DR, Tam JP, Ploegh HL. Bioconjug Chem, 2018 29: 32454–3249

    Google Scholar 

  88. Saxon E, Bertozzi CR. Annu Rev Cell Dev Biol, 2001, 17: 14–23

    Google Scholar 

  89. Siegrist MS, Swarts BM, Fox DM, Lim SA, Bertozzi CR. FEMS Microbiol Rev, 2015, 39: 1844–202

    Google Scholar 

  90. Knappe TA, Linne U, Robbel L, Marahiel MA. Chem Biol, 2009, 16: 12904–1298

    Google Scholar 

  91. Hegemann JD, Zimmermann M, Xie X, Marahiel MA. Acc Chem Res, 2015, 48: 19094–1919

    Google Scholar 

  92. Weber W, Fischli W, Hochuli E, Kupfer E, Weibel EK. J Antibiot, 1991, 44: 1644–171

    Google Scholar 

  93. Yang R, Wong YH, Nguyen GKT, Tam JP, Lescar J, Wu B. J Am Chem Soc, 2017, 139: 53514–5358

    Google Scholar 

  94. Posnett DN, McGrath H, Tam JP. J Biol Chem, 1988, 263: 17194–1725

    Google Scholar 

  95. Tam JP. Proc Natl Acad Sci USA, 1988, 85: 54094–5413

    Google Scholar 

  96. Sadler K, Tam JP. Rev Mol Biotech, 2002, 90: 1954–229

    Google Scholar 

  97. Tam JP, Lu YA, Yang JL. Eur J Biochem, 2002, 269: 9234–932

    Google Scholar 

  98. Hemu X, Zhang X, Tam JP. Org Lett, 2019, 21: 20294–2032

    Google Scholar 

  99. Tam JP, Lu YA, Yang JL. Biochem Biophys Res Commun, 2000, 267: 7834–790

    Google Scholar 

  100. Tam JP, Wu C, Yang JL. Eur J Biochem, 2000, 267: 32894–3300

    Google Scholar 

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Acknowledgements

This work was supported by Academic Research Grant Tier 3 (MOE2016-T3-1-003) from the Singapore Ministry of Education. We thank every member of Tam’s lab for discussions and comments.

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Authors and Affiliations

  1. School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore

    James P. Tam, Ning-Yu Chan, Heng Tai Liew, Shaun J. Tan & Yu Chen

  2. Synzymes and Natural Products Center, Nanyang Technological University, Singapore, 637551, Singapore

    James P. Tam, Ning-Yu Chan, Heng Tai Liew, Shaun J. Tan & Yu Chen

  3. NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore

    James P. Tam

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Tam, J.P., Chan, NY., Liew, H.T. et al. Peptide asparaginyl ligases—renegade peptide bond makers. Sci. China Chem. 63, 296–307 (2020). https://doi.org/10.1007/s11426-019-9648-3

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