Amide-forming chemical ligation via O -acyl hydroxamic acids
| Autor: | Kyle A. Totaro, Daniel T. Cohen, Yuki Hirata, Zachary P. Gates, Bradley L. Pentelute, Daniel L. Dunkelmann, Chi Zhang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
chemistry.chemical_classification
Multidisciplinary Aqueous solution Hydroxamic acid 010405 organic chemistry Stereochemistry Peptide 010402 general chemistry Thioester Native chemical ligation 01 natural sciences 0104 chemical sciences chemistry.chemical_compound chemistry Amide Physical Sciences Peptide bond lipids (amino acids peptides and proteins) Chemical ligation |
| Zdroj: | Proceedings of the National Academy of Sciences. 115:3752-3757 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The facile rearrangement of “ S -acyl isopeptides” to native peptide bonds via S , N -acyl shift is central to the success of native chemical ligation, the widely used approach for protein total synthesis. Proximity-driven amide bond formation via acyl transfer reactions in other contexts has proven generally less effective. Here, we show that under neutral aqueous conditions, “ O -acyl isopeptides” derived from hydroxy-asparagine [aspartic acid-β-hydroxamic acid; Asp(β-HA)] rearrange to form native peptide bonds via an O , N -acyl shift. This process constitutes a rare example of an O , N -acyl shift that proceeds rapidly across a medium-size ring (t 1/2 ∼ 15 min), and takes place in water with minimal interference from hydrolysis. In contrast to serine/threonine or tyrosine, which form O -acyl isopeptides only by the use of highly activated acyl donors and appropriate protecting groups in organic solvent, Asp(β-HA) is sufficiently reactive to form O -acyl isopeptides by treatment with an unprotected peptide- α thioester, at low mM concentration, in water. These findings were applied to an acyl transfer-based chemical ligation strategy, in which an unprotected N -terminal Asp(β-HA)-peptide and peptide- α thioester react under aqueous conditions to give a ligation product ultimately linked by a native peptide bond. |
| Databáze: | OpenAIRE |
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