Expanded genetic code

Orthogonal pair to extend code

Tyr based non natural aa

Selection for nonnatural aa

Expanded Genetic Code refers to the modification or extension of the genetic code of organisms through the inclusion of non-standard amino acids. In nature, the genetic code is traditionally composed of 20 standard amino acids, which are encoded by specific sequences of three nucleotides (triplets) called codons. The expanded genetic code involves the incorporation of unnatural amino acids (uAAs) that are not found in nature, thereby increasing the diversity and functionality of proteins.

Overview

The concept of an expanded genetic code is rooted in the field of synthetic biology and molecular biology, where scientists aim to engineer organisms with new properties or capabilities. By introducing non-standard amino acids into proteins, researchers can impart new chemical functionalities, enhance stability, or introduce novel regulatory mechanisms. This expansion is achieved through various methods, including the reassignment of stop codons, the creation of new codons through base pair modifications, and the engineering of tRNA and aminoacyl-tRNA synthetase pairs that can recognize and incorporate the non-standard amino acids into proteins.

Methods of Expansion

The expansion of the genetic code is primarily achieved through two methods: the reassignment of codons and the creation of orthogonal tRNA/synthetase pairs.

Reassignment of Codons

One approach to expanding the genetic code is to reassign existing codons, typically one of the three stop codons, to encode a non-standard amino acid. This method requires the reduction of the genetic code's redundancy and the careful selection of a target codon to minimize disruption to the organism's proteome.

Orthogonal tRNA/Synthetase Pairs

Another approach involves the engineering of orthogonal tRNA/aminoacyl-tRNA synthetase pairs that are specific to the non-standard amino acid and do not cross-react with the organism's natural machinery. These engineered pairs can recognize and incorporate the non-standard amino acids in response to a specific codon, often a reassigned stop codon or a rare codon, thereby expanding the genetic code.

Applications

The expanded genetic code has numerous applications in research, medicine, and biotechnology. These include the design of proteins with novel functions, the development of new therapeutic agents, and the creation of bio-based materials with enhanced properties.

Protein Engineering

By incorporating non-standard amino acids with unique chemical functionalities, scientists can create proteins with novel catalytic activities, binding properties, or stability. This has implications for the development of new enzymes, biocatalysts, and therapeutic proteins.

Biomedical Applications

In medicine, the expanded genetic code can be used to develop novel biopharmaceuticals, including antibody-drug conjugates with improved efficacy and reduced side effects. It also opens avenues for the creation of site-specifically modified proteins, which can be used in targeted drug delivery and diagnostic applications.

Material Science

The inclusion of unnatural amino acids in proteins can also enhance the properties of bio-based materials, such as increased strength, flexibility, or environmental resistance. This has potential applications in the development of new biomaterials for medical, industrial, and environmental uses.

Challenges and Future Directions

Expanding the genetic code presents several challenges, including the efficient and accurate incorporation of non-standard amino acids, the potential toxicity of unnatural components, and the evolutionary stability of engineered organisms. Future research is directed towards overcoming these challenges, improving the efficiency of codon reassignment and orthogonal tRNA/synthetase systems, and exploring the full potential of proteins with expanded amino acid repertoires.

Expanded genetic code Resources
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