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Shikimic Acid Production in Escherichia coli: From Classical Metabolic Engineering Strategies to Omics Applied to Improve Its Production.

Martínez JA, Bolívar F, Escalante A - Front Bioeng Biotechnol (2015)

Bottom Line: Global transcriptomic analyses have been performed in SA-producing strains, resulting in the identification of possible key target genes for the design of a rational strain improvement strategy.Because possible target genes are involved in the transport, catabolism, and interconversion of different carbon sources and metabolic intermediates outside the central carbon metabolism and SA pathways, as genes involved in diverse cellular stress responses, the development of rational cellular strain improvement strategies based on omics data constitutes a challenging task to improve SA production in currently overproducing engineered strains.In this review, we discuss the main metabolic engineering strategies that have been applied for the development of efficient SA-producing strains, as the perspective of omics analysis has focused on further strain improvement for the production of this valuable aromatic intermediate.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, Universidad Nacional Autónoma de México , Cuernavaca , Mexico.

ABSTRACT
Shikimic acid (SA) is an intermediate of the SA pathway that is present in bacteria and plants. SA has gained great interest because it is a precursor in the synthesis of the drug oseltamivir phosphate (OSF), an efficient inhibitor of the neuraminidase enzyme of diverse seasonal influenza viruses, the avian influenza virus H5N1, and the human influenza virus H1N1. For the purposes of OSF production, SA is extracted from the pods of Chinese star anise plants (Illicium spp.), yielding up to 17% of SA (dry basis content). The high demand for OSF necessary to manage a major influenza outbreak is not adequately met by industrial production using SA from plants sources. As the SA pathway is present in the model bacteria Escherichia coli, several "intuitive" metabolically engineered strains have been applied for its successful overproduction by biotechnological processes, resulting in strains producing up to 71 g/L of SA, with high conversion yields of up to 0.42 (mol SA/mol Glc), in both batch and fed-batch cultures using complex fermentation broths, including glucose as a carbon source and yeast extract. Global transcriptomic analyses have been performed in SA-producing strains, resulting in the identification of possible key target genes for the design of a rational strain improvement strategy. Because possible target genes are involved in the transport, catabolism, and interconversion of different carbon sources and metabolic intermediates outside the central carbon metabolism and SA pathways, as genes involved in diverse cellular stress responses, the development of rational cellular strain improvement strategies based on omics data constitutes a challenging task to improve SA production in currently overproducing engineered strains. In this review, we discuss the main metabolic engineering strategies that have been applied for the development of efficient SA-producing strains, as the perspective of omics analysis has focused on further strain improvement for the production of this valuable aromatic intermediate.

No MeSH data available.


Related in: MedlinePlus

Relevant SA derivatives with high added value. OSF, viral inhibitor of diverse influenza virus types, including seasonal types A and B, avian virus H5N1, and human virus H1N1. (−)-Zeylenone is a compound with antiviral, anticancer, and antibiotic activities. (−)-Valiolamine, a very strong α-glucosidase with inhibitory activity against porcine intestinal enzymes sucrase, maltase, and isomaltase. [PT(datch)(SA)2] is an active compound against L1210 leukemia. 3,4-Oxo-isopropylidene-SA, with antithrombotic activity and anti-inflammatory effects. Analogs of 1α, dihydroxy-19-Nor previtamin D3 is a compound with promising applications in the treatment of osteoporosis and malignancies. Adapted from Estevez and Estevez (2012) and Diaz Quiroz et al. (2014).
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Figure 2: Relevant SA derivatives with high added value. OSF, viral inhibitor of diverse influenza virus types, including seasonal types A and B, avian virus H5N1, and human virus H1N1. (−)-Zeylenone is a compound with antiviral, anticancer, and antibiotic activities. (−)-Valiolamine, a very strong α-glucosidase with inhibitory activity against porcine intestinal enzymes sucrase, maltase, and isomaltase. [PT(datch)(SA)2] is an active compound against L1210 leukemia. 3,4-Oxo-isopropylidene-SA, with antithrombotic activity and anti-inflammatory effects. Analogs of 1α, dihydroxy-19-Nor previtamin D3 is a compound with promising applications in the treatment of osteoporosis and malignancies. Adapted from Estevez and Estevez (2012) and Diaz Quiroz et al. (2014).

Mentions: Compounds derived from the aromatic amino acid (AA) pathway play important roles in the pharmaceutical and food industries as raw materials, additives, or final products (Patnaik et al., 1995; Bongaerts, 2001; Báez et al., 2001; Yi et al., 2002; Chandran et al., 2003; Báez-Viveros et al., 2004; Gosset, 2009). This metabolic pathway is present in bacteria and plants, starting with condensation of the central carbon metabolism (CCM) intermediates phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P) to form the first AA pathway intermediate d-arabinoheptulosonate-7-phospate (DAHP). From this compound to chorismic acid (CHA), the pathway is mostly linear and represents the first part of the AA pathway, known as the common AA pathway or the shikimic acid (SA) pathway (Figure 1). One of the specific intermediates on this pathway is SA, which is a highly functionalized six-carbon cyclic compound with three asymmetric centers. Therefore, SA is an enantiomeric precursor for the production of many high valuable biological active compounds for different industries. SA is the precursor for the synthesis of compounds with diverse pharmaceutical applications, including as an antipyretic, antioxidant, anticoagulant, antithrombotic, anti-inflammatory, or analgesic agent, for the synthesis of anticancer drugs, such as (+)-zeylenone (which has been shown to inhibit nucleoside transport in Ehrlich carcinoma cells and to be cytotoxic to cultured cancer cells), and for antibacterial or hormonal applications [reviewed in Estevez and Estevez (2012), Liu et al. (2012), and Diaz Quiroz et al. (2014)] (Figure 2).


Shikimic Acid Production in Escherichia coli: From Classical Metabolic Engineering Strategies to Omics Applied to Improve Its Production.

Martínez JA, Bolívar F, Escalante A - Front Bioeng Biotechnol (2015)

Relevant SA derivatives with high added value. OSF, viral inhibitor of diverse influenza virus types, including seasonal types A and B, avian virus H5N1, and human virus H1N1. (−)-Zeylenone is a compound with antiviral, anticancer, and antibiotic activities. (−)-Valiolamine, a very strong α-glucosidase with inhibitory activity against porcine intestinal enzymes sucrase, maltase, and isomaltase. [PT(datch)(SA)2] is an active compound against L1210 leukemia. 3,4-Oxo-isopropylidene-SA, with antithrombotic activity and anti-inflammatory effects. Analogs of 1α, dihydroxy-19-Nor previtamin D3 is a compound with promising applications in the treatment of osteoporosis and malignancies. Adapted from Estevez and Estevez (2012) and Diaz Quiroz et al. (2014).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585142&req=5

Figure 2: Relevant SA derivatives with high added value. OSF, viral inhibitor of diverse influenza virus types, including seasonal types A and B, avian virus H5N1, and human virus H1N1. (−)-Zeylenone is a compound with antiviral, anticancer, and antibiotic activities. (−)-Valiolamine, a very strong α-glucosidase with inhibitory activity against porcine intestinal enzymes sucrase, maltase, and isomaltase. [PT(datch)(SA)2] is an active compound against L1210 leukemia. 3,4-Oxo-isopropylidene-SA, with antithrombotic activity and anti-inflammatory effects. Analogs of 1α, dihydroxy-19-Nor previtamin D3 is a compound with promising applications in the treatment of osteoporosis and malignancies. Adapted from Estevez and Estevez (2012) and Diaz Quiroz et al. (2014).
Mentions: Compounds derived from the aromatic amino acid (AA) pathway play important roles in the pharmaceutical and food industries as raw materials, additives, or final products (Patnaik et al., 1995; Bongaerts, 2001; Báez et al., 2001; Yi et al., 2002; Chandran et al., 2003; Báez-Viveros et al., 2004; Gosset, 2009). This metabolic pathway is present in bacteria and plants, starting with condensation of the central carbon metabolism (CCM) intermediates phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P) to form the first AA pathway intermediate d-arabinoheptulosonate-7-phospate (DAHP). From this compound to chorismic acid (CHA), the pathway is mostly linear and represents the first part of the AA pathway, known as the common AA pathway or the shikimic acid (SA) pathway (Figure 1). One of the specific intermediates on this pathway is SA, which is a highly functionalized six-carbon cyclic compound with three asymmetric centers. Therefore, SA is an enantiomeric precursor for the production of many high valuable biological active compounds for different industries. SA is the precursor for the synthesis of compounds with diverse pharmaceutical applications, including as an antipyretic, antioxidant, anticoagulant, antithrombotic, anti-inflammatory, or analgesic agent, for the synthesis of anticancer drugs, such as (+)-zeylenone (which has been shown to inhibit nucleoside transport in Ehrlich carcinoma cells and to be cytotoxic to cultured cancer cells), and for antibacterial or hormonal applications [reviewed in Estevez and Estevez (2012), Liu et al. (2012), and Diaz Quiroz et al. (2014)] (Figure 2).

Bottom Line: Global transcriptomic analyses have been performed in SA-producing strains, resulting in the identification of possible key target genes for the design of a rational strain improvement strategy.Because possible target genes are involved in the transport, catabolism, and interconversion of different carbon sources and metabolic intermediates outside the central carbon metabolism and SA pathways, as genes involved in diverse cellular stress responses, the development of rational cellular strain improvement strategies based on omics data constitutes a challenging task to improve SA production in currently overproducing engineered strains.In this review, we discuss the main metabolic engineering strategies that have been applied for the development of efficient SA-producing strains, as the perspective of omics analysis has focused on further strain improvement for the production of this valuable aromatic intermediate.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, Universidad Nacional Autónoma de México , Cuernavaca , Mexico.

ABSTRACT
Shikimic acid (SA) is an intermediate of the SA pathway that is present in bacteria and plants. SA has gained great interest because it is a precursor in the synthesis of the drug oseltamivir phosphate (OSF), an efficient inhibitor of the neuraminidase enzyme of diverse seasonal influenza viruses, the avian influenza virus H5N1, and the human influenza virus H1N1. For the purposes of OSF production, SA is extracted from the pods of Chinese star anise plants (Illicium spp.), yielding up to 17% of SA (dry basis content). The high demand for OSF necessary to manage a major influenza outbreak is not adequately met by industrial production using SA from plants sources. As the SA pathway is present in the model bacteria Escherichia coli, several "intuitive" metabolically engineered strains have been applied for its successful overproduction by biotechnological processes, resulting in strains producing up to 71 g/L of SA, with high conversion yields of up to 0.42 (mol SA/mol Glc), in both batch and fed-batch cultures using complex fermentation broths, including glucose as a carbon source and yeast extract. Global transcriptomic analyses have been performed in SA-producing strains, resulting in the identification of possible key target genes for the design of a rational strain improvement strategy. Because possible target genes are involved in the transport, catabolism, and interconversion of different carbon sources and metabolic intermediates outside the central carbon metabolism and SA pathways, as genes involved in diverse cellular stress responses, the development of rational cellular strain improvement strategies based on omics data constitutes a challenging task to improve SA production in currently overproducing engineered strains. In this review, we discuss the main metabolic engineering strategies that have been applied for the development of efficient SA-producing strains, as the perspective of omics analysis has focused on further strain improvement for the production of this valuable aromatic intermediate.

No MeSH data available.


Related in: MedlinePlus