Evolution of fluorinated enzymes: An emerging trend for biocatalyst stabilization

Nature uses remarkably limited sets of chemistries in its repertoire, especially when compared to synthetic organic chemistry. This limits both the chemical and structural diversity that can ultimately be achieved with biocatalysis, unless the powers of chemical synthesis are merged with biological systems by integrating nonnatural synthetic chemistries into the protoplasma of living cells. Of particular interest, here is the fluorous effect that has recently established the potential to generate enzymes with an increased resistance toward both high temperature and organic solvents. For these reasons, we are witnessing a rapid development of efficient methodologies for the incorporation of fluorinated amino acids in protein synthesis, using both in vivo and in vitro strategies. In this review, we highlight relevant and trendsetting results in the design and engineering of stable fluorinated proteins and peptides along with whole-cell biocatalysis as an economically attractive and convenient application with exclusive focus on industrial biocatalysis. Finally, we envision new strategies to improve current achievements and enable the field to progress far beyond the current state-of-the-art.