14.3 Synthetic Biology and Metabolic Engineering
3 min read•july 22, 2024
merges biology with engineering to create or modify biological systems. It uses standardized parts, computer-aided design, and genetic tools to build predictable systems for producing valuable compounds like and drugs.
The field applies , rational approaches, and to optimize biological processes. A notable success is the production of in engineered , demonstrating synthetic biology's potential to solve real-world problems and improve global health.
Introduction to Synthetic Biology and Metabolic Engineering
Core concepts of synthetic biology
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- Designing and constructing new biological systems or modifying existing ones applies engineering principles to biology (, )
- Creating novel functions or optimizing existing processes enables production of valuable compounds (biofuels, pharmaceuticals)
- Synthetic biology combines principles from biology, engineering, and computer science to create predictable and controllable biological systems
Design principles for biological systems
- Modular design uses standardized biological parts () as interchangeable components for easy assembly and optimization of genetic circuits
- Rational design employs computer-aided design (CAD) tools for pathway construction and (FBA) for predicting metabolic fluxes
- (GEMs) enable in silico simulations of cellular metabolism to guide rational design and optimization
- Directed evolution improves enzyme properties or pathway performance through iterative rounds of mutagenesis and selection (, )
- Genetic engineering tools include restriction enzymes and DNA ligases for cutting and joining DNA fragments, polymerase chain reaction (PCR) for amplifying DNA sequences, and for precise genome editing and regulation
Case study in synthetic biology
- Production of artemisinin, an antimalarial drug naturally produced by the plant Artemisia annua, using engineered yeast demonstrates successful application of synthetic biology
- Introduction of plant-derived genes for artemisinin biosynthesis pathway into yeast
- Optimization of the mevalonate pathway to increase precursor supply for artemisinin production
- Balancing redox cofactors (NADH/NAD+, NADPH/NADP+) and improving pathway efficiency through
- Resulted in a scalable and cost-effective production process for artemisinin, increasing global access to this life-saving drug
Proposal for metabolic pathway design
- Target compound: Biodegradable plastic (PHAs) as an environmentally friendly alternative to petroleum-based plastics
- Enzyme selection involves for polymerizing hydroxyalkanoate monomers and for releasing free hydroxyalkanoate monomers from acyl-CoA precursors
- Cofactor balance ensures sufficient supply of acetyl-CoA and NADPH for PHA biosynthesis by introducing pathways for regenerating cofactors (, )
- Pathway optimization strategies include:
- Overexpressing rate-limiting enzymes () to increase flux through the PHA biosynthesis pathway
- Knocking out competing pathways (fatty acid biosynthesis) to redirect carbon flux towards PHA production
- Implementing dynamic regulation (, ) to minimize metabolic burden and improve stability of the engineered strain
- Considerations for industrial production:
- Selecting a suitable host organism (Escherichia coli, Cupriavidus necator) based on growth characteristics and metabolic capabilities
- Optimizing fermentation conditions (carbon source, aeration, pH) to maximize PHA yield and productivity
- Developing efficient downstream processing methods for PHA extraction and purification to obtain high-quality biodegradable plastic
Key Terms to Review (31)
Acetyl-CoA Carboxylase: Acetyl-CoA carboxylase (ACC) is an enzyme that plays a critical role in the synthesis of fatty acids by converting acetyl-CoA into malonyl-CoA, which is a key building block for fatty acid biosynthesis. This enzyme is important for metabolic regulation and is influenced by various factors such as energy levels and nutrient availability, making it a target for synthetic biology and metabolic engineering applications aimed at enhancing lipid production.
Artemisinin: Artemisinin is a naturally occurring compound derived from the sweet wormwood plant, Artemisia annua, and is primarily known for its potent anti-malarial properties. This compound has gained attention due to its effectiveness in treating malaria, particularly in combination therapies, and serves as a critical example of how natural products can be optimized through synthetic biology and metabolic engineering techniques to enhance yields and accessibility.
Biobricks: Biobricks are standardized biological parts that can be combined to create new genetic circuits and biological systems. They are essentially modular DNA sequences that allow scientists to engineer organisms by assembling them like building blocks, enabling precise control over metabolic pathways and gene expression.
Biofuels: Biofuels are renewable energy sources derived from organic materials, such as plants, algae, and waste, that can be used for transportation and energy production. They serve as an alternative to fossil fuels, contributing to reduced greenhouse gas emissions and promoting sustainability. Their production and utilization are closely linked to advances in technology and engineering practices that optimize the conversion of biomass into usable energy forms.
Biopharmaceuticals: Biopharmaceuticals are medical drugs produced using biotechnology, often derived from living organisms, such as proteins, nucleic acids, or cells. They include a wide range of products, including monoclonal antibodies, vaccines, and gene therapies, that harness the biological processes of living systems to treat diseases more effectively than traditional pharmaceuticals.
Biosafety: Biosafety refers to the measures and practices designed to protect human health and the environment from the potential risks posed by biological materials, including genetically modified organisms and pathogens. It encompasses a range of guidelines and regulations aimed at minimizing exposure to harmful biological agents while allowing for research and innovation, particularly in areas like synthetic biology and metabolic engineering.
Biosecurity: Biosecurity refers to the measures and protocols aimed at preventing the introduction and spread of harmful biological agents, including pathogens, pests, and invasive species. It is crucial in synthetic biology and metabolic engineering as it ensures that engineered organisms do not negatively impact human health or the environment. Implementing biosecurity measures safeguards against accidental releases and potential misuse of biotechnological advancements.
Biosensors: Biosensors are analytical devices that combine a biological sensing element with a transducer to detect and measure specific substances, often in complex biological samples. They play a crucial role in various fields, including healthcare, environmental monitoring, and food safety, by providing real-time analysis and detection of biological molecules such as enzymes, antibodies, or nucleic acids. The integration of biosensors with synthetic biology and metabolic engineering enhances their functionality and specificity, enabling innovative applications in diagnostics and personalized medicine.
Crispr-cas9: Crispr-Cas9 is a revolutionary gene-editing technology that allows for precise alterations in DNA sequences within organisms. By utilizing a guide RNA to direct the Cas9 enzyme to specific locations in the genome, it enables scientists to add, delete, or modify genetic material with high accuracy. This technology has transformed the fields of genetics and molecular biology, significantly impacting areas such as synthetic biology and metabolic engineering.
Directed Evolution: Directed evolution is a laboratory technique used to mimic the process of natural selection in order to evolve proteins or nucleic acids toward a user-defined goal. By introducing random mutations and selecting for desirable traits, researchers can rapidly generate variants with improved functions, which is particularly useful in synthetic biology and metabolic engineering for developing new biochemical pathways or optimizing existing ones.
Dna shuffling: DNA shuffling is a technique used to create genetic diversity by randomly recombining fragments of DNA from different sources. This method allows for the generation of novel genetic sequences, which can enhance the properties of proteins or metabolic pathways in synthetic biology and metabolic engineering applications. The process is critical for developing organisms with improved traits, such as better enzyme activity or higher resistance to stress.
E. coli: E. coli, or Escherichia coli, is a type of bacteria that is commonly found in the intestines of humans and warm-blooded animals. While many strains are harmless and play a crucial role in gut health, certain pathogenic strains can cause serious foodborne illnesses and infections. Its genetic simplicity and rapid growth make it a favored organism in synthetic biology and metabolic engineering for research and applications.
Error-Prone PCR: Error-prone PCR is a variation of the polymerase chain reaction (PCR) that intentionally introduces mutations into the DNA sequence being amplified. This technique is primarily used in synthetic biology and metabolic engineering to create diversity in genetic material, enabling researchers to study protein function or develop novel enzymes. By increasing the mutation rate during amplification, it allows for the exploration of new biological functions and pathways that can be harnessed for various applications.
Flux balance analysis: Flux balance analysis (FBA) is a mathematical approach used to analyze the flow of metabolites through a metabolic network, allowing researchers to predict the behavior of biological systems under various conditions. It is particularly useful in synthetic biology and metabolic engineering as it helps identify optimal pathways for production and understand how organisms can be modified for improved yield or efficiency. By using constraints like nutrient availability and enzyme capacities, FBA provides insights into how cellular metabolism can be engineered to achieve desired outcomes.
Gene editing: Gene editing is a biotechnological process that enables scientists to make precise modifications to an organism's DNA. This technique allows for the addition, deletion, or alteration of genetic material at specific locations in the genome, thus creating organisms with desired traits or functions. It plays a crucial role in synthetic biology and metabolic engineering by allowing researchers to engineer biological systems for various applications, including medicine, agriculture, and environmental sustainability.
Gene expression: Gene expression is the process by which information from a gene is used to synthesize functional gene products, typically proteins, that perform specific functions within a cell. This process involves two main steps: transcription, where the DNA sequence of a gene is transcribed into messenger RNA (mRNA), and translation, where the mRNA is translated into a specific protein. Understanding gene expression is crucial for synthetic biology and metabolic engineering, as manipulating this process allows for the design and optimization of biological systems.
Genetic circuits: Genetic circuits are synthetic biological systems that combine genes and regulatory elements to control cellular behaviors in a predictable manner. By engineering these circuits, scientists can program cells to perform specific functions, such as producing certain proteins or responding to environmental stimuli. This capability is crucial for advancing fields like synthetic biology and metabolic engineering, where precision in cellular processes is key to developing new biotechnologies.
Genome-scale metabolic models: Genome-scale metabolic models (GEMs) are comprehensive representations of the metabolic networks of an organism, constructed using genome sequencing data and biochemical information. These models integrate information about genes, enzymes, and metabolic pathways to predict cellular behavior and allow for the simulation of various metabolic scenarios. They are powerful tools in synthetic biology and metabolic engineering, enabling researchers to design and optimize biological systems for specific applications.
Inducible promoters: Inducible promoters are specific DNA sequences that control the expression of genes and can be activated in response to particular stimuli or conditions. These promoters provide a powerful tool in synthetic biology and metabolic engineering, allowing for the precise regulation of gene expression, which is crucial for optimizing metabolic pathways and producing desired compounds in microorganisms or cells.
Metabolic Engineering: Metabolic engineering is a discipline that focuses on the optimization of metabolic pathways within an organism to enhance the production of specific substances or to create novel compounds. This field combines principles from biochemistry, genetics, and synthetic biology to modify cellular processes, allowing for improved yields of products such as biofuels, pharmaceuticals, and other valuable chemicals. It plays a crucial role in designing organisms that can efficiently convert substrates into desired products.
Modular Design: Modular design is an approach in engineering and product development where a system is built using standardized, interchangeable components or modules. This method allows for flexibility, scalability, and ease of modification, making it particularly useful in areas such as synthetic biology and metabolic engineering, where complex biological systems can be constructed from simpler, well-defined parts.
Nadh kinase: NADH kinase is an enzyme that catalyzes the phosphorylation of NADH to NADPH, utilizing ATP as a phosphate donor. This conversion is essential in various metabolic pathways, particularly in maintaining the balance between NADH and NADPH, which plays a critical role in cellular redox reactions and biosynthetic processes.
Pathway engineering: Pathway engineering refers to the design and modification of biological pathways within organisms to enhance or create desired metabolic functions. This involves manipulating the biochemical reactions that occur within cells, allowing for improved production of specific compounds, such as biofuels, pharmaceuticals, or other valuable metabolites. By combining principles of synthetic biology and metabolic engineering, pathway engineering enables researchers to optimize cellular processes for various applications.
Pha synthases: Pha synthases are enzymes responsible for the biosynthesis of polyhydroxyalkanoates (PHAs), which are biodegradable polymers produced by certain microorganisms as carbon and energy storage compounds. These enzymes play a critical role in synthetic biology and metabolic engineering, enabling the design and modification of microbial pathways to enhance PHA production, which has significant implications for sustainable materials and bioplastics.
Polyhydroxyalkanoates: Polyhydroxyalkanoates (PHAs) are a class of biodegradable polyesters produced by various microorganisms as a form of carbon and energy storage. These biopolymers have garnered significant interest due to their potential as sustainable alternatives to conventional plastics, particularly in the fields of materials science and biotechnology, as they can be produced from renewable resources through microbial fermentation processes.
Riboregulators: Riboregulators are RNA molecules that play a crucial role in regulating gene expression at the post-transcriptional level. They function by binding to messenger RNA (mRNA) and either promoting or inhibiting translation, thus controlling the production of specific proteins within a cell. This regulatory mechanism is essential for fine-tuning cellular processes and responding to environmental changes, which is especially important in synthetic biology and metabolic engineering applications.
Synthetic biology: Synthetic biology is an interdisciplinary field that involves the design and construction of new biological parts, devices, and systems or the redesign of existing biological systems for useful purposes. It combines principles from biology, engineering, and computer science to create organisms with novel functionalities, allowing for advancements in areas like medicine, agriculture, and environmental sustainability.
Thioesterases: Thioesterases are enzymes that catalyze the hydrolysis of thioesters, breaking the bond between a sulfur atom and a carbon atom in a thioester compound. These enzymes play a significant role in various metabolic pathways, especially in the context of synthetic biology and metabolic engineering, where they can be engineered to alter metabolic flux and produce valuable compounds.
Transgenic organisms: Transgenic organisms are living entities that have been genetically modified to contain DNA from another species, often achieved through recombinant DNA technology. This manipulation allows for the expression of new traits, which can enhance growth, resistance to pests, or production of specific substances. Transgenic organisms play a crucial role in various fields, including agriculture, medicine, and environmental science, by improving crop yields and creating models for studying diseases.
Transhydrogenase: Transhydrogenase is an enzyme that catalyzes the transfer of hydrogen ions (protons) between NADH and NADP+, facilitating the conversion of energy in cellular respiration. This enzyme plays a crucial role in cellular metabolism by linking the electron transport chain to various metabolic pathways, ultimately influencing the balance between oxidative phosphorylation and biosynthetic reactions.
Yeast: Yeast is a type of single-celled fungus that plays a crucial role in fermentation, a metabolic process that converts sugars into alcohol and carbon dioxide. It is widely used in baking, brewing, and bioengineering due to its ability to efficiently produce various metabolites and enzymes. Yeast serves as a model organism in synthetic biology, allowing researchers to manipulate its genetic makeup for the development of new products and processes.