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Chapter 41 : Metabolic Engineering Strategies for Production of Commodity and Fine Chemicals: Escherichia coli as a Platform Organism
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This chapter presents a summary of examples in which various metabolic engineering strategies were employed to improve microbial production of small molecules having a range of commercial value (commodity and fine chemicals). Specifically, notable achievements in engineering the biotechnological workhorse organism Escherichia coli for chemical production are described. In terms of commodity chemicals, metabolic engineering has found the most application and success toward the production of small organic acids and amino acids (perhaps with the exception of engineering E. coli to produce 1,3- propanediol from glucose), owing largely to the natural coupling between growth and production of the compounds through fermentation. Recent progress in microbial production of acetate, pyruvate, lactate, and succinate is also described followed by examples of increased amino acid production. Organic acids including acetic acid, pyruvic acid and lactic acid have been discussed in the chapter. A variety of amino acids find applications in industries including food, animal feed, pharmaceuticals, and cosmetics. Considering the low titers of amino acids obtained from wild-type E. coli cultures, improvements of the host through metabolic engineering have been impressive. Isoprenoids (or terpenoids) represent a wide variety of specialty and pharmaceutical compounds synthesized biologically by the assembly of two or more branched, five-carbon isopentenyl pyrophosphate (IPP) subunits. and mechanisms of inhibition.
E. coli primary metabolic pathways involved in production of acetate, pyruvate, lactate, and succinate. Relevant genes are listed with the corresponding transformation catalyzed. ~P represents utilization or production of ATP. Genes encoding pyruvate carboxylase (pyc) and l-specific lactate dehydrogenase (IdhL) are labeled with an asterisk to indicate that they are not native to E. coli.
L-Alanine production from pyruvate by alanine dehydrogenase (alaD).
Engineering the cysteine biosynthetic pathway (starting from serine) for production of unnatural amino acids (AA). The O-acetylserine sulfhydrylases encoded by cysK and cysM utilize sulfide as a cosubstrate to produce cysteine, but the enzymes have relaxed specificity such that addition of select, nonnative nucleophiles (R-H) results in production of unnatural amino acids. cysEfbr encodes a feedback-resistant variant of serine acetyltransferase.
Engineered biosynthesis of shikimic acid, quinic acid, and ccMA from the E. coli aromatic amino acid synthesis pathway. PCA, protocatechuic acid.
Biosynthesis of 2,3-trans-CHD starting from chorismate. The genes entC, entB, and entA encode isochorismate synthase, isochorismatase, and 2,3-dihydroxybenzoate synthase, respectively, which catalyze the corresponding reactions depicted.
(a) Two different pathways to IPP; (b) pathways to carotenoids.