The EcoCyc database: reflecting new knowledge about<i>Escherichia coli</i>K-12

Keseler, Ingrid M.; Mackie, Amanda; Santos-Zavaleta, Alberto; Billington, Richard; Bonavides-Martínez, César; Caspi, Ron; Fulcher, Carol A.; Gama-Castro, Socorro; Kothari, Anamika; Krummenacker, Markus; Latendresse, Mario; Muñiz-Rascado, Luis; Ong, Quang; Paley, Suzanne M.; Peralta-Gil, Martín; Subhraveti, Pallavi; Velázquez-Ramírez, David Alberto; Weaver, Daniel; Paulsen, Ian T.; Karp, Peter D.

doi:10.1093/nar/gkw1003

Cited by 535 publications

(603 citation statements)

References 46 publications

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“…The alternative possibility is that FA starvation inhibits lysine biosynthesis. In E. coli , lysine is synthesized from aspartate (Keseler et al , ). Interestingly, the two initial steps in the lysine, threonine and methionine biosynthesis pathways are common and they all utilize the common substrate aspartate 4‐semialdehyde.…”

Section: Resultsmentioning

confidence: 99%

Fatty acid starvation activates RelA by depleting lysine precursor pyruvate

Sinha

Winther

Roghanian³

et al. 2019

Molecular Microbiology

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Summary Bacteria undergoing nutrient starvation induce the ubiquitous stringent response, resulting in gross physiological changes that reprograms cell metabolism from fast to slow growth. The stringent response is mediated by the secondary messengers pppGpp and ppGpp collectively referred to as (p)ppGpp or ‘alarmone’. In Escherichia coli, two paralogs, RelA and SpoT, synthesize (p)ppGpp. RelA is activated by amino acid starvation, whereas SpoT, which can also degrade (p)ppGpp, responds to fatty acid (FA), carbon and phosphate starvation. Here, we discover that FA starvation leads to rapid activation of RelA and reveal the underlying mechanism. We show that FA starvation leads to depletion of lysine that, in turn, leads to the accumulation of uncharged tRNALys and activation of RelA. SpoT was also activated by FA starvation but to a lower level and with a delayed kinetics. Next, we discovered that pyruvate, a precursor of lysine, is depleted by FA starvation. We also propose a mechanism that explains how FA starvation leads to pyruvate depletion. Together our results raise the possibility that RelA may be a major player under many starvation conditions previously thought to depend principally on SpoT. Interestingly, FA starvation provoked a ~100‐fold increase in relA dependent ampicillin tolerance.

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Section: Resultsmentioning

confidence: 99%

Fatty acid starvation activates RelA by depleting lysine precursor pyruvate

Sinha

Winther

Roghanian³

et al. 2019

Molecular Microbiology

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“…Metabolite Set Enrichment Analysis (MSEA) was performed in Ecocyc (v. 20.1) (Keseler et al, 2017). SmartTables were created comprised of metabolites from each metabolite signature and pathways were identified using the “Enrichment and Depletion” analysis type.…”

Section: Star Methodsmentioning

confidence: 99%

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Yang

Bhargava

McCloskey

et al. 2017

Cell Host & Microbe

210

160

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SUMMARY Bactericidal antibiotics alter microbial metabolism as part of their lethality and can damage mitochondria in mammalian cells. In addition, antibiotic susceptibility is sensitive to extracellular metabolites, but it remains unknown if metabolites present at an infection site can affect either treatment efficacy or immune function. Here, we quantify local metabolic changes in the host microenvironment following antibiotic treatment for a peritoneal Escherichia coli infection. Antibiotic treatment elicits microbiome-independent changes in local metabolites but not those distal to the infection site by acting directly on host cells. The metabolites induced during treatment, such as AMP, reduce antibiotic efficacy and enhance phagocytic killing. Moreover, antibiotic treatment impairs immune function by inhibiting respiratory activity in immune cells. Collectively, these results highlight the immunomodulatory potential of antibiotics and reveal the local metabolic microenvironment to be an important determinant of infection resolution.

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“…We then explored Crp-cAMP regulation on the genes in each category in silico. Based on RegulonDB (Gama-Castro et al, 2016), Ecocyc (Keseler et al, 2017) and recent studies of Crp-cAMP regulon (Zheng et al, 2004;Shimada et al, 2011), the Crp-cAMP binding percentage in the genome is 20% (928/4639). For the upregulated genes, we found genes with promoters binding to Crp-cAMP enriched in 'carbon', 'nitrogen' and 'regulator' categories because Crp-cAMP binding percentage in each of the three categories was > 10% higher as compared to 20% (Fig.…”

Section: Cellular Functions Of Degs Identifiedmentioning

confidence: 99%

Deciphering global gene expression and regulation strategy in Escherichia coli during carbon limitation

Pan

Xiao

et al. 2018

Microbial Biotechnology

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Summary Despite decades of studies meant to analyse the bacterial response to carbon limitation, we still miss a high‐resolution overview of the situation. All gene expression changes observed in such conditions cannot solely be accounted for by the global regulator Crp either free or bound to its effector, cyclic AMP . Here, for the first time, we evaluated the response of both CDS (protein‐coding sequence) and nc RNA (non‐coding RNA ) genes to carbon limitation, revealed cellular functions of differentially expressed genes systematically, quantified the contribution of Crp‐ cAMP and other factors to regulation and deciphered regulation strategies at a genomewide scale. Approximately one‐third of the differentially expressed genes we identified responded to Crp‐ cAMP via its direct or indirect control, while the remaining genes were subject to growth rate‐dependent control or were controlled by other regulators, especially RpoS. Importantly, gene regulation mechanisms can be established by expression pattern studies. Here, we propose a comprehensive picture of how cells respond to carbon scarcity. The global regulation strategies thus exposed illustrate that the response of cell to carbon scarcity is not limited to maintaining sufficient carbon metabolism via cAMP signalling while the main response is to adjust metabolism to cope with a slow growth rate.

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The EcoCyc database: reflecting new knowledge aboutEscherichia coliK-12

Cited by 535 publications

References 46 publications

Fatty acid starvation activates RelA by depleting lysine precursor pyruvate

Fatty acid starvation activates RelA by depleting lysine precursor pyruvate

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function

Deciphering global gene expression and regulation strategy in Escherichia coli during carbon limitation

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