Metabolic pathway engineering

Kennedy, J., Murli, S. and Kealey, J.T. (2003) 6-Deoxyerythronolide B analogue production in Escherichia coli through metabolic pathway engineering. Biochemistry, 42, 14342. 

Mutka, S.C., Bondi, S.M., Carney, J.R. et al. (2006) Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Research, 6, 4047. 

Another example where metabolic pathway engineering has made a dramatic impact is in the biodegradable polymer field. One of the most widely studied polymers in this family is poly-P-hydroxybutyrate (PHB) (64). A related member of the poly-P-hydroxyalkanoate (PHA) family commercialized by Imperial Chemical Industries (ICI), which later became Zeneca Bio Products,... 

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

The combination of identifying metabolic compounds that are accessible by state-of-the-art techniques of metabolic pathway engineering, and examination of their synthetic application potential implies a number of advantages when compared with other current approaches to the production of new compound classes. On the one hand, this approach is based on sustainable access and the production of compounds by a safe and environmental friendly route (green chemistry). On the other hand, the amount of functionalization makes it possible to apply diversity-oriented chemical methods for modification (combinatorial chemistry). 

Deanda, K., Zhang, M., Eddy, C., Picataggio, S. (1996) Development of an arabinose-fermenting Zymomonas mobilis strain by metabolic pathway engineering. Appl. Environ. Microbiol. 62,4465 1470. 

Metabolic pathway engineering [125] is used to optimise the production of the required product based on the amount of substrate (usually biomass-derived) consumed. A so-called biobased economy is envisaged in which commodity chemicals (including biofuels), specialty chemicals such as vitamins, flavors and fragrances and industrial monomers will be produced in biorefineries (see Chapter 8 for a more detailed discussion). 

In the cases described below we will generally focus on metabolic pathway engineering rather than on classical strain improvement, for obvious reasons. One should be aware, however, that the classical approach has strengths that can make it a powerful partner of the rational approach. Thus, regulation problems have been addressed by the development of a feedback-resistant enzyme, using selective pressure and random mutagenesis as described above, in a research species, followed by introduction of the altered gene in the production species via recombinant techniques. 

The need for novel catalytic processes is clear and, as discussed in Chapter 9, combining catalytic steps into cascade processes, thus obviating the need for isolation of intermediate products, results in a further optimization of both the economics and the environmental footprint of the process. In vivo this amounts to metabolic pathway engineering [20] of the host microorganism (see Chapter 8) and in vitro it constitutes a combination of chemo- and/or biocatalytic steps in series and is referred to as cascade catalysis (see Chapter 9). Metabolic engineering involves, by necessity, renewable raw materials and is a vital component of the future development of renewable feedstocks for fuels and chemicals. 

Metabolic pathway engineering involves the directed improvement of product formation or cellular properties through the modification of specific biochemical... 

Metabolic pathway engineering has numerous applications in food, agriculture, chemical, and pharmaceutical industries. Examples include, but are not limited to, increasing the yield of antibiotics, biosynthetic precursors, or polymers, expanding the metabolic capacity to degrade harmful compounds, or producing novel compounds that cannot be found in nature. 

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