Expanding the enzyme universe with genetically encoded unnatural amino acids


The emergence of robust methods to expand the genetic code allows incorporation of non-canonical amino acids into the polypeptide chain of proteins, thus making it possible to introduce unnatural chemical functionalities in enzymes. In this Perspective, we show how this powerful methodology is used to create enzymes with improved and novel, even new-to-nature, catalytic activities. We provide an overview of the current state of the art, and discuss the potential benefits of developing and using enzymes with genetically encoded non-canonical amino acids compared with enzymes containing only canonical amino acids.

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Fig. 1: Schematic representation of the two main strategies for in vivo incorporation of ncAAs.
Fig. 2: Ancillary functions of ncAAs.
Fig. 3: ncAAs as metal-binding and metal-coordinating residues.
Fig. 4: ncAAs as catalytic residues.


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G.R. acknowledges financial support from the Netherlands Organisation for Scientific Research (NWO, Vici grant 724.013.003) and the Ministry of Education Culture and Science (Gravitation programme no. 024.001.035).

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I.D. researched data for the article. I.D. and G.R. wrote the article and both authors contributed to the discussion, reviewing and editing of the manuscript before submission.

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Correspondence to Ivana Drienovská or Gerard Roelfes.

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Drienovská, I., Roelfes, G. Expanding the enzyme universe with genetically encoded unnatural amino acids. Nat Catal 3, 193–202 (2020). https://doi.org/10.1038/s41929-019-0410-8

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