Phosphorylation of 1‐deoxy‐D‐xylulose by D‐xylulokinase of <i>Escherichia coli</i>

Wungsintaweekul, Juraithip; Herz, Stefan; Hecht, Stefan; Eisenreich, Wolfgang; Feicht, Richard; Rohdich, Felix; Bacher, Adelbert; Zenk, Meinhart H.

doi:10.1046/j.1432-1033.2001.01875.x

Cited by 43 publications

(10 citation statements)

References 30 publications

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“…Previous reports demonstrate labeling of downstream MEP pathway intermediates in E. coli in feeding experiments using labeled 1-deoxy-D-xylulose (DX), suggesting DX is cell permeable and undergoes intracellular phosphorylation at some level to produce DXP (38, 39) . Here, partial rescue of BAP inhibitory activity is observed when the growth medium is supplemented with DX (50% reduction in growth inhibition by BAP in the presence of DX) (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate

et al. 2013

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The unique methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis is essential in most bacterial pathogens. The first enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes a distinct thiamin diphosphate (ThDP)-dependent reaction to form DXP from D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate and represents a potential anti-infective drug target. We have previously demonstrated that the unnatural bisubstrate analog, butylacetylphosphonate (BAP), exhibits selective inhibition of Escherichia coli DXP synthase over mammalian ThDP-dependent enzymes. Here, we report the selective inhibition by BAP against recombinant DXP synthase homologs from Mycobacterium tuberculosis, Yersinia pestis, and Salmonella enterica. We also demonstrate antimicrobial activity of BAP against both Gram-negative and Gram-positive strains (including E. coli, S. enterica, Bacillus anthracis), and several clinically isolated pathogens. Our results suggest a mechanism of action involving inhibition of DXP synthase and show that BAP acts synergistically with established antimicrobial agents, highlighting a potential strategy to combat emerging resistance in bacterial pathogens.

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Section: Resultsmentioning

confidence: 99%

Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate

et al. 2013

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“…1-Deoxy- d -xylulose 5-phosphate (DXP) is the first C 5 precursor of the MEP pathway (Scheme 2). Bacteria and plant cell cultures incorporate, however, into isoprenoids the non-phosphorylated free 1-deoxy- d -xylulose (DX), which has to be phosphorylated by a non-specific d -xylulose kinase into DXP before entering the MEP pathway [39,40]. A possible contribution of the MEP pathway to the isoprenoid biosynthesis in E. lathyris was thus investigated using (5,5- 2 H 2 )deoxy- d -xylulose added to the culture medium of plantlets grown in axenic conditions (1 mM) [23,41].…”

Section: Resultsmentioning

confidence: 99%

Biosynthesis of Isoprene Units in Euphorbia lathyris Laticifers vs. Other Tissues: MVA and MEP Pathways, Compartmentation and Putative Endophytic Fungi Contribution

et al. 2019

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Euphorbia species are characterized by a net of laticifers producing large amounts of triterpenes. These hydrocarbon-like metabolites can be converted into fuel by the methods of the oil industry. Euphorbia lathyris is easily grown at an industrial scale. In an attempt to increase its triterpene production, the metabolic pathways leading to isoprenoid were investigated by incorporation of 13C labeled glucose and mevalonate and 2H labeled deoxyxylulose as well as by natural abundance isotope ratio GC-MS. Latex triterpenes are exclusively synthesized via the mevalonate (MVA) pathway: this may orient future search for improving the triterpene production in E. lathyris. Phytosterols and their precursors are mainly derived from MVA pathway with a slight contribution of the methylerythritol phosphate (MEP) pathway, whereas phytol is issued from MEP pathway with a minor contribution of the MVA pathway: this is in accordance with the metabolic cross-talk between cytosolic and plastidial compartments in plants. In addition, hopenol B behaved differently from the other latex triterpenes. Its 13C isotope abundance after incorporation of 13C labeled glucose and its natural abundance δ2H signature clearly differed from those of the other latex triterpenes indicating another metabolic origin and suggesting that it may be synthesized by an endophytic fungus.

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“…Retro-biosynthetic analysis applies the logic of retrosynthesis from organic chemistry to the modular reconstruction of metabolic pathways . Our analysis began with the insight of Wungsintaweekul et al that DXP could be generated in vivo by the aberrant activity of the enzyme xylulose kinase (XK), encoded by the native E. coli gene xylB . We hypothesized that a non-native reaction with an E. coli aldolase might produce the 1-deoxyxylulose scaffold by a syn -aldol addition of the donor hydroxyacetone (HA) into the acceptor molecule glycolaldehyde (GA).…”

Section: Resultsmentioning

confidence: 99%

Designing a New Entry Point into Isoprenoid Metabolism by Exploiting Fructose-6-Phosphate Aldolase Side Reactivity of Escherichia coli

2017

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The 2C-methyl-d-erythritol-4-phosphate (MEP) pathway in Escherichia coli has been highlighted for its potential to provide access to myriad isoprenoid chemicals of industrial and therapeutic relevance and discover antibiotic targets to treat microbial human pathogens. Here, we describe a metabolic engineering strategy for the de novo construction of a biosynthetic pathway that produces 1-dexoxy-d-xylulose-5-phosphate (DXP), the precursor metabolite of the MEP pathway, from the simple and renewable starting materials d-arabinose and hydroxyacetone. Unlike most metabolic engineering efforts in which cell metabolism is reprogrammed with enzymes that are highly specific to their desired reaction, we highlight the promiscuous activity of the native E. coli fructose-6-phosphate aldolase as central to the metabolic rerouting of carbon to DXP. We use mass spectrometric isotopomer analysis of intracellular metabolites to show that the engineered pathway is able to support in vivo DXP biosynthesis in E. coli. The engineered DXP synthesis is further able to rescue cells that were chemically inhibited in their ability to produce DXP and to increase terpene titers in strains harboring the non-native lycopene pathway. In addition to providing an alternative metabolic pathway to produce isoprenoids, the results here highlight the potential role of pathway evolution to circumvent metabolic inhibitors in the development of microbial antibiotic resistance.

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Phosphorylation of 1‐deoxy‐D‐xylulose by D‐xylulokinase of Escherichia coli

Cited by 43 publications

References 30 publications

Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate

Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate

Biosynthesis of Isoprene Units in Euphorbia lathyris Laticifers vs. Other Tissues: MVA and MEP Pathways, Compartmentation and Putative Endophytic Fungi Contribution

Designing a New Entry Point into Isoprenoid Metabolism by Exploiting Fructose-6-Phosphate Aldolase Side Reactivity of Escherichia coli

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