Abstract:
Enniatins are mycotoxins with well-known antibacterial, antifungal, antihelmintic and antiviral activity, which have recently come to attention as potential mitochondriotoxic anticancer agents. The cytotoxicity of enniatins is traced back to ionophoric properties, in which the cyclodepsipeptidic structure results in enniatin:cation-complexes of various stoichiometries proposed as membrane-active species. In this work, we employed a combination of surface-enhanced infrared absorption (SEIRA) spectroscopy, tethered bilayer lipid membranes (tBLMs) and density functional theory (DFT)-based computational spectroscopy to monitor the cation-dependence (Mz+=Na+, K+, Cs+, Li+, Mg2+, Ca2+) on the mechanism of enniatin B (EB) incorporation into membranes and identify the functionally relevant EBn : Mz+ complexes formed. We find that Na+ promotes a cooperative incorporation, modelled via an autocatalytic mechanism and mediated by a distorted 2 : 1-EB2 : Na+ complex. K+ (and Cs+) leads to a direct but less efficient insertion into membranes due to the adoption of \"ideal\" EB2 : K+ sandwich complexes. In contrast, the presence of Li+, Mg2+, and Ca2+ causes a (partial) extraction of EB from the membrane via the formation of \"belted\" 1 : 1-EB : Mz+ complexes, which screen the cationic charge less efficiently. Our results point to a relevance of the cation dependence for the transport into the malignant cells where the mitochondriotoxic anticancer activity is exerted.
摘要:
Enniatins是真菌毒素,具有众所周知的抗菌作用,抗真菌药,抗蠕虫和抗病毒活性,最近作为潜在的线粒体毒性抗癌剂引起了人们的注意。Enniatins的细胞毒性可以追溯到离子通道性质,其中环缩肽结构产生了各种化学计量的nanniatin:阳离子复合物被提议作为膜活性物质。在这项工作中,我们采用了表面增强红外吸收(SEIRA)光谱的组合,系留双层脂质膜(tBLMs)和基于密度泛函理论(DFT)的计算光谱法监测阳离子依赖性(Mz=Na,K+,Cs+,Li+,Mg2+,Ca2)对EnniatinB(EB)掺入膜中的机制,并鉴定形成的功能相关的EBn:Mz复合物。我们发现Na+促进了合作合并,通过自催化机理建模,并由扭曲的2:1-EB2:Na复合物介导。由于采用了“理想的”EB2:K三明治复合物,K(和Cs)导致直接但效率较低的插入膜。相比之下,Li+的存在,Mg2+,和Ca2+通过形成“束带”1:1-EB:Mz+复合物,从膜中(部分)提取EB,从而较不有效地筛选阳离子电荷。我们的结果表明,阳离子依赖性与转运到发挥线粒体毒性抗癌活性的恶性细胞有关。