TU Berlin, Department of Chemistry, Biocatalysis Group, Franklinstrasse 29 (OE1), D-10587 Berlin, Germany.
Org Biomol Chem. 2012 Sep 28;10(36):7241-61. doi: 10.1039/c2ob06922a.
Traditionally, the biological fluorination of complex biological systems like proteins is achieved through substitution of canonical amino acids or addition of fluorinated amino acids in the context of the standard genetic code. Ribosomal translation of monofluorinated amino acids into proteins often yields structures with minimal local changes in the interior but, on the same time, results in large global effects on characteristic features of the biopolymers (such as dramatically changed activity profile or folding stability). This is due to the novel and unique local interactions delivered by fluorine atoms such as (i) increase in the covalent radii (ii) changed polarities; (iii) changed hydrogen bond acceptor ability; (iv) altered water solubility as well as water ↔ organic solvent energy transfer. On the other hand, the biological incorporation of tri- or global fluorinated amino acids (such as trifluoroleucine, triflurovaline, and their hexafluoro counterparts, fluoromethionine and trifluoronorleucine etc.) represents still a challenge, as the natural structural scaffolds are optimized for hydrocarbon during evolution but not for fluorocarbon cores. Future work will be focused on the re-design of existing or de novo design of novel protein scaffolds capable of accommodating such building blocks into functional biologically active proteins and proteomes in the context of the viable cells.
传统上，通过取代典型氨基酸或在标准遗传密码的背景下添加氟化氨基酸，可以实现对蛋白质等复杂生物系统的生物氟化。核糖体将单氟化氨基酸翻译到蛋白质中，通常会导致蛋白质内部的局部变化最小，但同时对生物聚合物的特征（如活性谱或折叠稳定性的显著改变）产生较大的全局影响。这是由于氟原子提供的新的独特的局部相互作用，如 (i) 共价半径增加，(ii) 极性变化，(iii) 氢键接受能力改变，(iv) 溶解度改变以及水与有机溶剂的能量转移。另一方面，三氟或全氟化氨基酸（如三氟亮氨酸、三氟缬氨酸及其六氟对应物氟甲硫氨酸和三氟正亮氨酸等）的生物掺入仍然是一个挑战，因为自然结构支架在进化过程中是针对碳氢化合物进行优化的，而不是针对氟碳核心进行优化的。未来的工作将集中于重新设计现有的或从头设计新的蛋白质支架，使其能够在可行的细胞环境中容纳这些结构单元，形成功能性生物活性蛋白质和蛋白质组。
