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Protein Building Blocks and the Expansion of the Genetic Code

  • Birgit Wiltschi

Abstract

The proteins of all known organisms are built of a set of 20 canonical amino acids prescribed by the genetic code. Many more amino acids occur in nature but they are excluded from ribosomal translation. Nevertheless, nature exploits their vast chemical diversity for the production of highly bioactive peptides by non-ribosomal biosynthesis routes. The extraordinarily rich structural and functional repertoire of the noncanonical amino acids holds great promise for the future of protein engineering, yet we have only just begun to tap the cornucopia of noncanonical building blocks for the biosynthesis of synthetic proteins.

This chapter provides a broad overview of canonical as well as noncanonical amino acids as building blocks for proteins and peptides. It recapitulates the genetic code and its natural deviations. The structures of selected naturally occurring noncanonical amino acids are listed referencing their source and biosynthesis pathways where known. The principles of current approaches to engineer and expand the genetic code are described. Numerous examples illustrate their application in protein engineering, and they are complemented by a compilation of the noncanonical building blocks involved.

Keywords

Genetic Code Chloramphenicol Acetyl Transferase SECIS Element Standard Genetic Code Sense Codon 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

aaRS

Aminoacyl-tRNA synthetase

BOC

Bioorthogonal conjugation

BONCAT

Bioorthogonal noncanonical amino acid tagging

cAA

Canonical amino acid

CAGE

Conjugative assembly genome engineering

CFP

Cyan fluorescent protein

CuAAC

Copper(I)-catalyzed azide–alkyne cycloaddition

FUNCAT

Fluorescent noncanonical amino acid tagging

GFP

Green fluorescent protein

IEDDA

Inverse electron-demand Diels–Alder reaction

MAGE

Multiplex automated genome engineering

MmPylRS/MmtRNACUAPyl

Orthogonal PylRS/tRNACUA Pyl pair from Methanosarcina mazei

ncAA

Noncanonical amino acid

ncAARS

ncAA-specific aminoacyl-tRNA synthetase

NRP

Non-ribosomal peptide

NRPS

Non-ribosomal peptide synthesis

o-pair

Orthogonal pair

PFAA

Polyfluorinated amino acid

PTM

Posttranslational modification

SCR

Sense codon recoding

SCS

Stop codon suppression

SpAAC

Strain-promoted Huisgen 1,3-dipolar cycloadditions between azides and cyclooctynes

SPI

Supplementation-based incorporation

Notes

Acknowledgments

This work has been supported by the Federal Ministry of Science, Research and Economy (BMWFW); the Federal Ministry of Traffic, Innovation and Technology (bmvit); the Styrian Business Promotion Agency SFG; the Standortagentur Tirol; the government of Lower Austria; and ZIT—Technology Agency of the City of Vienna through the COMET Funding Program managed by the Austrian Research Promotion Agency FFG.

I am grateful for support by CHEM21 in the frame of the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115360, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution.

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Austrian Centre of Industrial Biotechnology – ACIBGrazAustria

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