Ultrafast Biomimetic Oxidative Folding of Cysteine-rich Peptides and Microproteins in Organic Solvents
Dr. Antony Kam
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Wuzhong No.111, Renai Road, Suzhou, Jiangsu, 215123 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorDr. Shining Loo
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Wisedom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Wuzhong No. 111, Renai Road, Suzhou, Jiangsu, 215123 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorDr. Yibo Qiu
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorProf. Chuan-Fa Liu
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorCorresponding Author
Prof. James P. Tam
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorDr. Antony Kam
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Wuzhong No.111, Renai Road, Suzhou, Jiangsu, 215123 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorDr. Shining Loo
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Wisedom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Wuzhong No. 111, Renai Road, Suzhou, Jiangsu, 215123 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorDr. Yibo Qiu
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorProf. Chuan-Fa Liu
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorCorresponding Author
Prof. James P. Tam
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551 Singapore
Search for more papers by this authorAbstract
Disulfides in peptides and proteins are essential for maintaining a properly folded structure. Their oxidative folding is invariably performed in an aqueous-buffered solution. However, this process is often slow and can lead to misfolded products. Here, we report a novel concept and strategy that is bio-inspired to mimic protein disulfide isomerase (PDI) by accelerating disulfide exchange rates many thousand-fold. The proposed strategy termed organic oxidative folding is performed under organic solvents to yield correctly folded cysteine-rich microproteins instantaneously without observable misfolded or dead-end products. Compared to conventional aqueous oxidative folding strategies, enormously large rate accelerations up to 113,200-fold were observed. The feasibility and generality of the organic oxidative folding strategy was successfully demonstrated on 15 cysteine-rich microproteins of different hydrophobicity, lengths (14 to 58 residues), and numbers of disulfides (2 to 5 disulfides), producing the native products in a second and in high yield.
Conflict of interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
| Filename | Description |
|---|---|
| ange202317789-sup-0001-misc_information.pdf4.8 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1M. Gongora-Benitez, J. Tulla-Puche, F. Albericio, Chem. Rev. 2014, 114, 901–926.
- 2
- 2aA.-H. Jin, M. Muttenthaler, S. Dutertre, S. Himaya, Q. Kaas, D. J. Craik, R. J. Lewis, P. F. Alewood, Chem. Rev. 2019, 119, 11510–11549;
- 2bS. J. de Veer, M.-W. Kan, D. J. Craik, Chem. Rev. 2019, 119, 12375–12421;
- 2cJ. P. Tam, S. Wang, K. H. Wong, W. L. Tan, Pharmaceuticals 2015, 8, 711–757.
- 3R. P. Hellens, C. M. Brown, M. A. Chisnall, P. M. Waterhouse, R. C. Macknight, Trends Plant Sci. 2016, 21, 317–328.
- 4
- 4aA. Kam, S. Loo, B. Dutta, S. K. Sze, J. P. Tam, J. Biol. Chem. 2019, 294, 4000–4011;
- 4bA. Kam, S. Loo, J.-S. Fan, S. K. Sze, D. Yang, J. P. Tam, J. Biol. Chem. 2019, 294, 19604–19615;
- 4cS. Loo, A. Kam, T. Xiao, G. K. Nguyen, C. F. Liu, J. P. Tam, Sci. Rep. 2016, 6, 39401;
- 4dS. Loo, A. Kam, T. Xiao, J. P. Tam, Front. Plant Sci. 2017, 8, 2162;
- 4eJ. P. Tam, G. K. Nguyen, S. Loo, S. Wang, D. Yang, A. Kam, Sci. Rep. 2018, 8, 16201;
- 4fS. Loo, S. V. Tay, A. Kam, F. Tang, J.-S. Fan, D. Yang, J. P. Tam, Molecules 2021, 26, 5909;
- 4gS. Loo, S. V. Tay, A. Kam, W. Lee, J. P. Tam, Front. Plant Sci. 2022, 13, 899740.
- 5
- 5aX. Hemu, J. P. Tam, Curr. Pharm. Des. 2017, 23, 2131–2138;
- 5bC. T. Wong, D. K. Rowlands, C. H. Wong, T. W. Lo, G. K. Nguyen, H. Y. Li, J. P. Tam, Angew. Chem. Int. Ed. 2012, 51, 5620–5624;
- 5cS. Loo, A. Kam, B. B. Li, N. Feng, X. Wang, J. P. Tam, J. Med. Chem. 2021, 64, 7746–7759;
- 5dC. T. Wong, M. Taichi, H. Nishio, Y. Nishiuchi, J. P. Tam, Biochemistry 2011, 50, 7275–7283;
- 5eJ. P. Tam, C. T. Wong, J. Biol. Chem. 2012, 287, 27020–27025.
- 6
- 6aC. B. Anfinsen, E. Haber, M. Sela, F. White Jr, Proc. Natl. Acad. Sci. USA 1961, 47, 1309;
- 6bC. B. Anfinsen, Biochem. J. 1972, 128, 737;
- 6cC. B. Anfinsen, Science 1973, 181, 223–230;
- 6dJ. P. Tam, C. R. Wu, W. Liu, J. W. Zhang, J. Am. Chem. Soc. 1991, 113, 6657–6662;
- 6eK. Arai, M. Iwaoka, Molecules 2021, 26, 195;
- 6fD. A. Hudson, S. A. Gannon, C. Thorpe, Free Radical Biol. Med. 2015, 80, 171–182.
- 7
- 7aP. A. Fernandes, M. J. Ramos, Chem. Eur. J. 2004, 10, 257–266;
- 7bG. Bulaj, T. Kortemme, D. P. Goldenberg, Biochemistry 1998, 37, 8965–8972;
- 7cM. Narayan, E. Welker, W. J. Wedemeyer, H. A. Scheraga, Acc. Chem. Res. 2000, 33, 805–812.
- 8
- 8aM. Reinwarth, B. Glotzbach, M. Tomaszowski, S. Fabritz, O. Avrutina, H. Kolmar, ChemBioChem 2013, 14, 137–146;
- 8bJ.-Y. Chang, Biochemistry 2011, 50, 3414–3431;
- 8cT. R. Jahn, S. E. Radford, Arch. Biochem. Biophys. 2008, 469, 100–117.
- 9
- 9aJ. P. Tam, Y.-A. Lu, J.-L. Yang, K.-W. Chiu, Proc. Natl. Acad. Sci. USA 1999, 96, 8913–8918;
- 9bL. Moroder, D. Besse, H. J. Musiol, S. Rudolph-Böhner, F. Siedler, Pept. Sci. 1996, 40, 207–234.
10.1002/(SICI)1097-0282(1996)40:2<207::AID-BIP2>3.0.CO;2-# CAS PubMed Web of Science® Google Scholar
- 10S. Laps, F. Atamleh, G. Kamnesky, H. Sun, A. Brik, Nat. Commun. 2021, 12, 870.
- 11
- 11aN. Metanis, D. Hilvert, Chem. Sci. 2015, 6, 322–325;
- 11bR. Mousa, T. Hidmi, S. Pomyalov, S. Lansky, L. Khouri, D. E. Shalev, G. Shoham, N. Metanis, Commun. Chem. 2021, 4, 30;
- 11cN. Metanis, D. Hilvert, Angew. Chem. Int. Ed. 2012, 51, 5585–5588;
- 11dA. D. de Araujo, B. Callaghan, S. T. Nevin, N. L. Daly, D. J. Craik, M. Moretta, G. Hopping, M. J. Christie, D. J. Adams, P. F. Alewood, Angew. Chem. Int. Ed. 2011, 123, 6657–6659;
10.1002/ange.201101642 Google Scholar
- 11eW.-W. Shi, C. Shi, T.-Y. Wang, Y.-L. Li, Y.-K. Zhou, X.-H. Zhang, D. Bierer, J.-S. Zheng, L. Liu, J. Am. Chem. Soc. 2022, 144, 349–357.
- 12
- 12aL. Ellgaard, A. Helenius, Nat. Rev. Mol. Cell Biol. 2003, 4, 181–191;
- 12bI. Braakman, D. N. Hebert, Cold Spring Harbor Perspect. Biol. 2013, 5, a013201.
- 13A. Zapun, T. E. Creighton, P. J. Rowling, R. B. Freedman, Proteins Struct. Funct. Genet. 1992, 14, 10–15.
- 14
- 14aZ. e Shaked, R. P. Szajewski, G. M. Whitesides, Biochemistry 1980, 19, 4156–4166;
- 14bR. Singh, G. M. Whitesides, J. Am. Chem. Soc. 1990, 112, 1190–1197;
- 14cR. P. Szajewski, G. M. Whitesides, J. Am. Chem. Soc. 1980, 102, 2011–2026.
- 15O. Saether, D. J. Craik, I. D. Campbell, K. Sletten, J. Juul, D. G. Norman, Biochemistry 1995, 34, 4147–4158.
- 16S. Loo, A. Kam, J. P. Tam, Front. Pharmacol. 2022, 13, 942168.
- 17P. Q. T. Nguyen, J. S. G. Ooi, N. T. K. Nguyen, S. Wang, M. Huang, D. X. Liu, J. P. Tam, J. Biol. Chem. 2015, 290, 31138–31150.
- 18A. P. Bryant, R. W. Busby, W. P. Bartolini, E. A. Cordero, G. Hannig, M. M. Kessler, C. M. Pierce, R. M. Solinga, J. V. Tobin, S. Mahajan-Miklos, Life Sci. 2010, 86, 760–765.
- 19
- 19aL. J. Cruz, W. R. Gray, D. Yoshikami, B. M. Olivera, J. Toxicol. Toxin Rev. 1985, 4, 107–132;
- 19bB. M. Olivera, L. J. Cruz, Toxicon 2001, 39, 7–14.
- 20B. Kassell, M. Radicevic, M. J. Ansfield, M. Laskowski Sr, Biochem. Biophys. Res. Commun. 1965, 18, 255–258.
- 21C. V. Jennings, K. J. Rosengren, N. L. Daly, M. Plan, J. Stevens, M. J. Scanlon, C. Waine, D. G. Norman, M. A. Anderson, D. J. Craik, Biochemistry 2005, 44, 851–860.
- 22W. L. Tan, K. H. Wong, J. Lei, N. Sakai, H. W. Tan, R. Hilgenfeld, J. P. Tam, Sci. Rep. 2017, 7, 5194.
- 23R.-H. Huang, Y. Xiang, X.-Z. Liu, Y. Zhang, Z. Hu, D.-C. Wang, FEBS Lett. 2002, 521, 87–90.
- 24
- 24aN. L. Daly, S. Love, P. F. Alewood, D. J. Craik, Biochemistry 1999, 38, 10606–10614;
- 24bT. L. Aboye, R. J. Clark, R. Burman, M. B. Roig, D. J. Craik, U. Göransson, Antioxid. Redox Signaling 2011, 14, 77–86.
- 25M. Góngora-Benítez, J. Tulla-Puche, M. Paradís-Bas, O. Werbitzky, M. Giraud, F. Albericio, Pept. Sci. 2011, 96, 69–80.
- 26M. Price-Carter, W. R. Gray, D. P. Goldenberg, Biochemistry 1996, 35, 15537–15546.
- 27
- 27aS. Luckett, R. S. Garcia, J. Barker, A. V. Konarev, P. Shewry, A. Clarke, R. Brady, J. Mol. Biol. 1999, 290, 525–533;
- 27bY. Qiu, M. Taichi, N. Wei, H. Yang, K. Q. Luo, J. P. Tam, J. Med. Chem. 2017, 60, 504–510.
- 28T. Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M. Niwa, T. Takao, Y. Shimonishi, J. Biol. Chem. 1988, 263, 16709–16713.
- 29M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Goto, T. Masaki, Nature 1988, 332, 411–415.
- 30V. N. Kokryakov, S. S. Harwig, E. A. Panyutich, A. A. Shevchenko, G. M. Aleshina, O. V. Shamova, H. A. Korneva, R. I. Lehrer, FEBS Lett. 1993, 327, 231–236.
- 31
- 31aA. Puig, H. F. Gilbert, J. Biol. Chem. 1994, 269, 7764–7771;
- 31bA. Puig, H. F. Gilbert, J. Biol. Chem. 1994, 269, 25889–25896.
- 32J. S. Weissman, P. S. Kimt, Nature 1993, 365, 185–188.
- 33K. W. Walker, H. F. Gilbert, Biochemistry 1995, 34, 13642–13650.
- 34B. van den Berg, R. J. Ellis, C. M. Dobson, The EMBO J. 1999, 18, 6927–6933.
- 35
- 35aP. Nagy, Antioxid. Redox Signaling 2013, 18, 1623–1641;
- 35bD. A. Keire, E. Strauss, W. Guo, B. Noszal, D. L. Rabenstein, J. Org. Chem. 1992, 57, 123–127.
- 36
- 36aA. Rozhkova, C. U. Stirnimann, P. Frei, U. Grauschopf, R. Brunisholz, M. G. Grütter, G. Capitani, R. Glockshuber, The EMBO J. 2004, 23, 1709–1719;
- 36bU. Grauschopf, A. Fritz, R. Glockshuber, The EMBO J. 2003, 22, 3503–3513;
- 36cD. L. Rabenstein, K. K. Millis, Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1995, 1249, 29–36;
- 36dU. Srinivasan, P. A. Mieyal, J. J. Mieyal, Biochemistry 1997, 36, 3199–3206;
- 36eA. P. Wiita, R. Perez-Jimenez, K. A. Walther, F. Gräter, B. Berne, A. Holmgren, J. M. Sanchez-Ruiz, J. M. Fernandez, Nature 2007, 450, 124–127.
- 37A. Serra, X. Hemu, G. K. Nguyen, N. T. Nguyen, S. K. Sze, J. P. Tam, Sci. Rep. 2016, 6, 23005.
- 38B. Dutta, S. Loo, A. Kam, J. P. Tam, Cell. Mol. Life Sci. 2023, 80, 293.
- 39R. C. Stephenson, S. Clarke, J. Biol. Chem. 1989, 264, 6164–6170.
- 40K. Neumann, J. Farnung, S. Baldauf, J. W. Bode, Nat. Commun. 2020, 11, 982.
- 41
- 41aS. N. Mthembu, A. Chakraborty, R. Schönleber, F. Albericio, B. G. de la Torre, J. Pept. Sci. 2023, e3538;
- 41bM. Taichi, T. Yamazaki, T. Kimura, Y. Nishiuchi, Tetrahedron Lett. 2009, 50, 2377–2380.
- 42B. P. Tu, J. S. Weissman, J. Cell Biol. 2004, 164, 341–346.
This is the
German version
of Angewandte Chemie.
Note for articles published since 1962:
Do not cite this version alone.
Take me to the International Edition version with citable page numbers, DOI, and citation export.
We apologize for the inconvenience.
