Protein building blocks and the expansion of the genetic code

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.