'Trojan horse' artificial enzyme smuggles unnatural reactions into cells
New-to-nature chemistry in mammalian cells made possible by metalloenzyme system
A team of Swiss scientists has engineered a mammalian cell with a synthetic gene switch regulated by a cell-penetrating artificial metalloenzyme in a bid to introduce chemistry that’s new-to-nature. They want to use this hybrid biocatalyst to bring new chemical reactions to cells to tackle malfunctions such as cancer.
To get the artificial ruthenium-containing metalloenzyme into the cell, the team developed a ‘Trojan-horse’ strategy. The hybrid catalyst consists of streptavidin, a catalytically inactive protein known for its high affinity towards biotin, which only becomes enzymatically active when it combines with a biotinylated ruthenium catalyst. The researchers also attached cell-penetrating poly(disulfides) to the metalloenzyme, allowing it to be smuggled into the cell, where it catalyses the uncaging of a protected thyroid hormone in the cell. Upon release, the free hormone turns on the overexpression of a reporter enzyme. ‘My ultimate goal is to cure a badly-functioning cell, such as cancer, by an on-demand non-canonical reaction, which is triggered by sensing cellular information,’ says Yasunori Okamoto, lead author of the study. ‘This project represents our first step in that direction.’