DNA Synthesis in Nucleotide-Permeable Escherichia coli Cells. The Effects of Nucleotide Analogues on DNA Synthesis

Geider, Klaus

doi:10.1111/j.1432-1033.1972.tb01872.x

Cited by 25 publications

(11 citation statements)

References 17 publications

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“…Unlike mammals, bacteria rely on an NAD + dependent DNA ligase that is inhibited by NMN, the product of its own reaction (Chen et al, 2002;Geider, 1972;Zimmerman and Oshinsky, 1969), resulting in the accumulation of intracellular NMN during exponential growth (Olivera and Lehman, 1967). NMN is salvaged through the bacterial NMN deamidase PncC, yielding NaMN as a substrate for NAD + synthesis by the Preiss-Handler pathway (Galeazzi et al, 2011).…”

Section: Nmn Deamidation By Bacteriamentioning

confidence: 99%

Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Kim

Chalmers

Smith

et al. 2020

Preprint

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Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into NAD+ in mammals by the canonical recycling pathway, however the need for NAD+ is conserved across evolution, including bacteria in the gut microbiome, which can deamidate NMN to nicotinic acid mononucleotide (NaMN). Here, we use strategic isotope labelling studies to demonstrate a role for the gut microbiome in deamidating orally delivered NMN into NaMN prior to its uptake and incorporation in mammals. Microbiome depletion increased the overall abundance of NAD metabolites, suggesting a competition relationship. Strikingly, treatment with labelled NMN increased the production of unlabelled NAD precursors, with a greater than 3-fold increase in endogenous NR levels in the gut of antibiotics treated animals upon labelled NMN treatment. These data suggest that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation, including through the production of endogenous NR via an as-yet unidentified pathway, and demonstrate an important role for the gut microbiome in the assimilation of orally delivered NMN.

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Section: Nmn Deamidation By Bacteriamentioning

confidence: 99%

Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Kim

Chalmers

Smith

et al. 2020

Preprint

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“…01-5-H18, p. 39, 1979), and (ii) there are differences in the intrinsic susceptibility of bacterial and mammalian DNA polymerases to dideoxynucleoside triphosphates. Bacterial polymerases are strongly inhibited by dideoxynucleoside triphosphates (2,9,16), whereas the mammalian polymerases involved in cellular DNA replication are relatively insusceptible (1,16,18,19).…”

Section: Resultsmentioning

confidence: 99%

Antibacterial activity of 2',3'-dideoxyadenosine in vivo and in vitro

Beskid¹,

Eskin²,

Cleeland³

et al. 1981

Antimicrob Agents Chemother

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2',3'-Dideoxyadenosine (DDA) was shown not only to possess antibacterial activity in vitro against a variety of Enterobacteriaceae, but also to be effective in vivo, DDA was active in experimental mouse infections by the oral route against 5 Salmonella strains, 2 of 3 Arizona strains, 5 of 7 Citrobacter strains, 3 of 8 Klebsiella strains, 3 of 5 Escherichia strains, 1 of 3 Shigella strains, and 3 of 15 Serratia strains at concentrations generally well below the toxic level. Closely related compounds, with the exception of 2',3'-dideoxyinosine, were found to be inactive in vivo, indicating that a high degree of structural specificity was required for activity. The synthesis of deoxyribonucleic acid was inhibited by DDA in those strains susceptible in vitro to DDA, whereas ribonucleic acid and protein syntheses were not affected. The concentration of DDA which inhibited bacterial deoxyribonucleic acid synthesis by 50% was calculated based on the relative rates of deoxyribonucleic acid synthesis in ;the absence and in the presence of DDA. This value correlated well with the minimal inhibitory concentration determined by the in vitro broth dilution assay but not always with in vivo activity determined by the mouse protection test.

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“…Uracil residues can be introduced into DNA either by deamination of cytosine residues (1) or by incorporation of dUMP in place of dTMP during polymerization (24). Studies performed in vivo (5-8) or with cell-free systems (9)(10)(11) indicate that the frequency of stable dUMP incorporation depends largely upon the relative intracellular pool size of dUTP and dTTP. When the level of dUTP increases in relationship to that of dTTP, uracil residues accumulate in the genome of most organisms (5-11).…”

Section: Introdjctionmentioning

confidence: 99%

Purification and characterization of porcine liver DNA polymerase γ: utilitzation of dUTP and dTTP duringin vitroDNA synthesis

Mosbaugh¹

1988

Nucl Acids Res

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Porcine liver DNA polymerase gamma has been demonstrated to preferentially incorporate dTMP over dUMP during in vitro DNA synthesis. When polymerase activity was measured in standard reactions containing saturating levels of either dTTP or dUTP, the polymerization rate was slightly faster in the reaction containing dTTP. However, under conditions where both dTTP and dUTP competed, at an equal molar concentration, approximately 3-times more thymine residues were incorporated than uracil residues into DNA. Similarly, preferential incorporation of dTMP was observed on several substrates including poly (dA).oligo p(dT), poly (rA).oligo p(dT) and poly (dA-dT). The discrimination against dUMP incorporation was even more apparent with reduced levels of dUTP. These observations were consistent with the finding that the Km for DNA polymerase gamma was about 3-fold lower for dTTP (0.4 microM) than for dUTP (1.1 microM). On the other hand, the Vmax for these two reactions was very similar. Discrimination against dUMP incorporation was also observed during inhibition of polymerase gamma by dideoxyribonucleoside triphosphates. Dideoxythymidine triphosphate preferentially inhibited dUMP incorporation compared to that of dTMP, whereas ddATP, ddCTP and ddGTP inhibited both reactions equally.

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DNA Synthesis in Nucleotide-Permeable Escherichia coli Cells. The Effects of Nucleotide Analogues on DNA Synthesis

Cited by 25 publications

References 17 publications

Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Antibacterial activity of 2',3'-dideoxyadenosine in vivo and in vitro

Purification and characterization of porcine liver DNA polymerase γ: utilitzation of dUTP and dTTP duringin vitroDNA synthesis

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