A cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell

Yasunori Okamoto, Ryosuke Kojima, Fabian Schwizer, Eline Bartolami, Tillmann Heinisch, Stefan Matile (), Martin Fussenegger () and Thomas R. Ward ()
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Yasunori Okamoto: University of Basel
Ryosuke Kojima: ETH Zurich
Fabian Schwizer: University of Basel
Eline Bartolami: University of Geneva
Tillmann Heinisch: University of Basel
Stefan Matile: University of Geneva
Martin Fussenegger: ETH Zurich
Thomas R. Ward: University of Basel

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract Complementing enzymes in their native environment with either homogeneous or heterogeneous catalysts is challenging due to the sea of functionalities present within a cell. To supplement these efforts, artificial metalloenzymes are drawing attention as they combine attractive features of both homogeneous catalysts and enzymes. Herein we show that such hybrid catalysts consisting of a metal cofactor, a cell-penetrating module, and a protein scaffold are taken up into HEK-293T cells where they catalyze the uncaging of a hormone. This bioorthogonal reaction causes the upregulation of a gene circuit, which in turn leads to the expression of a nanoluc-luciferase. Relying on the biotin–streptavidin technology, variation of the biotinylated ruthenium complex: the biotinylated cell-penetrating poly(disulfide) ratio can be combined with point mutations on streptavidin to optimize the catalytic uncaging of an allyl-carbamate-protected thyroid hormone triiodothyronine. These results demonstrate that artificial metalloenzymes offer highly modular tools to perform bioorthogonal catalysis in live HEK cells.

Date: 2018
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DOI: 10.1038/s41467-018-04440-0

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