Key Points
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The rise of synthetic biology defines a new era in the metabolic engineering of microorganisms, an era characterized by the biosynthesis of biofuels and natural products through the de novo construction of biochemical pathways using parts from disparate origins. The development and effective implementation of computational tools is crucial to make such approaches possible.
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Several algorithms have been devised to find the metabolic pathways that are theoretically most suitable for thermodynamically efficient production of a certain compound. After detection of all possible pathways on the basis of enzyme classifications and/or possible chemical transformations, they can be ranked according to, for example, pathway length, thermodynamic efficiency and maximum predicted yields.
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Promising pathways can be integrated into genome-scale metabolic models of candidate host organisms to test how well the topology of their metabolic networks can accommodate the synthetic heterologous pathway. Such metabolic models can now be reconstructed rapidly because of the emergence of high-throughput model generation software, and pathway visualization tools facilitate quick and efficient analysis of modelling results.
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Various strategies are available for the computational identification of candidate parts, depending on the type and diversity of the parts that are searched for. For the identification of single enzyme-encoding genes, homology searches coupled to phylogenetic analysis can sometimes suffice. In more complex cases, automated in silico prediction of substrate specificities in enzyme families may allow more efficient prioritization of possible targets. Additionally, several algorithms have recently been developed for detecting multigene modules, such as biosynthetic operons or gene clusters.
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In order to effectively integrate foreign enzymatic parts into a given host organism, the codon usage of the genes encoding the enzymes can be matched to that of the host. Thus, the probability of obtaining efficient translation is increased. Using computer-aided design, the codon-optimized parts can then be integrated into transcriptional units with designed regulatory circuits that can be simulated in silico before commencing the DNA synthesis of the final constructs.
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There is still a wide range of opportunities for developing novel computational tools in this field. If these developments go hand-in-hand with developments in experimental approaches, the field of synthetic microbiology is likely to obtain a central position in the field of microbial biotechnology.
Abstract
As the field of synthetic biology is developing, the prospects for de novo design of biosynthetic pathways are becoming more and more realistic. Hence, there is an increasing need for computational tools that can support these efforts. A range of algorithms has been developed that can be used to identify all possible metabolic pathways and their corresponding enzymatic parts. These can then be ranked according to various properties and modelled in an organism-specific context. Finally, design software can aid the biologist in the integration of a selected pathway into smartly regulated transcriptional units. Here, we review key existing tools and offer suggestions for how informatics can help to shape the future of synthetic microbiology.
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Glossary
- Parts
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Basic building blocks that can be incorporated into a design in synthetic biology; for example, a ribosome binding site, promoter or enzyme coding sequence.
- Biosynthetic pathway
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Sequence of enzymatically catalysed reactions that convert one or more source metabolites into a product compound.
- Flux balance analysis
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Computational method for analysing a metabolic system under the assumption of metabolic steady state.
- KEGG
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The Kyoto Encyclopedia of Genes and Genomes, a portal of web databases on genomes, metabolic pathways and enzymes. The KEGG PATHWAY database contains biochemical pathways in the context of the rest of the metabolic network, and the KEGG LIGAND database contains chemical substances and the biochemical reactions that interconvert them.
- Enzyme Commission classification
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Hierarchical numerical classification of enzymes standardized by the Enzyme Commission; the complete Enzyme Commission number of an enzyme consists of four numbers, separated by dots, that define with increasing detail the enzyme class and subclasses that it belongs to.
- Metabolic flux
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Flow of metabolites through a metabolic system.
- Genome-scale metabolic models
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Models of all of the enzymatic reactions encoded in a genome, based on the genome annotation.
- Support vector machines
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Machine learning classification algorithms based on hyperplanes that separate two or more classes in a multidimensional parameter space.
- Computer-aided design
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(CAD). The use of computers for the design process in engineering, including, for example, functionalities for drafting and simulation.
- Codon usage
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Genome-specific frequency of occurrence of the different codons that can encode each amino acid.
- Orthologue
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Orthologues are genes with similar functions that derive from a common ancestor through vertical descent.
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Medema, M., van Raaphorst, R., Takano, E. et al. Computational tools for the synthetic design of biochemical pathways. Nat Rev Microbiol 10, 191–202 (2012). https://doi.org/10.1038/nrmicro2717
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DOI: https://doi.org/10.1038/nrmicro2717
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