期刊
COMMUNICATIONS CHEMISTRY
卷 1, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42004-018-0024-0
关键词
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资金
- Japan Society for the Promotion of Science (JSPS)
- KAKENHI [26888016]
- Research and Study Project of Tokai University, Educational System General Research Organization
- Collaborative Research Program of Institute for Protein Research, Osaka University [CR-15-01]
- Cooperative Research Program of Network Joint Research Center for Material and Devices
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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