Biocatalysis with Unnatural Amino Acids: Enzymology Meets Xenobiology

Abstract

The goal of xenobiology is to design biological systems endowed with unusual biochemical functions, whereas enzymology concerns the study of enzymes, the workhorses of biocatalysis. Biocatalysis employs enzymes and organisms to perform useful biotransformations in synthetic chemistry and biotechnology. During the past few years, the effects of incorporating noncanonical amino acids (ncAAs) into enzymes with potential applications in biocatalysis have been increasingly investigated. In this Review, we provide an overview of the effects of new chemical functionalities that have been introduced into proteins to improve various facets of enzymatic catalysis. We also discuss future research avenues that will complement unnatural mutagenesis with standard protein engineering to produce novel and versatile biocatalysts with applications in synthetic organic chemistry and biotechnology.

Nucleophile Promiscuity of Natural and Engineered Aldolases

“…The novel superfamily panels offer the capacity to rapidly discover enzymes that produce either native or complementary stereoisomers . Protein engineering technologies to incorporate non‐canonical amino acids or artificial cofactors into proteins at specifically chosen sites, either by genetic means or by chemical modification, are also important opportunities to improve the carboligase scope of substrates and type of C−C bond reactions.…”

Direct Enzymatic Synthesis of a Deep‐Blue Fluorescent Noncanonical Amino Acid from Azulene and Serine

“…These molecules resemble the natural building blocks of proteins but contain distinct structures and functional groups. When incorporated into proteins, ncAAs can serve as handles for chemical reactions or as spectroscopic probes to examine protein function, including reactivity, localization, and interaction with other biomolecules . Unfortunately, the applications of many potentially useful ncAAs are limited owing to their high cost and lack of availability.…”

Engineered Biosynthesis of β‐Alkyl Tryptophan Analogues

“…Alongside the standard proteinogenic amino acids are diverse non-canonical amino acids (ncAAs) that are structurally similar but are not ribosomally incorporated into proteins. Due to the presence of functional groups that confer novel chemical and biological properties, [1] ncAAs can be found in natural products and 12% of the 200 top-grossing pharmaceuticals. [2,3] Of interest are β-branched ncAAs, which possess a chiral center at the β-position in addition to the standard chirality at the α-position of an amino acid (Figure 1a).…”