Help Privacy Policy Disclaimer
  Advanced SearchBrowse




Journal Article

Characterization and optimization of two-chain folding pathways of insulin via native chain assembly


Moroder,  Luis
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

External Resource
No external resources are shared
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
Fulltext (public)

(Publisher version), 2MB

Supplementary Material (public)
There is no public supplementary material available

Arai, K., Takei, T., Shinozaki, R., Noguchi, M., Fujisawa, S., Katayama, H., et al. (2018). Characterization and optimization of two-chain folding pathways of insulin via native chain assembly. Communications Chemistry, 1: UNSP 26. doi:10.1038/s42004-018-0024-0.

Cite as: https://hdl.handle.net/21.11116/0000-0002-A4BB-2
Until recently the total synthesis of insulin, with its characteristic heterodimeric structure crosslinked by two interchain and one intrachain disulfide (SS) bridge, remained largely an unsolved challenge. By optimizing the synthesis and directed disulfide crosslinking of the two chains, and by applying biomimetic monocomponent proinsulin approaches, efficient insulin syntheses have been realized. Here we report the optimization and characterisation of an alternative strategy, oxidative native chain assembly. In this method unprotected A- and B-chains assemble oxidatively under thermodynamic control to afford bovine pancreatic insulin in 39% yield. Folding is found to proceed predominantly via structured 1SS(star) and 2SS(star) intermediates with a common interchain Cys(A20)-Cys(B19) disulfide. These results suggest that native chain assembly, long considered inefficient, may represent a reasonable strategy to access insulin variants. This is supported by the synthesis of human insulin and human type-II relaxin in yields of up to 49 and 47%, respectively, although the application to human insulin Val(A16) variant is unsuccessful.