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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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Related in: MedlinePlus

Microbial polyketide synthases are modular assembly lines that fit polyketides together from monomeric building blocks. In the first step of the reaction, the starter module is acylated with the first unit (1). This unit is subsequently transferred to the first of a row of extender modules that catalyze the elongation of the polyketide. All extender modules contain at least a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP) domain. In each step, the KS receives the acyl group unit from the ACP of the preceding module and the AT adds an appropriate extender unit from its CoA ester to the prosthetic group of the ACP (2). The KS then catalyzes a decarboxylative Claisen condensation between the acylated KS and the extender unit to give a β-keto-acylated acyl carrier protein (3). Other modules may be included to further modify the growing polyketide chain. Upon completion of the elongation process, the polyketide chain is cleaved from the polyketide synthase by the thioesterase (TE) of the termination module (4)
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Fig2: Microbial polyketide synthases are modular assembly lines that fit polyketides together from monomeric building blocks. In the first step of the reaction, the starter module is acylated with the first unit (1). This unit is subsequently transferred to the first of a row of extender modules that catalyze the elongation of the polyketide. All extender modules contain at least a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP) domain. In each step, the KS receives the acyl group unit from the ACP of the preceding module and the AT adds an appropriate extender unit from its CoA ester to the prosthetic group of the ACP (2). The KS then catalyzes a decarboxylative Claisen condensation between the acylated KS and the extender unit to give a β-keto-acylated acyl carrier protein (3). Other modules may be included to further modify the growing polyketide chain. Upon completion of the elongation process, the polyketide chain is cleaved from the polyketide synthase by the thioesterase (TE) of the termination module (4)

Mentions: Another important class of natural products are the polyketides. Polyketides are synthesized by large multi-enzyme complexes, the polyketide synthases. These “assembly lines” are built from modular components that catalyze the formation of the carbon chain of the final product in a stepwise manner (Fig. 2). The modular composition of polyketide synthases makes them an ideal playground for synthetic biologists. Their individual modules can be split and recombined to form active hybrid enzymes (Watanabe et al. 2003b). The combinatorial recombination of individual modules has been achieved, and the new enzymes were shown to successfully catalyze the formation of polyketides in E. coli (Menzella et al. 2005). This approach can potentially be used to produce libraries of polyketides with novel biological activities in vivo. Presently, simple recombination of different modules often produces inactive synthases because the transfer of intermediates between modules might be blocked or the connectivity between modules disturbed. Growing information on the structure of individual modules and their connectivity (Alekseyev et al. 2007; Keatinge-Clay and Stroud 2006; Tang et al. 2006) together with increasing experimental experience will help to develop predictive algorithms to rationally design synthases for “unnatural” polyketides in a combinatorial biosynthetical approach (Khosla et al. 2009). If a system to produce large libraries of hybrid enzymes is connected to a selectable output (Yin et al. 2007), active clones can be identified, even if their frequency in the library is very low (Menzella and Reeves 2007). A combination of computer-assisted prediction, combinatorial library design guided by structural information and selection might eventually develop into the mainstream of drug discovery.Fig. 2


Synthetic biology approaches in drug discovery and pharmaceutical biotechnology.

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

Microbial polyketide synthases are modular assembly lines that fit polyketides together from monomeric building blocks. In the first step of the reaction, the starter module is acylated with the first unit (1). This unit is subsequently transferred to the first of a row of extender modules that catalyze the elongation of the polyketide. All extender modules contain at least a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP) domain. In each step, the KS receives the acyl group unit from the ACP of the preceding module and the AT adds an appropriate extender unit from its CoA ester to the prosthetic group of the ACP (2). The KS then catalyzes a decarboxylative Claisen condensation between the acylated KS and the extender unit to give a β-keto-acylated acyl carrier protein (3). Other modules may be included to further modify the growing polyketide chain. Upon completion of the elongation process, the polyketide chain is cleaved from the polyketide synthase by the thioesterase (TE) of the termination module (4)
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: Microbial polyketide synthases are modular assembly lines that fit polyketides together from monomeric building blocks. In the first step of the reaction, the starter module is acylated with the first unit (1). This unit is subsequently transferred to the first of a row of extender modules that catalyze the elongation of the polyketide. All extender modules contain at least a ketosynthase (KS), an acyl transferase (AT) and an acyl carrier protein (ACP) domain. In each step, the KS receives the acyl group unit from the ACP of the preceding module and the AT adds an appropriate extender unit from its CoA ester to the prosthetic group of the ACP (2). The KS then catalyzes a decarboxylative Claisen condensation between the acylated KS and the extender unit to give a β-keto-acylated acyl carrier protein (3). Other modules may be included to further modify the growing polyketide chain. Upon completion of the elongation process, the polyketide chain is cleaved from the polyketide synthase by the thioesterase (TE) of the termination module (4)
Mentions: Another important class of natural products are the polyketides. Polyketides are synthesized by large multi-enzyme complexes, the polyketide synthases. These “assembly lines” are built from modular components that catalyze the formation of the carbon chain of the final product in a stepwise manner (Fig. 2). The modular composition of polyketide synthases makes them an ideal playground for synthetic biologists. Their individual modules can be split and recombined to form active hybrid enzymes (Watanabe et al. 2003b). The combinatorial recombination of individual modules has been achieved, and the new enzymes were shown to successfully catalyze the formation of polyketides in E. coli (Menzella et al. 2005). This approach can potentially be used to produce libraries of polyketides with novel biological activities in vivo. Presently, simple recombination of different modules often produces inactive synthases because the transfer of intermediates between modules might be blocked or the connectivity between modules disturbed. Growing information on the structure of individual modules and their connectivity (Alekseyev et al. 2007; Keatinge-Clay and Stroud 2006; Tang et al. 2006) together with increasing experimental experience will help to develop predictive algorithms to rationally design synthases for “unnatural” polyketides in a combinatorial biosynthetical approach (Khosla et al. 2009). If a system to produce large libraries of hybrid enzymes is connected to a selectable output (Yin et al. 2007), active clones can be identified, even if their frequency in the library is very low (Menzella and Reeves 2007). A combination of computer-assisted prediction, combinatorial library design guided by structural information and selection might eventually develop into the mainstream of drug discovery.Fig. 2

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
Related in: MedlinePlus