Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
J Am Chem Soc. 2021 Mar 31;143(12):4741-4750. doi: 10.1021/jacs.1c00466. Epub 2021 Mar 18.
Here, we report a method for the one-pot ribosomal synthesis of macrocyclic depsipeptides. This method is based on a Ser-Pro-Cys-Gly (SPCG) motif discovered by selection of peptides for the function of self-acylation in the presence of a thioester acyl donor, which forms an -acyl isopeptide bond via intramolecular -to- acyl transfer. Ribosomal synthesis of linear peptides containing the SPCG motif and a backbone "acyl donor" thioester at a downstream position results in spontaneous conversion to the corresponding cyclic depsipeptides (CDPs) in a nearly independent manner of ring size and sequence context. Mutational analysis of the SPCG motif revealed that the P and G residues are dispensable to some extent, but the arrangement of residues in SXCX is crucial for efficient acyl transfer, e.g., CPSG is much less efficient. Finally, one-pot ribosomal synthesis of macrocyclic depsipeptides with various ring sizes and sequences has been demonstrated. This synthetic method can facilitate the ribosomal construction of highly diverse CDP libraries for the discovery of bioactive CDPs.
在这里，我们报告了一种通过核糖体一锅法合成大环内脂肽的方法。该方法基于在硫酯酰供体存在下，通过肽的选择而发现的 Ser-Pro-Cys-Gly（SPCG）基序，该基序通过分子内-to-酰基转移形成 -酰基异肽键。在核糖体上合成含有 SPCG 基序和位于下游位置的骨架“酰基供体”硫酯的线性肽，以几乎独立于环大小和序列背景的方式自发转化为相应的环内脂肽（CDP）。对 SPCG 基序的突变分析表明，P 和 G 残基在某种程度上是可有可无的，但 SXCX 中残基的排列对于有效的酰基转移至关重要，例如，CPSG 的效率要低得多。最后，已经证明了具有各种环大小和序列的大环内脂肽的一锅式核糖体合成。这种合成方法可以促进核糖体构建高度多样化的 CDP 文库，以发现具有生物活性的 CDP。
