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J Biol Chem, Vol. 275, Issue 6, 3931-3935, February 11, 2000
From the The ATP and GTP pools of Escherichia
coli have recently been reported to increase approximately
10-fold with increasing growth rates in the range from 0.4 to 1.4 generations/hour (Gaal, T., Bartlett, M. S., Ross, W., Turnbough,
C. L., and Gourse, R. L. (1997) Science 278, 2092-2097). Moreover, it was proposed that this variation of the
nucleotide pools, particularly the ATP pool, might be responsible for
the well known growth rate-dependent regulation of rRNA
synthesis in E. coli. To test this hypothesis we have
measured the nucleoside triphosphate pools as a function of growth rate
for several E. coli strains. We found that the size of all
four RNA precursor pools are essentially invariant with growth rate, in
the range from 0.5 to 2.3 generations/hour. Nevertheless we observed
the expected growth rate-dependent increase of RNA
accumulation in these strains. In light of these results, it seems
unlikely that nucleotide pool variations should be responsible for the
growth rate-dependent regulation of rRNA synthesis.
It has been known for more than 30 years that the ribosome content
of bacterial cells increases with increasing growth rates, governed by
regulatory mechanisms which adjust the rate of ribosome biosynthesis to
match the available resources present in the growth medium (for
reviews, see Refs. 1 and 2). The seven rRNA operons of
Escherichia coli are each preceded by two unusually strong
promoters and are influenced by several elaborate control mechanisms.
These include transcriptional activation by the FIS protein, repression
by the regulatory nucleotide guanosine 5',3'-bispyrophosphate (ppGpp),1 as well as an
antitermination mechanism that depends on the interaction of RNA
polymerase with several protein factors (reviewed in Ref. 2).
While it is generally accepted that ppGpp is responsible for the abrupt
decrease of rRNA synthesis that occurs in response to sudden
restrictions of the amino acid or carbon source supply, the mechanisms
responsible for the growth rate-dependent regulation of
rRNA synthesis during exponential growth have been a subject of
controversy (reviewed in Ref. 3). Many observations indicate that
growth rate-dependent control of rRNA synthesis may be
achieved by a feedback-mechanism, which somehow senses the presence of excess functional ribosomes and regulates rRNA transcription
accordingly (4). However, the molecular nature of the feedback signal
generated by excess translation has remained obscure.
Recently Gaal et al. (5) showed that the activity of the
ribosomal RNA P1 promoters in vitro correlates specifically
with the concentration of the initiating nucleotide, which is GTP for the rrnD operon and ATP for the remaining six ribosomal RNA
operons of E. coli. Moreover, it was reported that the ATP
and GTP pools increase approximately 10-fold with increasing growth
rates in the range from 0.4 to 1.4 generations/h. Based on these
observations it was proposed that the ATP and GTP pool variations may
be responsible for the growth rate-dependent regulation of
rRNA synthesis in vivo. Furthermore, it was proposed that
the size of the ATP and GTP pools might constitute the elusive feedback
signal that is sensed by the ribosomal RNA operons as an indicator of
the translational capacity in the cell. Excessive translation should
drain these nucleotide pools resulting in a reduction of ribosome
synthesis, whereas insufficient translational activity should cause an
increase of the nucleoside triphosphate (NTP) pools, thereby increasing ribosome synthesis.
Here we have reinvestigated the relationship between growth rate and
the size of the NTP pools. We found that the ATP, GTP, CTP, and UTP
pools of several E. coli strains were essentially invariant
with growth rate. Nevertheless, these strains showed the normal growth
rate-dependent increase of RNA accumulation. In light of
these results we find it unlikely that growth
rate-dependent regulation of ribosome synthesis should be
mediated by variation of the ATP or GTP pools. Moreover, we argue that
these nucleotide pools do not function as sensitive feedback signals
reflecting the total translational activity of the cell, since they are
essentially unaffected by perturbations of the translation process.
Bacterial Strains
The bacterial strains used in this study are all derivatives of
E. coli K12.
CN1539--
ara CN1709--
F MG1655--
F CF7968--
F Measurements of Nucleotide Pools
Bacteria were grown with shaking in Tris-buffered medium (10)
with the phosphate concentration lowered to 0.3 mM. The
medium was supplemented with 1 µg/ml thiamine, and the different
carbon sources were added to a final concentration of 0.2%. When
appropriate cultures were supplemented with all 20 amino acids in the
concentrations specified by Neidhardt et al. (11).
Procedures for labeling of cultures with [32P]phosphate
and for determination of nucleotide pools by thin layer chromatography
have been described previously (12). These experiments were performed
two or three times for each strain with similar results. The data shown
in Fig. 1 are from a single representative experiment.
Measurements of RNA Accumulation
The accumulation of total RNA per A436
was determined by measuring the incorporation of
32P-phosphate into acid-precipitable, KOH-labile material
by a modification of the procedure described by Vogel et al.
(13). Briefly, [32P]phosphate-labeled samples, harvested
as for nucleotide determinations, were mixed with 1 ml of 0.5 M perchloric acid containing unlabeled cells
(A436 = 1). After 10 min on ice the acid
precipitate was collected by centrifugation, and the resulting pellet
was washed twice with 1 ml of 0.5 M perchloric acid to
remove acid-soluble labeled material and subsequently with 1 ml of 96%
ethanol to remove phospholipids. The washed pellet was resuspended in
0.5 ml of 0.5 M KOH and incubated at 37 °C for 20 h. Alkali-stable DNA was then precipitated by addition of 100 µl of 6 M perchloric acid, and following a 2 min centrifugation,
the radioactivity in the supernatant was determined by liquid
scintillation counting. In control experiments we subjected supernatant
samples to two-dimensional thin layer chromatography and found that
80-90% of the radioactivity was present in the eight spots
corresponding to the 2'- or 3'-ribonucleoside monophosphates formed by
alkaline hydrolysis of RNA. No other distinct products were detectable.
Effect of Growth Rate on the NTP Pools--
In connection with
studies of nucleotide metabolism in RNase-deficient strains we found
that the nucleotide pools in a wild type control strain, CN1539, were
not increased by supplementation of glycerol minimal medium with all 20 amino acids, even though the amino acid enrichment more than doubled
the growth rate (Fig. 1a).
This result was in direct conflict with the recent report by Gaal
et al. (5), according to which a doubling of the growth rate
should lead to a 4-fold increase of the ATP and GTP pools.
Consequently, we decided to investigate the growth rate dependence of
the nucleotide pools in more detail using several different growth
media giving a larger span of growth rates. For these measurements we
used the strain CN1709, which like CN1539 is a derivative of strain
CSH26 (see "Experimental Procedures"). As shown in Fig. 1b, the size of all four rNTP pools were essentially
invariant in the investigated range of growth rates from 0.5 to 2.3 generations/h, in marked contrast to the 10-fold increase reported in
Ref. 5.
We considered the possibility that the conflicting results might be
caused by strain differences. Noting that the strains used by Gaal
et al. (5) were derivatives of MG1655, we performed some
preliminary experiments to measure the nucleotide pools in MG1655
itself. We found that the ATP and GTP pools were essentially constant
for growth rates between 0.4 and 1.9 generations/h, if the growth
medium was supplemented with uracil (data not shown). MG1655 is not a
pyrimidine requiring strain, but it suffers from pyrimidine limitation
at fast growth rates due to the rph1 mutation, which
interferes with expression of the downstream pyrE gene (14). Pyrimidine limitation is known to cause a swelling of the purine nucleotide pools (13), and the ATP and GTP pools of MG1655 were indeed
2.5-fold higher during rapid growth in the absence of uracil, whereas
uracil supplementation had no significant effect on the purine
nucleotide pools during slow growth (data not shown).
To avoid the complications with uracil supplementation, we chose to
measure the nucleotide pools in CF7968, a derivative of MG1655, in
which the rph1 allele have been replaced by the wild type
gene (kindly provided by Dr. M. Cashel). As shown in Fig. 1c, the nucleotide pools of CF7968 showed very little
variation with growth rate in agreement with the findings for CN1539,
CN1709, and MG1655 (in the presence of uracil). In the experiment shown in Fig. 1, the nucleotide pools of CF7968 appeared slightly larger than
those of CN1709. However, this difference was not observed in other
experiments and, thus, was probably not significant.
In general determinations of the absolute size of the nucleotide pools
may show some day to day variation, due to slight differences of the
phosphate concentration in different batches of growth medium or due to
minor pipetting errors occurring during sample preparation and loading
of the thin layer chromatograms. The relative size of the nucleotide
pools determined from a single chromatogram, however, is not affected
by these uncertainties and thus can generally be determined with
greater accuracy. As shown in Fig. 1d, the relative size of
the four rNTP pools was also largely invariant with growth rate, except
perhaps for a tendency of the GTP pool to increase slightly with growth
rate relatively to the three other pools.
Growth Rate-dependent RNA Accumulation--
To see if
the strains used here would show the normal growth
rate-dependent increase of stable RNA accumulation despite
their essentially constant nucleotide pools, we measured the
accumulation of total cellular RNA, of which 98% is rRNA and tRNA (1).
This was done by measuring the incorporation of
[32P]phosphate into alkali-labile nucleic acid (see
"Experimental Procedures"). As shown in Fig.
2, CN1709 and CF7968 showed the normal
growth rate-dependent increase of RNA per
A436.
Invariance of NTP Pools with Growth Rate--
The present work
shows that the NTP substrate pools for RNA polymerase are essentially
invariant with growth rate, which is not compatible with the idea that
nucleotide pool variations should be responsible for the growth
rate-dependent regulation of rRNA synthesis. The NTP pools
have been implicated in the regulation of rRNA synthesis before
(e.g. Refs. 15 and 16). However, the idea was generally
abandoned, because evidence accumulated, showing that shifts of growth
conditions, which greatly affect the growth rate and rRNA synthesis,
have little or no effect on the NTP pools (17-20) or even affect the
NTP pools and the rate of rRNA synthesis in opposite directions (21,
22).
Moreover, numerous studies performed with cells in steady-state
exponential growth have shown the ATP pool to be essentially invariant
with growth rate (23-26), in agreement with the present results. In
two studies (27, 28), however, the ATP pool was reported to increase
moderately with growth rate (1.5- and 2-fold, respectively). We cannot
account for these discrepancies, but our results with MG1655 show that
strains with a slightly compromised pyrimidine biosynthesis may show
such a 2-fold increase of the purine nucleotide pools with growth rate,
due to partial pyrimidine limitation at the higher growth rates. This
may not be an uncommon phenomenon.
In summary, the present work adds to the large body of evidence showing
that the ATP pool is strongly buffered around a fairly constant value,
varying less than 2-fold over a wide range of growth rates. We cannot
explain the discrepancy with the 10-fold variation reported for ATP and
GTP by Gaal et al. (5), which primarily reflects their
finding of approximately 4-fold greater pools at the highest growth
rates compared with the present work. It should be emphasized, however,
that this difference was not caused by a technical limitation in our
extraction procedure, which has been used to measure nucleotide
concentrations that are even 10-fold higher than the normal ATP
concentration (12). The only difference between the strain CF7968 used
here, and RLG3492 used in Ref. 5, is the presence in the latter strain
of a lambda prophage with an rrnP1-lacZ fusion.
Considering the low growth rate of RLG3492 in amino acid-supplemented
glucose medium (µ = 1.35 compared with µ = 2.3 for
CF7968, Fig. 1c), it is conceivable that the high rate of
Mechanisms Controlling the Size of the ATP Pool--
The size of
the ATP pool is determined by the interplay of many metabolic fluxes as
illustrated in Fig. 3. All the
biosynthetic reactions, that are driven by the conversion of ATP to ADP
or AMP, together with the reactions that regenerate ATP constitute a
large cyclic flux, which is 2 orders of magnitude greater than the
fluxes that feed and drain the total adenylate pool, i.e. the de novo synthesis flux and the incorporation of adenine
nucleotides into nucleic acids and metabolites. Most importantly the
recycling fluxes between the ATP, ADP, and AMP pools are also very
large compared with the size of these pools, which turn over in a
fraction of a second (Fig. 3). Thus, the recycling fluxes must be
strictly balanced, to avoid depletion of any of the pools, and to
maintain the "energy charge," defined as ([ATP] + 0.5[ADP])/([ATP] + [ADP] + [AMP]) (30, 31). If for instance the
ATP to ADP conversion should be blocked, the rate of ADP
phosphorylation would have to be reduced accordingly within seconds, if
not for anything else then for the lack of substrate.
Apart from substrate limitation, two major factors contribute to
maintain the balance between the adenine nucleotide pools and the
fluxes between them. One is the high capacity adenylate kinase enzyme,
which catalyzes the reversible reaction, AMP + ATP = 2 ADP (32,
33). The other is the general tendency of enzymes that utilize or
regenerate ATP, respectively, to respond reciprocally to changes in
energy charge (30, 31). Together these mechanisms balance the
phosphorylation-dephosphorylation fluxes on a time scale of seconds to
maintain a constant energy charge over a wide range of growth
conditions (17, 34-36).
Even though the translation process accounts for a substantial fraction
of the ATP recycling (Fig. 3), it does not necessarily have a strong
influence on the size of the ATP pool, because a reduction of
translation and the associated ATP turnover may be balanced within a
second by a corresponding decrease of ATP regeneration. Indeed the ATP
and GTP pools remain unaffected for several minutes following a
complete block of translation with
chloramphenicol2 (28), as
does the energy charge (34). Thus, the NTP pools do not function as a
sensitive feedback signal informing the rRNA operons about the
translational activity in the cell.
The total adenine nucleotide pool turns over in less than a minute
determined by the balance between the de novo synthesis flux
and the fluxes into nucleic acids and metabolites (Fig. 3). Like the
adenine nucleotide distribution the size of the total pool seems to be
strongly buffered against perturbations. Even when RNA synthesis is
inhibited with rifampicin, the ATP pool increases less than 2-fold and
the GTP pool even less2 (37), while the energy charge
remains unaffected (34). Apparently this homeostasis is predominantly
mediated by regulation of the purine de novo synthesis via
feedback signals from purine nucleotides to phosphoribosylpyrophosphate
synthetase and to the PurF enzyme (see Ref. 12 for a discussion).
The Mechanism of Growth Rate-dependent Control of rRNA
Synthesis--
We emphasize that the present finding of growth
rate-independent NTP pools does not preclude that variations of the ATP
and GTP concentrations, if they should occur, might affect the activity of the rRNA promoters. However, it should be noted that the rate of
rRNA synthesis shows an inverse relationship with the ATP pool during
pyrimidine limited growth (13) or during an amino acid-induced upshift
(22). Thus, the effect of the initiating nucleotide concentration on
the rrn P1 promoter activity can be completely overruled by
other control mechanisms acting on rRNA synthesis.
Unfortunately the present results do not provide an alternative
explanation for the growth rate-dependent control of rRNA synthesis. Several mechanisms may contribute to the phenomenon, e.g. growth rate-dependent inhibition of rRNA
synthesis by ppGpp (38), passive redistribution of RNA polymerase from
biosynthetic genes to rRNA operons in richer media (39), degradation of
nascent rRNA during slow growth (40), growth rate-dependent
variations in the concentration of free RNA polymerase (37), or
modulation of antitermination or FIS-mediated activation (2). Most
discussions of growth rate-dependent regulation have
tacitly assumed that one mechanism should be solely responsible for the
effect; however, the answer to the problem may well be that several
mechanisms are involved (3, 13). It should be noted that the amount of
RNA per cell mass barely increases 2-fold over the entire range of
growth rates3 (Fig.
2b). If four or five different mechanisms each contributed say 15-20% to this increase, then any one of them could be eliminated without severely affecting the growth rate-dependent regulation.
We acknowledge the expert technical
assistance of Jeanette Lundin, and we thank Drs. M. Cashel and K. F. Jensen for the generous donation of bacterial strains. Furthermore,
we are grateful to K. F. Jensen for helpful comments on the manuscript.
*
This work was supported by the Danish Natural Science
Research Council.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
2
C. Petersen, unpublished data.
3
The modest increase of RNA per cell
mass with growth rate may seem surprising, because the amount of
RNA per genome is proportional to the growth rate, implying
that the rate of RNA accumulation per genome increases with the square
of the growth rate. However, it should be noted that the latter
relationships partly reflect the fact that DNA per cell mass decreases
considerably with increasing growth rate (1).
The abbreviations used are:
ppGpp, guanosine
5',3'-bispyrophosphate;
NTP, nucleoside triphosphate.
Invariance of the Nucleoside Triphosphate Pools of
Escherichia coli with Growth Rate*
and Department of Biological Chemistry,
Institute of Molecular Biology, University of Copenhagen, Sølvgade
83H, DK-1307 Copenhagen K, Denmark and § The John F. Kennedy
Institute, Gl. Landevej 7, DK-2600 Glostrup, Denmark
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
(gpt-pro-lac) thi
zce-726::Tn10/F'(gpt+
proAB+ codAB+
lacIq1 lacZ::Tn5) is the wild
type member of an isogenic
rne+/rne3071 strain pair, which was
constructed by P1-mediated transduction of
zce-726::Tn10 from CH1826 (6) into CSH26 (7). The
F' factor, which complements the (gpt-pro-lac) deletion,
was subsequently introduced by conjugation with NF1829 (8).
ara (codB-lac)3 thi,
is a derivative of CSH26, in which the (gpt-pro-lac)
deletion has been replaced by the shorter (codB-lac) deletion, also known as (lac)X74, from NF1829.
rph1 (9) was obtained
from Dr. K. F. Jensen.
(lacIZ) is an
rph+ derivative of MG1655, kindly provided by
Dr. M. Cashel.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
View larger version (16K):
[in a new window]
Fig. 1.
Size of the NTP pools as a function of growth
rate. ATP and GTP, filled and open squares,
respectively. CTP and UTP, filled and open
triangles, respectively. a, CN1539 growing in glycerol
minimal with or without amino acid supplementation. b,
CN1709 growing in minimal medium with ribose, succinate, glycerol, or
glucose as carbon source, for the fastest growth rate a glucose culture
was supplemented with all 20 amino acids. c, CF7968 growing
in the same media as CN1709. d, relative nucleotide pools
measured for all strains in several different experiments.
View larger version (20K):
[in a new window]
Fig. 2.
Accumulation of RNA as a function of growth
rate. a, incorporation of [32P]phosphate
into alkali-labile nucleic acid in CF7968 growing in different media:
succinate, open triangles; ribose, filled
triangles; glycerol, circles; glucose, open
squares; glucose+amino acids, filled squares. The data
are from the same experiment as shown in Fig. 1c.
b, the accumulation of total RNA/A436
in CF7968 (filled squares), calculated from the slopes of
the incorporation curves in a. For comparison we have also
plotted the results of similar experiments with CN1709 (filled
triangles), as well as the values of
RNA/A460, previously determined (1) for E. coli B/r (open squares). No correction was made for the
slight difference between A436 and
A460.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-galactosidase synthesis from this fusion at the higher growth rates
may have perturbed cellular physiology to cause an abnormal swelling of
the ATP and GTP pools, for instance by imposing some kind of pyrimidine
restriction. It is known that gratuitous protein overproduction can
severely distort cellular metabolism (29).
View larger version (24K):
[in a new window]
Fig. 3.
Dynamics of adenine nucleotide
metabolism. The numbers associated with the
arrows indicate the magnitude of the fluxes (in µmol/min/g
dry weight) and were calculated from the compilation of metabolic data
for E. coli B/r growing in glucose minimal medium (41). The
numbers in parentheses represent the size of the
various pools, given as their adenine content in µmol/g dry weight
(from Ref. 42). The pool sizes may be divided by 5 to be expressed in
nmol/ml/A436 for comparison with the data in
Fig. 1. The turnover time of a pool is calculated as the pool size
divided by the flux through the pool. The boxes symbolizing
the adenine nucleotide pools, and the arrows representing
the recycling fluxes between them are drawn to scale, so that the area
of the arrows corresponds to the amount of nucleotide
converted in 1 min. For simplicity unstable RNA has been depicted as
being degraded to AMP, although the fraction of mRNA that is
degraded by polynucleotide phosphorylase will actually yield ADP.
Fluxes to S-adenosylmethionine, adenosine, and adenine have
been omitted due to uncertainty of their magnitudes. The estimated
total ATP turnover given here (740 µmol/min/g dry weight) is a
minimal estimate based on the known requirements for synthesis of
biomass. A substantial additional turnover of ATP, approaching half of
the ATP requirement for biomass synthesis, may occur to energize
various cellular maintenance processes (43). Thus, the numerical
estimates of the fluxes should not be taken too literally, they simply
serve to give a quantitative impression of the overall dynamics of the
system.
ACKNOWLEDGEMENTS
FOOTNOTES
ABBREVIATIONS
REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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