# Evolution of Pyrrolysyl-tRNA Synthetase: From Methanogenesis to Genetic Code Expansion

## TL;DR

This paper reviews how an enzyme involved in archaea's methane production evolved into a tool for expanding the genetic code to create new proteins.

## Contribution

The paper compiles a comprehensive list of non-canonical amino acids usable with the PylRS system and highlights recent therapeutic applications.

## Key findings

- Pyrrolysyl-tRNA synthetase (PylRS) has been engineered to recognize new substrates for genetic code expansion.
- The PylRS system has been successfully applied in developing antibody–drug conjugates and new vaccine modalities.
- Recent advancements suggest potential for producing novel antimicrobials using the PylRS system.

## Abstract

Over 20 years ago,
the pyrrolysine encoding translation system
was discovered in specific archaea. Our Review provides an overview
of how the once obscure pyrrolysyl-tRNA synthetase (PylRS) tRNA pair,
originally responsible for accurately translating enzymes crucial
in methanogenic metabolic pathways, laid the foundation for the burgeoning
field of genetic code expansion. Our primary focus is the discussion
of how to successfully engineer the PylRS to recognize new substrates
and exhibit higher in vivo activity. We have compiled
a comprehensive list of ncAAs incorporable with the PylRS system.
Additionally, we also summarize recent successful applications of
the PylRS system in creating innovative therapeutic solutions, such
as new antibody–drug conjugates, advancements in vaccine modalities,
and the potential production of new antimicrobials.