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Acetyl-CoA synthetase overexpression in Escherichia coli demonstrates more efficient acetate assimilation and lower acetate accumulation: a potential tool in metabolic engineering.

The overexpression of acetyl-CoA (CoA) synthetase (ACS) in Escherichia coli showed significant reduction in acetate during glucose fermentation. It also greatly enhanced acetate assimilation when acetate was used as a carbon source. These features are ideal for applications in metabolic engineering. ACS overexpression can be strategically applied to reduce acetate byproduct, recover wasted carbon, and redirect carbon flux toward more favorable pathways. The native acs gene was cloned and overexpressed in E. coli. Studies showed significant effects on acetate production and assimilation in cultures grown in minimal and complex media with glucose or acetate as the carbon source.

Acetate-CoA Ligase↗

Metabolic engineering and applications of flavonoids.

During the past decade, the increasing knowledge of flavonoid biosynthesis and the important function of flavonoid compounds in plants and in human and animal nutrition have made the biosynthetic pathways to flavonoids and isoflavonoids excellent targets for metabolic engineering. Recent strategies have included introducing novel structural or regulatory genes, and the antisense or sense suppression of genes in these pathways.

Flavonoids↗

Phenylalanine production by metabolically engineered Corynebacterium glutamicum with the pheA gene of Escherichia coli.

The bifunctional enzyme chorismate mutase (CM)-prephenate dehydratase (PD), which is encoded by the pheA gene of Escherichia coli, catalyses the two consecutive key steps in phenylalanine biosynthesis. To utilize the enzyme for metabolic engineering of phenylalanine-producing Corynebacterium glutamicum KY10694, the intact gene was cloned on a multicopy vector to yield pEA11.C. glutamicum cells transformed with pEA11 exhibited a more than tenfold increase in CM and PD activities relative to the host cells. Moreover, the level of pheA expression was further elevated a fewfold when cells were starved of phenylalanine, suggesting that the attenuation regulation of pheA expression functions in heterogeneous C. glutamicum. Plasmid pEA11 encoding the wild-type enzyme was mutated to yield pEA22, which specified CM-PD exhibiting almost complete resistance to end-product inhibition. When pEA22 was introduced into KY10694, both the activities of CM and PD were highly maintained throughout the cultivation, thus leading to a 35% increased production (23 g/l) of phenylalanine.

Biotechnology↗

Metabolic engineering of aminocoumarins: inactivation of the methyltransferase gene cloP and generation of new clorobiocin derivatives in a heterologous host.

Aminocoumarin antibiotics are highly potent inhibitors of bacterial gyrase and represent a class of antibiotics that are very suitable for the generation of new compounds by metabolic engineering. In this study, the putative methyltransferase gene cloP in the biosynthetic gene cluster of clorobiocin was inactivated. Expression of the modified gene cluster in the heterologous host Streptomyces coelicolor M512 gave three new aminocoumarin antibiotics. The structures of the new compounds were elucidated by MS and 1H NMR, and their antibacterial activities were determined. All three compounds lacked clorobiocin's methyl group at 4-OH of the deoxysugar moiety, noviose. They differed from each other in the position of the 5-methylpyrrole-2-carbonyl group, which was found to be attached to either 2-OH, 3-OH or 4-OH of noviose. Attachment at 4-OH resulted in the highest antibacterial activity. This is the first time that an aminocoumarin antibiotic acylated at 4-OH in noviose has been detected.

Acylation↗

Enhancement of folates in plants through metabolic engineering.

Humans depend on plants as a major source of dietary folates. Inadequate dietary levels of the vitamin folate can lead to megaloblastic anemia, birth defects, impaired cognitive development, and increased risk of cardiovascular disease and cancer. The biofortification of folate levels in food crops is a target for metabolic engineering. Folates are synthesized de novo from pterins and para-amino benzoic acid, which are subsequently combined to form dihydropteroate, the direct precursor to dihydrofolate. We postulated that GTP cyclohydrolase-1, which catalyzes the first committed step in pterin biosynthesis, was a rate-limiting step in pterin synthesis in plants and, therefore, in folate synthesis. On this basis, we proposed that the expression of an unregulated bacterial GTP cyclohydrolase-1 in plants would increase pterin biosynthesis with a concomitant enhancement of folate levels. The folE gene encoding GTP cyclohydrolase-1 was cloned from Escherichia coli and introduced into Arabidopsis thaliana through plant transformation. The expression of bacterial GTP cyclohydrolase-1 in transgenic Arabidopsis resulted in a 1,250-fold and 2- to 4-fold enhancement of pterins and folates, respectively. These results helped to identify other potential factors regulating folate synthesis, suggesting ways to further enhance folate levels in food crops.

Arabidopsis↗

Metabolic engineering of the E. coli L-phenylalanine pathway for the production of D-phenylglycine (D-Phg).

D-phenylglycine (D-Phg) is an important side chain building block for semi-synthetic penicillins and cephalosporins such as ampicillin and cephalexin. To produce d-Phg ultimately from glucose, metabolic engineering was applied. Starting from phenylpyruvate, which is the direct precursor of L-phenylalanine, an artificial D-Phg biosynthesis pathway was created. This three-step route is composed of the enzymes hydroxymandelate synthase (HmaS), hydroxymandelate oxidase (Hmo), and the stereoinverting hydroxyphenylglycine aminotransferase (HpgAT). Together they catalyse the conversion of phenylpyruvate via mandelate and phenylglyoxylate to D-Phg. The corresponding genes were obtained from Amycolatopsis orientalis, Streptomyces coelicolor, and Pseudomonas putida. Combined expression of these activities in E. coli strains optimized for the production of L-phenylalanine resulted in the first completely fermentative production of D-Phg.

Escherichia coli↗

Performance testing of Zymomonas mobilis metabolically engineered for cofermentation of glucose, xylose, and arabinose.

IOGEN Corporation of Ottawa, Canada, has recently built a 40t/d biomass-to-ethanol demonstration plant adjacent to its enzyme production facility. It has partnered with the University of Toronto to test the C6/C5 cofermenta-tion performance characteristics of the National Renewable Energy Labora-tory's metabolically engineered Zymomonas mobilis using various biomass hydrolysates. IOGEN's feedstocks are primarily agricultural wastes such as corn stover and wheat straw. Integrated recombinant Z. mobilis strain AX101 grows on D-xylose and/or L-arabinose as the sole carbon/energy sources and ferments these pentose sugars to ethanol in high yield. Strain AX101 lacks the tetracycline resistance gene that was a common feature of other recombinant Zm constructs. Genomic integration provides reliable cofermentation performance in the absence of antibiotics, another characteristic making strain AX101 attractive for industrial cellulosic ethanol production. In this work, IOGEN's biomass hydrolysate was simulated by a pure sugar medium containing 6% (w/v) glucose, 3% xylose, and 0.35% arabinose. At a level of 3 g/L (dry solids), corn steep liquor with inorganic nitrogen (0.8 g/L of ammonium chloride or 1.2 g/L of diammonium phosphate) was a cost-effective nutritional supplement. In the absence of acetic acid, the maximum volumetric ethanol productivity of a continuous fermentation at pH 5.0 was 3.54 g/L x h. During prolonged continuous fermentation, the efficiency of sugar-to-ethanol conversion (based on total sugar load) was maintained at >85%. At a level of 0.25% (w/v) acetic acid, the productivity decreased to 1.17 g/L x h at pH 5.5. Unlike integrated, xylose-utilizing rec Zm strain C25, strain AX101 produces less lactic acid as byproduct, owing to the fact that the Escherichia coli arabinose genes are inserted into a region of the host chromosome tentatively assigned to the gene for D-lactic acid dehydrogenase. In pH-controlled batch fermentations with sugar mixtures, the order of sugar exhaustion from the medium was glucose followed by xylose and arabinose. Both the total sugar load and the sugar ratio were shown to be important determinants for efficient cofermentation. Ethanol at a level of 3% (w/v) was implicated as both inhibitory to pentose fermentation and as a potentiator of acetic acid inhibition of pentose fermentation at pH 5.5. The effect of ethanol may have been underestimated in other assessments of acetic acid sensitivity. This work underscores the importance of employing similar assay conditions in making comparative assessments of biocatalyst fermentation performance.

Arabinose↗

Alternative pathways of galactose assimilation: could inverse metabolic engineering provide an alternative to galactosemic patients?

The galactose assimilation pathway has been extensively studied as an example of a genetic regulatory switch. Besides the importance of this pathway as a tool in basic biological research, unraveling its structure and regulation is also of major medical importance. Impairment of galactose assimilation is the cause of the genetic metabolic disease known as "galactosemia", while the in vivo activity of the pathway affects the production of glycans. The latter have been connected to tumor metastasis, anti-cancer drug resistance and various cardiovascular diseases. Despite the vast amount of studies, however, galactose assimilation and its interaction with other parts of the metabolic network have not been fully elucidated yet. In yeast and higher eukaryotes, it is still being studied as comprising only the linear Leloir pathway. Recent observations, however, indicate that alternative pathways of galactose assimilation identified in prokaryotes and fungi might also be present in yeast. Such a result is valuable per se, because it could lead to the discovery of these pathways in humans. Even more importantly, these pathways provide alternative phenotypes with known genetic fingerprints that can be used in the context of classical and inverse metabolic engineering to examine and treat the mechanisms of defects of galactose assimilation.

Animals↗

Enhancing the atom economy of polyketide biosynthetic processes through metabolic engineering.

Polyketides, a large family of bioactive natural products, are synthesized from building blocks derived from alpha-carboxylated Coenzyme A thioesters such as malonyl-CoA and (2S)-methylmalonyl-CoA. The productivity of polyketide fermentation processes in natural and heterologous hosts is frequently limited by the availability of these precursors in vivo. We describe a metabolic engineering strategy to enhance both the yield and volumetric productivity of polyketide biosynthesis. The genes matB and matC from Rhizobium trifolii encode a malonyl-CoA synthetase and a putative dicarboxylate transport protein, respectively. These proteins can directly convert exogenous malonate and methylmalonate into their corresponding CoA thioesters with an ATP requirement of 2 mol per mol of acyl-CoA produced. Heterologous expression of matBC in a recombinant strain of Streptomyces coelicolor that produces the macrolactone 6-deoxyerythronolide B results in a 300% enhancement of macrolactone titers. The unusual efficiency of the bioconversion is illustrated by the fact that approximately one-third of the methylmalonate units added to the fermentation medium are converted into macrolactones. The direct conversion of inexpensive feedstocks such as malonate and methylmalonate into polyketides represents the most carbon- and energy-efficient route to these high value natural products and has implications for cost-effective fermentation of numerous commercial and development-stage small molecules.

Acyl Coenzyme A↗

Metabolic engineering of Escherichia coli for industrial production of glucosamine and N-acetylglucosamine.

Glucosamine and N-acetylglucosamine are currently produced by extraction and acid hydrolysis of chitin from shellfish waste. Production could be limited by the amount of raw material available and the product potentially carries the risk of shellfish protein contamination. Escherichia coli was modified by metabolic engineering to develop a fermentation process. Over-expression of glucosamine synthase (GlmS) and inactivation of catabolic genes increased glucosamine production by 15 fold, reaching 60 mg l(-1). Since GlmS is strongly inhibited by glucosamine-6-P, GlmS variants were generated via error-prone PCR and screened. Over-expression of an improved enzyme led to a glucosamine titer of 17 g l(-1). Rapid degradation of glucosamine and inhibitory effects of glucosamine and its degradation products on host cells limited further improvement. An alternative fermentation product, N-acetylglucosamine, is stable, non-inhibitory to the host and readily hydrolyzed to glucosamine under acidic conditions. Therefore, the glucosamine pathway was extended to N-acetylglucosamine by over-expressing a heterologous glucosamine-6-P N-acetyltransferase. Using a simple and low-cost fermentation process developed for this strain, over 110 g l(-1) of N-acetylglucosamine was produced.

Acetylglucosamine↗

Directed evolution of metabolically engineered Escherichia coli for carotenoid production.

We have previously introduced a reconstructed isoprenoid pathway into Escherichia coli that exhibits amplified biosynthetic flux to geranylgeranyl diphosphate (GGPP), a common isoprenoid precursor. It was shown that GGPP synthase is an important rate-controlling enzyme in this reconstructed isoprenoid pathway. In this investigation, we applied directed evolution to GGPP synthase from Archaeoglobus fulgidus to enable the enhanced production of carotenoids in metabolically engineered E. coli. Eight mutants were isolated, and the best one increased lycopene production by 100%. Among the mutants that were isolated, mutation points were clustered in four "hot regions". The "hottest" region is located in the sequence upstream of the coding region, which presumably improves the expression level of the enzyme. The other three are within the coding sequence and are believed to improve the enzyme-specific activity in E coli. These results demonstrate that modulating both enzymatic expression and specific activity are important for optimizing the metabolic flux distribution.

Base Sequence↗

Metabolic engineering of plant secondary products.

Plants interact with their environment by producing a diverse array of secondary metabolites. Many of these compounds are valued for their medicinal, industrial or agricultural properties. Other secondary products are toxic or otherwise undesirable and can reduce the commercial value of crops. Gene transfer technology offers new opportunities to modify directly plant secondary product synthesis through metabolic engineering. This article reviews some of the strategies which have been used to increase or decrease the synthesis of specific plant metabolites, as well as methods for expanding the biosynthetic capabilities of individual species.

Gene Expression↗

Metabolic engineering of the carotenoid biosynthetic pathway in the yeast Xanthophyllomyces dendrorhous (Phaffia rhodozyma).

The crtYB locus was used as an integrative platform for the construction of specific carotenoid biosynthetic mutants in the astaxanthin-producing yeast Xanthophyllomyces dendrorhous. The crtYB gene of X. dendrorhous, encoding a chimeric carotenoid biosynthetic enzyme, could be inactivated by both single and double crossover events, resulting in non-carotenoid-producing transformants. In addition, the crtYB gene, linked to either its homologous or a glyceraldehyde-3-phosphate dehydrogenase promoter, was overexpressed in the wild type and a beta-carotene-accumulating mutant of X. dendrorhous. In several transformants containing multiple copies of the crtYB gene, the total carotenoid content was higher than in the control strain. This increase was mainly due to an increase of the beta-carotene and echinone content, whereas the total content of astaxanthin was unaffected or even lower. Overexpression of the phytoene synthase-encoding gene (crtI) had a large impact on the ratio between mono- and bicyclic carotenoids. Furthermore, we showed that in metabolic engineered X. dendrorhous strains, the competition between the enzymes phytoene desaturase and lycopene cyclase for lycopene governs the metabolic flux either via beta-carotene to astaxanthin or via 3,4-didehydrolycopene to 3-hydroxy-3'-4'-didehydro-beta-psi-caroten-4-one (HDCO). The monocylic carotenoid torulene and HDCO, normally produced as minority carotenoids, were the main carotenoids produced in these strains.

Alkyl and Aryl Transferases↗

Metabolic engineering of fatty acid biosynthesis in plants.

Fatty acids are the most abundant form of reduced carbon chains available from nature and have diverse uses ranging from food to industrial feedstocks. Plants represent a significant renewable source of fatty acids because many species accumulate them in the form of triacylglycerol as major storage components in seeds. With the advent of plant transformation technology, metabolic engineering of oilseed fatty acids has become possible and transgenic plant oils represent some of the first successes in design of modified plant products. Directed gene down-regulation strategies have enabled the specific tailoring of common fatty acids in several oilseed crops. In addition, transfer of novel fatty acid biosynthetic genes from noncommercial plants has allowed the production of novel oil compositions in oilseed crops. These and future endeavors aim to produce seeds higher in oil content as well as new oils that are more stable, are healthier for humans, and can serve as a renewable source of industrial commodities. Large-scale new industrial uses of engineered plant oils are on the horizon but will require a better understanding of factors that limit the accumulation of unusual fatty acid structures in seeds.

Crops, Agricultural↗

Identification of a developmental chemoattractant in Myxococcus xanthus through metabolic engineering.

Fruiting body formation of Myxococcus xanthus requires the ordered migration of tens of thousands of cells by using a form of surface motility known as gliding and chemical signal(s) that have yet to be elucidated. Directed movement is regulated by phosphatidylethanolamine (PE) purified from M. xanthus cell membranes. Because the purified PE preparation contains a remarkably diverse mixture of fatty acids, metabolic engineering was used to elucidate the biologically active fatty acid component. The mutational block in an esg mutant, which renders it defective in producing primers for branched-chain fatty acid biosynthesis, was bypassed with one of a series of primers that enriches for a particular family of branched-chain fatty acids. Each PE enrichment was observed for chemotactic activity by using an excitation assay and for fatty acid content. The excitation activity of a PE preparation was generally proportional with the concentration of the fatty acid 16:1 omega 5c. 1,2-O-Bis[11-(Z)-hexadecenoyl]-sn-glycero-3-phosphoethanolamine (PE-16:1 omega 5c/16:1 omega 5c) was synthesized and elicited an excitation peak at 2 ng. This peak activity occurred at a 1,000-fold lower concentration than dilauroyl PE (PE-12:0/12:0) and the peak magnitude was 2-fold higher. PE containing 16:1 omega 5c is likely to play a role in development because it is active at physiological concentrations and only under developmental conditions.

Chemotactic Factors↗

Metabolic Engineering of Probiotic Saccharomyces boulardii Enables Intestinal 3-Hydroxybutyrate Delivery and Alters Short-Chain Fatty Acid Profiles in Mice.

3-Hydroxybutyric acid (3-HB) is a bioactive ketone body involved in the regulation of intestinal inflammation and metabolic homeostasis. Although engineered bacterial probiotics have been developed for localized 3-HB delivery, their susceptibility to antibacterial antibiotics may limit their use during concurrent antibiotic treatment. The probiotic yeast Saccharomyces boulardii offers an alternative host for intestinal 3-HB delivery because of its compatibility with antibacterial antibiotics and the availability of well-established genetic engineering tools. Here, we engineered S. boulardii for 3-HB production using Cas9-mediated genome editing. A heterologous 3-HB biosynthetic pathway was introduced into S. boulardii MYA-797, and endogenous acetyl-CoA and ethanol metabolism was subsequently rewired by overexpressing ACS1, deleting ADH1, and overexpressing ADH7. The optimized strain, SbDY02, produced 1.7 g/L 3-HB under microaerobic conditions. Oral administration of SbDY02 to C57BL/6J mice increased fecal 3-HB and short-chain fatty acid (SCFA) concentrations by 1.89-fold and 1.68-fold, respectively, compared with mice receiving the parental strain. Repeated administration also increased fecal acetate and circulating total SCFAs, butyrate, and propionate. In human colonic epithelial cells, purified 3-HB attenuated lipopolysaccharide-induced p38 MAPK phosphorylation, supporting its direct activity toward inflammation-associated epithelial signaling. To our knowledge, this study provides the first demonstration of a 3-HB-producing probiotic yeast and links central metabolic engineering of S. boulardii with increased 3-HB availability, altered SCFA profiles, and a host-relevant epithelial response.

3-hydroxybutyrate↗

Process development and metabolic engineering for the overproduction of natural and unnatural polyketides.

Polyketide natural products are a rich source of bioactive substances that have found considerable use in human health and agriculture. Their complex structures require that they be produced via fermentation processes. This review describes the strategies and challenges used to develop practical fermentation strains and processes for polyketide production. Classical strain improvement procedures, process development methods, and metabolic engineering approaches are described. The elucidation of molecular mechanisms that underlie polyketide biosynthesis has played an important role in each of these areas over the past few years.

Biological Factors↗

Metabolic engineering of carotenoid biosynthesis in Escherichia coli by ordered gene assembly in Bacillus subtilis.

We attempted to optimize the production of zeaxanthin in Escherichia coli by reordering five biosynthetic genes in the natural carotenoid cluster of Pantoea ananatis. Newly designed operons for zeaxanthin production were constructed by the ordered gene assembly in Bacillus subtilis (OGAB) method, which can assemble multiple genes in one step using an intrinsic B. subtilis plasmid transformation system. The highest level of production of zeaxanthin in E. coli (820 microg/g [dry weight]) was observed in the transformant with a plasmid in which the gene order corresponds to the order of the zeaxanthin metabolic pathway (crtE-crtB-crtI-crtY-crtZ), among a series of plasmids with circularly permuted gene orders. Although two of five operons using intrinsic zeaxanthin promoters failed to assemble in B. subtilis, the full set of operons was obtained by repressing operon expression during OGAB assembly with a p(R) promoter-cI repressor system. This result suggests that repressing the expression of foreign genes in B. subtilis is important for their assembly by the OGAB method. For all tested operons, the abundance of mRNA decreased monotonically with the increasing distance of the gene from the promoter in E. coli, and this may influence the yield of zeaxanthin. Our results suggest that rearrangement of biosynthetic genes in the order of the metabolic pathway by the OGAB method could be a useful approach for metabolic engineering.

Bacillus subtilis↗