Drane Stephen B, Robinson Samuel D, MacRaild Christopher A, Chhabra Sandeep, Chittoor Balasubramanyam, Morales Rodrigo A V, Leung Eleanor W W, Belgi Alessia, Espino Samuel S, Olivera Baldomero M, Robinson Andrea J, Chalmers David K, Norton Raymond S
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia.
Toxicon. 2017 Apr;129:113-122. doi: 10.1016/j.toxicon.2017.02.012. Epub 2017 Feb 17.
In natural proteins and peptides, amino acids exist almost invariably as l-isomers. There are, however, several examples of naturally-occurring peptides containing d-amino acids. In this study we investigated the role of a naturally-occurring d-amino acid in a small peptide identified in the transcriptome of a marine cone snail. This peptide belongs to a family of peptides known as contryphans, all of which contain a single d-amino acid residue. The solution structure of this peptide was solved by NMR, but further investigations with molecular dynamics simulations suggest that its solution behaviour may be more dynamic than suggested by the NMR ensemble. Functional tests in mice uncovered a novel bioactivity, a depressive phenotype that contrasts with the hyperactive phenotypes typically induced by contryphans. Trp3 is important for bioactivity, but this role is independent of the chirality at this position. The d-chirality of Trp3 in this peptide was found to be protective against enzymatic degradation. Analysis by NMR and molecular dynamics simulations indicated an interaction of Trp3 with lipid membranes, suggesting the possibility of a membrane-mediated mechanism of action for this peptide.
在天然蛋白质和肽中，氨基酸几乎无一例外都以L-异构体的形式存在。然而，有几个天然存在的含有D-氨基酸的肽的例子。在本研究中，我们研究了一种在海洋芋螺转录组中鉴定出的小肽中天然存在的D-氨基酸的作用。这种肽属于一类被称为芋螺毒素的肽，它们都含有一个单一的D-氨基酸残基。该肽的溶液结构通过核磁共振（NMR）解析，但分子动力学模拟的进一步研究表明，其溶液行为可能比NMR集合所显示的更具动态性。在小鼠身上进行的功能测试发现了一种新的生物活性，即一种抑郁表型，这与通常由芋螺毒素诱导的多动表型形成对比。色氨酸3（Trp3）对生物活性很重要，但这一作用与该位置的手性无关。发现该肽中Trp3的D-手性可防止酶促降解。通过NMR和分子动力学模拟分析表明Trp3与脂质膜相互作用，提示该肽可能存在膜介导的作用机制。
