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Synthetic biology approaches in drug discovery and pharmaceutical biotechnology.

Neumann H, Neumann-Staubitz P - Appl. Microbiol. Biotechnol. (2010)

Bottom Line: New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries.New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability.This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology.

View Article: PubMed Central - PubMed

Affiliation: Free Floater (Junior) Research Group Applied Synthetic Biology, Institute for Microbiology and Genetics, Georg-August University Göttingen, Justus-von-Liebig Weg 11, 37077 Göttingen, Germany. hneumann@gwdg.de

ABSTRACT
Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology.

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The principle of genetic code expansion. The basic principle of genetic code expansion is the heterologous expression of an additional tRNA/aminoacyl-tRNA synthetase (aaRS) pair in the host cell. This pair is orthogonal to the host’s translational machinery, meaning that the tRNA is not a substrate for endogenous synthetases and that the aaRS does not charge host tRNAs. The orthogonal tRNA is mutated to decode amber stop codons and the orthogonal aaRS is evolved to specifically recognize an unnatural amino acid (UAA) supplied with the growth medium. Cells with such an expanded genetic code are able to produce proteins with the UAA incorporated at a position encoded by an amber codon in the mRNA
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Fig3: The principle of genetic code expansion. The basic principle of genetic code expansion is the heterologous expression of an additional tRNA/aminoacyl-tRNA synthetase (aaRS) pair in the host cell. This pair is orthogonal to the host’s translational machinery, meaning that the tRNA is not a substrate for endogenous synthetases and that the aaRS does not charge host tRNAs. The orthogonal tRNA is mutated to decode amber stop codons and the orthogonal aaRS is evolved to specifically recognize an unnatural amino acid (UAA) supplied with the growth medium. Cells with such an expanded genetic code are able to produce proteins with the UAA incorporated at a position encoded by an amber codon in the mRNA

Mentions: The diversity in the chemical nature of proteins and peptides has been tremendously increased by the invention of strategies to introduce unnatural amino acids in vivo. Peter Schultz and his co-workers have artificially expanded the genetic code of several organisms (Chin et al. 2003; Liu et al. 2007; Wang et al. 2001) and succeeded in incorporating a wide range of unnatural amino acids (Xie and Schultz 2006). The basic principle of genetic code expansion is the expression of an additional pair of tRNA and its cognate aaRS in the host system (Fig. 3). Both, tRNA and aaRS, must not be substrates for the host aaRSs and tRNAs to ensure correct translation of host proteins. Under these prerequisites, the tRNA can be mutated to decode amber stop codons, for example, and the aaRS can be evolved to specifically recognize unnatural amino acids. This system allows the incorporation of additional, unnatural amino acids in response to amber stop codons. In the past decade, the list of unnatural amino acids that can be incorporated in this way has grown continuously (Neumann et al. 2008; Nguyen et al. 2009b; Xie and Schultz 2006). Recent developments of amber and quadruplet suppressor ribosomes now allow the efficient incorporation of multiple different unnatural amino acids into the same protein (Neumann et al. 2010; Wang et al. 2007). These unnatural amino acids have side chains with unusual chemical properties and reactivities and could be used to increase the chemical diversity of peptides and proteins.Fig. 3


Synthetic biology approaches in drug discovery and pharmaceutical biotechnology.

Neumann H, Neumann-Staubitz P - Appl. Microbiol. Biotechnol. (2010)

The principle of genetic code expansion. The basic principle of genetic code expansion is the heterologous expression of an additional tRNA/aminoacyl-tRNA synthetase (aaRS) pair in the host cell. This pair is orthogonal to the host’s translational machinery, meaning that the tRNA is not a substrate for endogenous synthetases and that the aaRS does not charge host tRNAs. The orthogonal tRNA is mutated to decode amber stop codons and the orthogonal aaRS is evolved to specifically recognize an unnatural amino acid (UAA) supplied with the growth medium. Cells with such an expanded genetic code are able to produce proteins with the UAA incorporated at a position encoded by an amber codon in the mRNA
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2872025&req=5

Fig3: The principle of genetic code expansion. The basic principle of genetic code expansion is the heterologous expression of an additional tRNA/aminoacyl-tRNA synthetase (aaRS) pair in the host cell. This pair is orthogonal to the host’s translational machinery, meaning that the tRNA is not a substrate for endogenous synthetases and that the aaRS does not charge host tRNAs. The orthogonal tRNA is mutated to decode amber stop codons and the orthogonal aaRS is evolved to specifically recognize an unnatural amino acid (UAA) supplied with the growth medium. Cells with such an expanded genetic code are able to produce proteins with the UAA incorporated at a position encoded by an amber codon in the mRNA
Mentions: The diversity in the chemical nature of proteins and peptides has been tremendously increased by the invention of strategies to introduce unnatural amino acids in vivo. Peter Schultz and his co-workers have artificially expanded the genetic code of several organisms (Chin et al. 2003; Liu et al. 2007; Wang et al. 2001) and succeeded in incorporating a wide range of unnatural amino acids (Xie and Schultz 2006). The basic principle of genetic code expansion is the expression of an additional pair of tRNA and its cognate aaRS in the host system (Fig. 3). Both, tRNA and aaRS, must not be substrates for the host aaRSs and tRNAs to ensure correct translation of host proteins. Under these prerequisites, the tRNA can be mutated to decode amber stop codons, for example, and the aaRS can be evolved to specifically recognize unnatural amino acids. This system allows the incorporation of additional, unnatural amino acids in response to amber stop codons. In the past decade, the list of unnatural amino acids that can be incorporated in this way has grown continuously (Neumann et al. 2008; Nguyen et al. 2009b; Xie and Schultz 2006). Recent developments of amber and quadruplet suppressor ribosomes now allow the efficient incorporation of multiple different unnatural amino acids into the same protein (Neumann et al. 2010; Wang et al. 2007). These unnatural amino acids have side chains with unusual chemical properties and reactivities and could be used to increase the chemical diversity of peptides and proteins.Fig. 3

Bottom Line: New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries.New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability.This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology.

View Article: PubMed Central - PubMed

Affiliation: Free Floater (Junior) Research Group Applied Synthetic Biology, Institute for Microbiology and Genetics, Georg-August University Göttingen, Justus-von-Liebig Weg 11, 37077 Göttingen, Germany. hneumann@gwdg.de

ABSTRACT
Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology.

Show MeSH