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

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.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.

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Arai, Kenta1, Author
Takei, Toshiki1, Author
Shinozaki, Reina1, Author
Noguchi, Masato1, Author
Fujisawa, Shouta1, Author
Katayama, Hidekazu1, Author
Moroder, Luis2, Author           
Ando, Setsuko1, Author
Okumura, Masaki1, Author
Inaba, Kenji1, Author
Hojo, Hironobu1, Author
Iwaoka, Michio1, Author
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1external, ou_persistent22              
2Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565160              

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Free keywords: PROTEIN-DISULFIDE-ISOMERASE; CYSTINE-RICH PEPTIDES; ACYL ISOPEPTIDE METHOD; IN-VITRO; CHEMICAL-SYNTHESIS; A-CHAIN; SELENOXIDE REAGENT; ESTER INSULIN; KINETIC TRAP; B-CHAINChemistry;
 Abstract: 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.

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Language(s): eng - English
 Dates: 2018-05
 Publication Status: Published online
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000433895200003
DOI: 10.1038/s42004-018-0024-0
 Degree: -

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Title: Communications Chemistry
Source Genre: Journal
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Publ. Info: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 1 Sequence Number: UNSP 26 Start / End Page: - Identifier: ISSN: 2399-3669