Phosphoenolpyruvate Availability and the Biosynthesis of Shikimic Acid

Chandran, Sunil S.; Jiang, Yi; Draths, K. M.; Daeniken, Ralph Von; Frost, J. W.

doi:10.1021/bp025769p

Cited by 149 publications

(158 citation statements)

References 27 publications

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“…No hints for enhanced carbon flux via PEP carboxylase to oxaloacetate have been shown during PTS-independent growth and L-lysine production, since PEP carboxylase activity was comparable to that of the parental strain. In E. coli, strains engineered for PTSindependent glucose uptake showed the improved production of aromatic compounds such as phenylalanine, shikimate, and anthranilate (3,7,15,17,18,26,35,70) as a consequence of reduced pyruvate and increased PEP levels in the cells. For example, the expression of the genes for galactose permease and glucokinase in PTS-negative E. coli strains bypassed PEP usage for glucose phosphorylation and resulted in a higher yield of 3-deoxy-D-arabinoheptulosonate-7-phosphate, which was assumed to be a consequence of an increased level of PEP, the immediate precursor of 3-deoxy-D-arabinoheptulosonate-7-phosphate (18,21).…”

Section: Discussionmentioning

confidence: 99%

Phosphotransferase System-Independent Glucose Utilization in Corynebacterium glutamicum by Inositol Permeases and Glucokinases

Lindner

Seibold

Henrich

et al. 2011

Appl Environ Microbiol

103

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Phosphoenolpyruvate-dependent glucose phosphorylation via the phosphotransferase system (PTS) is the major path of glucose uptake in Corynebacterium glutamicum, but some growth from glucose is retained in the absence of the PTS. The growth defect of a deletion mutant lacking the general PTS component HPr in glucose medium could be overcome by suppressor mutations leading to the high expression of inositol utilization genes or by the addition of inositol to the growth medium if a glucokinase is overproduced simultaneously. PTSindependent glucose uptake was shown to require at least one of the inositol transporters IolT1 and IolT2 as a mutant lacking IolT1, IolT2, and the PTS component HPr could not grow with glucose as the sole carbon source. Efficient glucose utilization in the absence of the PTS necessitated the overexpression of a glucokinase gene in addition to either iolT1 or iolT2. IolT1 and IolT2 are low-affinity glucose permeases with K s values of 2.8 and 1.9 mM, respectively. As glucose uptake and phosphorylation via the PTS differs from glucose uptake via IolT1 or IolT2 and phosphorylation via glucokinase by the requirement for phosphoenolpyruvate, the roles of the two pathways for L-lysine production were tested. The L-lysine yield by C. glutamicum DM1729, a rationally engineered L-lysine-producing strain, was lower than that by its PTS-deficient derivate DM1729⌬hpr, which, however, showed low production rates. The combined overexpression of iolT1 or iolT2 with ppgK, the gene for PolyP/ATP-dependent glucokinase, in DM1729⌬hpr enabled L-lysine production as fast as that by the parent strain DM1729 but with 10 to 20% higher L-lysine yield.The Gram-positive soil bacterium Corynebacterium glutamicum is used industrially for the production of more than 2,160,000 tons of L-glutamate and more than 1,330,000 tons of L-lysine per year (Ajinomoto, Tokyo, Japan). The amino acid production with C. glutamicum is focused on glucose, fructose, and sucrose as carbon sources, with a preference for glucose (30,31). However, C. glutamicum also can use sugars like ribose and maltose, the alcohols inositol and ethanol, and organic acids like acetate, propionate, pyruvate, L-lactate, citrate, and L-glutamate as carbon and energy sources (2, 6).At the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node (PPON) (Fig. 1), the distribution of the carbon flux within the metabolism takes place and is especially important for amino acid synthesis (59). To improve L-lysine yields, the optimization of the PPON toward increased oxaloacetate supply is crucial (10, 46). Oxaloacetate utilized for L-lysine synthesis can be regenerated by PEP carboxylase (encoded by ppc) (13) or pyruvate carboxylase (pyc) (48). In terms of gluconeogenesis, oxaloacetate can be converted to either pyruvate by oxaloacetate decarboxylase (odx) (32) or to PEP by PEP carboxykinase (pck) (28). The irreversible conversion of PEP to pyruvate is catalyzed either by pyruvate kinase (pyk) with the formation of ATP (24) or by enzyme I (EI) of the PEP-dependent phosph...

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Section: Discussionmentioning

confidence: 99%

Phosphotransferase System-Independent Glucose Utilization in Corynebacterium glutamicum by Inositol Permeases and Glucokinases

Lindner

Seibold

Henrich

et al. 2011

Appl Environ Microbiol

103

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“…Successful metabolically engineered strategies resulting in high SA production in E. coli include the use of PEP:glucose phosphotransferase system (PTS)-deficient mutants (PTS -) strains in which PTS, the main glucose transport system, is inactivated, resulting in high PEP availability; 52,[71][72][73] introduction of glucose transport and phosphorylation capabilities (additional copies of the glf and glk genes from Zymomonas mobilis encoding the glucose facilitator system [Glf] 71 or the use of adaptive evolution to select E. coli derivatives that grow on glucose 74 ); modification of CCM and pentose phosphate pathway including the introduction of an additional plasmid-encoded-copy of the zwf and tktA genes encoding the glucose 6-phosphate-1-dehydrogenase (Zwf) and transketolase I (TktA I) enzymes, respectively, resulting in the increased availability of E4P;…”

Section: Microbial Production Of Samentioning

confidence: 99%

“…[71][72][73] A promising strategy by which to avoid the disadvantages associated with plasmid in engineered strains involves chromosomal integration of the ppsA, csrB, aroG fbr , aroB, aroE, and tktA genes encoding for PpsA, small regulatory RNA (CsrB), DAHPS AroG fbr , 3-dehydroquinic acid synthase (AroB), shikimic acid dehydrogenase (AroE), and TktA I, respectively, in an aroK -aroL -mutant strain, replacing their native promoters and subsequent chromosome evolution by triclosan induction. 75 These genetically modified E. coli strains with specific genetic backgrounds are grown using diverse culture conditions, which has led to the successful overproduction of SA, with yields ranging from 0.08 to 0.42 mol SA/mol glucose ( Table 2).…”

Section: Microbial Production Of Samentioning

confidence: 99%

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Quiroz¹,

Carmona²,

Bolívar³

et al. 2014

RRMC

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Aromatic metabolism comprises the shikimic acid (SA) and the aminoshikimic acid (ASA) pathways. The SA pathway is the common route for the biosynthesis of aromatic amino acids and other metabolites in bacteria, higher plants, fungi, and Apicomplexa parasites, but this pathway is absent in mammals. A variant of the SA pathway known as the ASA pathway branches off from the normal pathway in some bacteria, and its final product, 3-amino-5-hydroxybenzoic acid, is the precursor for many aminoglycoside antibiotics such as kanamycin, neomycin, butirosin, and spectinomycin. The SA pathway includes the key intermediate SA, which is the precursor for the chemical synthesis of the drug oseltamivir phosphate, known commercially as Tamiflu ® , an efficient inhibitor of the neuraminidase enzyme of the seasonal influenza viruses types A and B, avian influenza virus H5N1, and human influenza virus H1N1. Meanwhile, the intermediate of the ASA pathway, ASA, is an attractive candidate for use as the core scaffold for the synthesis of combinatorial libraries and is a potential alternative to SA as a precursor for oseltamivir phosphate synthesis. In this review, we discuss the relevance of the key intermediates SA and ASA as scaffold molecules for the synthesis of diverse chemicals. We highlight the current and potential pharmaceutical applications of these molecules and discuss the main strategies for the production of these aromatic compounds from natural sources and the application of metabolic engineering strategies in diverse bacterial strains for production through biotechnological processes.

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“…Detailed knowledge of these nodes permitted the development of strategies that allowed higher PEP availability for the biosynthesis of aromatic compounds, including the replacement of glucose transport and phosphorylation capabilities of the PTS by alternative enzymes such as the glucose facilitator and glucokinase from Zymomonas mobilis (coded by glf and glk, respectively) [26][27][28], the galactose permease and glucokinase from E. coli (coded by galP and glk, respectively) [29,30], or the use of an adaptive evolution process to select PTS − derivatives growing at high specific growth rates (μ) on glucose [31,32]. Additionally, high PEP availability has been achieved by modulation of the carbon flux from PEP to the TCA caused by the inactivation of one or both of the PYR kinases [33,34], as well as improving the recycling of PYR to PEP by a plasmid-encoded copy of PEP synthetase [35][36][37].…”

Section: Introductionmentioning

confidence: 99%

“…Apparent inability of L-TRP to totally inhibit this isoenzyme is proposed to be a mechanism to ensure a sufficient supply of CHA for the biosynthesis of other aromatic compounds when AAA are present in excess in the growth medium [3]. Specific amino acid residues involved in the allosteric sites have been identified by structural analysis of feedbackinsensitive mutant enzymes, resulting in the targeted generation of the feedback resistant (fbr) variants AroG fbr and AroF fbr [28,31,55]. Additionally to allosteric control of DAHPS isoenzymes, their transcriptional expression can be controlled by the tyr-and trp-repressors complexed with the AAA [3,11].…”

Section: Introductionmentioning

confidence: 99%

Engineering

et al. 2014

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The production of aromatic amino acids using fermentation processes with recombinant microorganisms can be an advantageous approach to reach their global demands. In addition, a large array of compounds with alimentary and pharmaceutical applications can potentially be synthesized from intermediates of this metabolic pathway. However, contrary to other amino acids and primary metabolites, the artificial channelling of building blocks from central metabolism towards the aromatic amino acid pathway is complicated to achieve in an efficient manner. The length and complex regulation of this pathway have progressively called for the employment of more integral approaches, promoting the merge of complementary tools and techniques in order to surpass metabolic and regulatory bottlenecks. As a result, relevant insights on the subject have been obtained during the last years, especially with genetically modified strains of Escherichia coli. By combining metabolic engineering strategies with developments in synthetic biology, systems biology and bioprocess engineering, notable advances were achieved regarding the generation, characterization and optimization of E. coli strains for the overproduction of aromatic amino acids, some of their precursors and related compounds. In this paper we review and compare recent successful reports dealing with the modification of metabolic traits to attain these objectives.

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Phosphoenolpyruvate Availability and the Biosynthesis of Shikimic Acid

Cited by 149 publications

References 27 publications

Phosphotransferase System-Independent Glucose Utilization in Corynebacterium glutamicum by Inositol Permeases and Glucokinases

Phosphotransferase System-Independent Glucose Utilization in Corynebacterium glutamicum by Inositol Permeases and Glucokinases

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Engineering

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