REVIEW ARTICLE
Ins and outs of glucose transport systems in eubacteria
Knut Jahreis1, Elisângela F. Pimentel-Schmitt2, Reinhold Brückner3 & Fritz Titgemeyer2
1
Department of Biology and Chemistry, University of Osnabrück, Osnabrück, Germany; 2Department of Microbiology, Friedrich-Alexander-University
Erlangen-Nürnberg, Erlangen, Germany; and 3Department of Microbiology, University Kaiserslautern, Kaiserslautern, Germany
Correspondence: Fritz Titgemeyer,
Department of Oecotrophology,
Fachhochschule Münster, Corrensstr. 25,
48149 Münster, Germany. Tel.: 149 9131
482482; fax: 149 251 8365402; e-mail:
[email protected]
Received 24 August 2007; revised 22 April
2008; accepted 21 May 2008.
First published online 18 July 2008.
Abstract
Glucose is the classical carbon source that is used to investigate the transport,
metabolism, and regulation of nutrients in bacteria. Many physiological phenomena like nutrient limitation, stress responses, production of antibiotics, and
differentiation are inextricably linked to nutrition. Over the years glucose transport systems have been characterized at the molecular level in more than 20
bacterial species. This review aims to provide an overview of glucose uptake
systems found in the eubacterial kingdom. In addition, it will highlight the diverse
and sophisticated regulatory features of glucose transport systems.
DOI:10.1111/j.1574-6976.2008.00125.x
Editor: Keith Chater
Keywords
carbon regulation; sugar transport;
phosphotransferase system; Mlc.
Introduction
Microorganisms have the capacity to utilize a variety of
nutrients and adapt to continuously changing environmental conditions. In general, the presence of a rapidly metabolizable carbon source leads to its immediate utilization and
is accompanied by a number of regulatory events that
hamper the use of other carbon sources of less energetic
value (reviewed in Brückner & Titgemeyer, 2002). This was
first investigated in detail by Monod (1942), who described
the phenomenon of diauxic growth, showing that the
bacterium Escherichia coli primarily chooses glucose when
exposed to a nutrient mixture of glucose and sorbitol. Since
then, glucose has been the classic ‘preferred’ carbon source
that has been studied for decades in order to reveal the
molecular mechanisms of carbon transport and regulation.
The first glucose transporter (GLT) was described in 1966
when a glucose-specific phosphoenolpyruvate-dependent
phosphotransferase system (PTS) in E. coli was identified
(Kundig et al., 1966). The corresponding DNA sequences of
the permease subunits were reported in 1984 and 1986
(Nelson et al., 1984; Erni & Zanolari, 1986). Today, we have
sequence information of hundreds of glucose transport
systems, disclosed through genome sequencing. About 30
of these are characterized experimentally at the molecular
FEMS Microbiol Rev 32 (2008) 891–907
level in more than 20 different bacterial species (Fig. 1 and
Table 1). Their mode of action, their regulation, and their
impact on the cellular physiology show fascinating features.
This review aims to survey and compare the currently
recognized glucose transport systems that have been characterized in eubacteria. The nutrient is taken up by carrier
systems of the PTS, by proton or cation gradient-driven
transporters, through ATP-dependent ATP-binding cassette
(ABC) permeases, and even via diffusion by specific facilitator proteins. The activity of the glucose transport systems
often determines the rate of the metabolic flux and thus has
a direct impact on the speed of growth (Brückner &
Titgemeyer, 2002; Bettenbrock et al., 2006). Besides this,
GLTs can act as sensory systems for carbon regulation and
chemotaxis, and have been associated with morphogenesis
(Lux et al., 1995; Brückner & Titgemeyer, 2002; Rigali et al.,
2006). Their importance is further underlined as they can
also serve as entry systems for phages or bacteriocins (Erni,
2006; Diep et al., 2007). Recent findings have illustrated that
the regulation of glucose transport can be quite sophisticated,
showing that one single glucose permease gene is regulated
at multiple levels, involving several transcription factors,
auxiliary regulatory proteins, small regulatory RNAs and
protein phosphorylation (Böhm & Boos, 2004; Vanderpool
& Gottesman, 2004; Becker et al., 2006).
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892
K. Jahreis et al.
Lactobacillus casei
Lactobacillus curvatus
Streptococcus mutans
Streptococcus bovis
Streptococcus thermophilus
Streptococcus salivarius
Lactococcus lactis
Enterococcus faecalis
Bacillus subitilis
Bifidobacterium longum
Corynebacterium glutamicum
Mycobacterium smegmatis
Vibrio parahaemolyticus
Glucose
er
an
ag
BA N
IIAGlc
IIC
IIABMan
Glucose
Glucose
GlkA
GlcU
A
Mgl
MglC
HPr-P
Fructose-6-P
Glucose
Fructose-1,6-bis-P
Bacillus subtilis
Staphylococcus xylosus
Staphylococcus carnosus
lc
EI-P
lS
IIA
G
PEP
GlcF
GlcG
g
MalF
MalG
Na
n
Ma
n
Ma
MalE
IIC
IIB
Malk1
IID
SGLT
Malk
1
IIA
B
+
Na
Vibrio parahaemolyticus
Xanthomonas oryzae
BM
IIC
n
Ma
II A an
M
IIC
alX
c
Gl
Sg
se
co
u
MglB
Glucose-6-P
Gl
H+
Glucose
GalP
F
ATP
?
co
li
GL
Zymomonas mobilis
ich
an
IIC M
IIABMan
ch
ia
IID M
IIDMan
IICMan
Es
IIB
C Glc
M
Glucose
Glc
Glucose
H+
G
lc
P
Glucose
e
A
FS
cos
Glu
IIBC
Streptomyces coelicolor
Bifidobacterium longum
Mycobacterium smegmatis
Bacillus subtilis
Cyanobacterium synechocystis sp
Brucella abortus
PTS
Glucose
Vibrio furnissii
GlcE
Glucose
Thermus thermophilus
ABC
Fig. 1. Glucose transport systems of the bacterial kingdom. A cell is presented in which all 21 molecular characterized glucose uptake systems are
displayed. The five transport systems of Escherichia coli are shown separately on the right side. The transporter families are coloured as follows: ABC,
red; MFS, light blue; PTS, yellow; SGLT, dark blue; GlcU, green. For further explanation, see text. MFS, major facilitator super family.
In our overview, we will highlight that (1) bacteria can
have up to five different glucose transport systems, that (2)
related species use predominantly the same permease type,
although their lifestyle is totally different, and that (3) the
distinct regulatory features are sometimes unrelated and
diverse, indicating that they have evolved separately to
respond optimally to the habitat conditions of each bacterial
species.
Gram-negative bacteria
Escherichia coli and other enteric bacteria
The molecular knowledge of glucose uptake and regulation
stems from investigations in E. coli. This bacterium has five
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different permeases for glucose, including the major uptake
system IICBGlc of the PTS type (Lengeler, 1993; Postma
et al., 1993) (Fig. 1). The PTS, which is the major uptake
system for carbohydrates in enteric bacteria, consists of two
general, cytoplasmic proteins, Enzyme I (EI) and the
phosphocarrier protein HPr, and a number of carbohydrate-specific transporters. These so-called Enzymes II
(IIABC) are composed of multidomain proteins present as
a single or as several individual polypeptides. While two
domains: IIA and IIB: are hydrophilic and involved in
phosphoryl group transfer, the IIC and IID (when it is
present) domains are membrane-bound and active in sugar
permeation across the membrane. The PTS-specific phosphorylation chain begins with the autophosphorylation of
EI at a histidine residue to histidines of HPr and then IIA,
FEMS Microbiol Rev 32 (2008) 891–907
893
Ins and outs of glucose transport systems in eubacteria
Table 1. Bacterial glucose transport systems
Protein family
Gram-negative bacteria
Brucella abortus
Escherichia coli
Synechocystis
Thermus thermophilus
Vibrio furnissii
Vibrio parahaemolyticus
Xanthomonas oryzae
Zymomonas mobilis
Low-GC Gram-positive bacteria
Bacillus subtilis
Enterococcus faecalis
Lactobacillus casei
Lactobacilus curvatus
Lactococcus lactis
Staphylococcus carnosus
Staphylococcus xylosus
Streptococcus bovis
Streptococcus mutans
Streptococcus salivarius
Streptococcus thermophilus
High-GC Gram-positive bacteria
Bifidobacterium longum
Corynebacterium glutamicum
Mycobacterium smegmatis
Streptomyces coelicolor
PTS
MFS
ABC
3
1
1
1
SGLT
GlcU
Essenberg et al. (1997)
Kundig et al. (1966), Lengeler (1993),
Postma et al. (1993), Ferenci (1996),
Saier et al. (1973), Postma (1977), Erni et al. (1987)
Zhang et al. (1989)
Chevance et al. (2006)
Bouma & Roseman (1996a, b)
Kubota et al. (1979), Sarker et al. (1994)
Tsuge et al. (2001)
Weisser et al. (1995), Parker et al. (1995)
1
2
3
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
References
Paulsen et al. (1998), Sutrina et al. (1990),
Fiegler et al. (1999), Abranches et al. (2003)
Muraoka et al. (1991)
Veyrat et al. (1994)
Veyrat et al. (1996)
Thompson & Chassy (1983)
Christiansen & Hengstenberg (1999)
Fiegler et al. (1999)
Asanuma et al. (2004)
Abranches et al. (2003)
Lortie et al. (2000)
Cochu et al. (2003)
Parche et al. (2006, 2007)
Moon et al. (2005)
Titgemeyer et al. (2007)
van Wezel et al. (2005)
MFS, major facilitator super family.
which finally phosphorylates a histidyl or a cysteyl residue of
IIB, the ‘IIB domain’. The carbohydrate is transported
through IIC or IICD, in the case of mannose-class PTSs,
into the cell by concomitant phosphorylation from the IIB
domain.
Escherichia coli K-12 utilizes three different PTS-transporters for the uptake of glucose. The regular glucose-PTS
consists of two subunits: the IIAGlc (also called IIACrr,
encoded by the crr gene) and the IICBGlc (encoded by the
ptsG gene) (Erni & Zanolari, 1986). The Km for glucose
transport was reported to be in the range of 5–20 mM
depending on the tested strain in the different laboratories (Adler & Epstein, 1974; Lengeler et al., 1981; Stock
et al., 1982; Lux et al., 1999). Moreover, wild-type IICBGlc
has a good affinity for a- and ß-methylglucosides, 1-thioglucose, 5-thio-glucose, and a low affinity for 2-deoxyglucose
and mannose (Erni, 2001). In addition, glucose can also
be internalized by the mannose-PTS IIMan (IIABMan
-IICMan-IIDMan) (Gutknecht et al., 1999) and the N-acetylglucosamine-PTS IINag (IICBANag) (Postma et al., 1993).
FEMS Microbiol Rev 32 (2008) 891–907
The mannose-specific PTS can transport glucose very
efficiently with an apparent Km of 15 mM (Stock et al.,
1982) and is characterized by a broad substrate specificity
for mannose, glucose, and other derivatives of glucose
altered at the C-2 carbon residue (Robillard & Broos,
1999). Enzyme IINag exhibits only a marginal glucose transport capacity. The capability of glucose uptake and phosphorylation by IINag, however, can be dramatically enhanced
by a single mutation, the substitution of phenylalanine 437
by serine (K. Jahreis, unpublished results).
All the enteric bacteria sequenced thus far carry a ptsG
gene. The deduced protein sequences usually exhibit more
than 90% identical amino acid residues. The IICBGlc from
E. coli K-12 and Salmonella enterica serovar Typhimurium
(reviewed in Erni, 2001), together with the mannitolspecific IICBAMtl (reviewed in Robillard & Broos, 1999)
and the b-glucoside-specific IIBCABgl (Yagur-Kroll &
Amster-Choder, 2005), are by far the best-characterized
PTS transporters. The hydrophilic IIB-domain of the GLT
carries the phosphorylation site Cys421, whereas the
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894
IIC-domain contains the sugar-binding site. Complementation between IIB and IIC domains on different subunits in a
IICBGlc dimer is possible (Lanz & Erni, 1998). Although the
sites of IICB phosphorylation are known and easily recognized from the amino acid motifs, residues that directly
participate in sugar binding have not been clearly identified
thus far. Seventeen different mutations in PtsG have been
described that cause a so-called ‘relaxed conformation,’
which leads to transport and phosphorylation of several
other carbohydrates (e.g. ribitol, arabinitol, ribose, xylose,
fructose, and mannitol, respectively) (Erni, 2001). These
amino acid substitutions are scattered all over the IICdomain, except for the second and third predicted transmembrane helix. The conformational changes caused by
these mutations, however, are still not clear. It has been
proposed that each monomer has a sugar-binding site of its
own with, logically, two sites in the dimer. These are
distinguished by their different affinities for the substrate,
being simultaneously accessible from the cytoplasmic face
and from the outside (Garcia-Alles et al., 2002). Furthermore, complementation analysis revealed that the IICBGlc
subunits co-operate insofar as phosphoryl group transfer
from one IIB domain to the other is possible (Lanz & Erni,
1998).
Structural considerations
Whereas information on the structure of the integral
membrane IIC domain is limited and controversially discussed, the structures of the IIBGlc-domain and the IIAGlc
protein have been solved (Worthylake et al., 1991; Eberstadt
et al., 1996; Gemmecker et al., 1997). For the IIC-domain,
two detailed secondary structure models exist (Buhr & Erni,
1993; Lengeler et al., 1994). Both predict a topology of eight
transmembrane helices with the carboxy- and the aminoterminal ends oriented to the cytosol. However, the models
differ completely in the regions and orientations of the last
three transmembrane segments. All data available present
cannot distinguish between the two models.
The IIBGlc-domain is a split a/b sandwich that consists of
a four-stranded antiparallel b-sheet and three helices packed
against one side of the sheet. The active Cys421-residue is
in the loop between strands b1 and b2. The IIB-domain
is connected to the IIC-domain by a flexible linker, which
contains a highly conserved ‘KTPGRED’ motif that is
present in all PTS permeases specific for glucose or
N-acetyglucosamine. Mutations or a deletion of this region
in PtsG were shown to be more deleterious to transport and
phosphorylation activity than its absence in split or circularly permuted forms of the protein (reviewed in Erni,
2001). The function of this sequence, however, is not clear.
The two domains can be split within their connecting linker
peptide, expressed as separate proteins and, when recom2008 Federation of European Microbiological Societies
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K. Jahreis et al.
bined, retain complete transport and phosphotransfer activity
(Buhr et al., 1994).
The IIAGlc forms a b-sandwich with six antiparallel
strands on either side. The two important residues His90,
which is transiently phosphorylated, and His75, which seems
to stabilize the negative charge of PHis90, face each other at
the centre of the active site (Dorschug et al., 1984). The
binding surface for its interaction partner HPr on the IIAGlc
is concave and located in a shallow depression, while that on
HPr is convex and located on a protrusion. The central
region of each binding surface is hydrophilic and surrounded by polar and charged residues. The latter are
entirely positive in the case of HPr and mostly negative in
the case of IIAGlc (Wang et al., 2000). The binding surface of
the other interaction partner IIBGlc, resembles the one from
HPr, a convex protrusion. The phosphoryl donor and
acceptor residues, His90 of IIAGlc and Cys421 of IIBGlc are in
close proximity and buried within the centre of the interface
(Cai et al., 2003).
Regulatory considerations
A number of studies in the last few years have revealed that
the regulation of ptsG expression in E. coli K-12 is very
complex and involves several transcription factors, auxiliary
proteins, a small regulatory RNA, and diverse sigma factors
(Fig. 2). Glucose uptake derepresses ptsG expression by
inactivation of the glucose repressor Mlc (mnemonic for
makes large colonies) (Hosono et al., 1995; Plumbridge,
2002; Böhm & Boos, 2004). The current model predicts that
dephosphorylated IICBGlc, generated during glucose transport, binds Mlc and sequesters the repressor away from its
DNA-binding sites (Lee et al., 2000; Tanaka et al., 2000; Nam
et al., 2001). Mlc is also involved in the glucose-dependent
regulation of the ptsHIcrr operon that encodes EI, HPr, and
IIAGlc, in regulation of the malT gene for the transcriptional
activator of the maltose regulon: and in regulation of the
genes for IIMan, manXYZ. Mlc is, therefore, considered
a pleiotropic-acting transcription factor responsible for
the induction of genes in the presence of glucose. Recently,
our group identified a novel regulatory factor called MtfA
(mnemonic for Mlc-titration factor A) (Becker et al., 2006).
This cytoplasmic, auxiliary protein binds to and inactivates
Mlc. In this way, it has a severe impact on ptsG regulation
and probably also on other Mlc-regulated genes. Interestingly, MtfA orthologues exist in many Proteobacteria.
The second major regulator of ptsG transcription is a
global regulator, the cAMP-receptor protein (CRP) (also
known as CAP for catabolite activator protein). Mlc and
cAMP–CRP work antagonistically, because cAMP levels are
low during growth on glucose. Hence, their action results in
precise control of ptsG expression under various growth
conditions. This can be explained, because IICBGlc is not
FEMS Microbiol Rev 32 (2008) 891–907
895
Ins and outs of glucose transport systems in eubacteria
Escherichia coli
+ glc
(Fine tuning regulation by global regulators)
– glc
(Specific repression by Mlc)
Glc
IIC
IIB
Fig. 2. Regulation of the major glucose
transport system IICBGlc (encoded by ptsG) in
Escherichia coli. In the absence of glucose, ptsG
expression is repressed by Mlc. In the presence of
glucose, Mlc is sequestered to the GLT IICBGlc or
to the auxiliary protein MtfA. Expression of ptsG
depends on the global-acting transcription
factors CAP, ArcA, and Fis and on several sigma
factors. The stability of the ptsG-mRNA is
regulated by the small regulatory RNA SgrS.
The small protein SgrT that is encoded in the 5 0
end of sgrS is somehow involved in the
downregulation of IICBGlc activity.
P
Glc-P
Mlc
–
SgrT
Fis
P
ArcA
CAP
–
+
Mlc
Mlc
MtfA MtfA
Mlc
cAMP
+
–
+
Mlc
ptsG OP
only involved in glucose transport but further has a major
influence on the phosphorylation levels of all other PTS
proteins, especially on the phosphorylation state of IIAGlc, a
central element in global carbon regulation (Brückner &
Titgemeyer, 2002). In this context, it was not surprising that
more transcription factors were identified (Fig. 2). Among
them are ArcA, a major transcription factor for the switch
between aerobic and anaerobic growth in E. coli (Jeong et al.,
2004), the two alternative sigma factors s32 for heat shock
response (Shin et al., 2001) and sS for the expression of
genes in the stationary growth phase (Seeto et al., 2004), and
the small globally acting DNA-binding protein Fis (Shin
et al., 2003).
In addition to these regulation mechanisms at the transcriptional level, ptsG expression is posttranscriptionally
regulated by the modulation of its mRNA stability in
response to the glycolytic flux in the cells (Kimata et al.,
2001; Morita et al., 2003). As revealed by the Gottesman
group, accumulation of glucose-6-phosphate or fructose-6phosphate activates the transcriptional activator SgrR,
which in turn leads to the synthesis of the small regulatory
RNA SgrS (Vanderpool & Gottesman, 2004). SgrS is complementary to the 5 0 end of the ptsG-mRNA and is capable
of forming Hfq-dependent RNA–RNA hybrids, which are
degraded in an RNAse E/degradosome-dependent manner.
The degradosome contains polynucleotide phosphorylase
(PNPase), RhlB helicase, and a glycolytic enzyme, enolase,
that appears to be crucial for the degradation in response to metabolic stress (Morita et al., 2004). It was
further shown that ptsG-mRNA localization to the inner
membrane, coupled with the membrane insertion of nasFEMS Microbiol Rev 32 (2008) 891–907
IIC
IIB
ptsG
ptsG OP
RNAseE
ptsG
–
SgrS
cent IIGlc peptide, mediates the Hfq/SgrS-dependent degradation presumably by reducing second rounds of translation
(Kawamoto et al., 2005; Vanderpool & Gottesman, 2005).
Last year, a novel regulatory feature was reported for the sgrS
locus, which seems to have a dual function (Wadler &
Vanderpool, 2007): the 5 0 end of sgrS, upstream of the
nucleotides involved in base pairing with the ptsG mRNA
(Fig. 2), contains a 43-aa ORF called sgrT. This small SgrT
polypeptide apparently inhibits glucose transport activity
during glucose-phosphate stress by directly inactivating
PtsG transport activity, which would be the first example
for such a regulatory mechanism within the PTS.
All these different regulatory effects might emphasize the
important function of the glucose–PTS in the global regulation of carbohydrate uptake in enteric bacteria. Especially
the role of the IIAGlc has been known for a long time.
Unphosphorylated IIAGlc, which is generated during the
uptake of glucose or other PTS carbohydrates, is an allosteric inhibitor of the lactose permease LacY, the glycerol
kinase GlpK, the MalK subunit of the maltose transport
complex, and raffinose permease (Brückner & Titgemeyer,
2002). Inhibition by IIAGlc always prevents uptake and
formation of metabolites, which are inducers for other
carbohydrate uptake systems. Thus, this mechanism has
been defined as ‘inducer exclusion’ (reviewed in Brückner
& Titgemeyer, 2002; Deutscher et al., 2006). As long as
glucose or other PTS substrates are available, the transcription of operons for alternative catabolite pathways is repressed. In contrast, the concentration of phospho-IIAGlc
starts to increase after the PTS substrates are consumed
(Bettenbrock et al., 2007). Phosphorylated IIAGlc directly or
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896
indirectly activates the enzyme adenylate cyclase and cAMP
concentrations increase (Park et al., 2006). Thus, genes and
operons whose transcription depends on the activation by
the cAMP–CAP complex are transcribed, provided the
specific inducer is also present. This type of regulation is
known as ‘carbon-catabolite repression’.
Last but not least, using the PEP-dependent phosphotransferase EI, the PTS is capable of sensing the physiological
state of the cell by measuring the intracellular PEP to
pyruvate ratio. Any change of this ratio, even caused by the
transport of non-PTS substrates like glucose-6-phosphate
(Hogema et al., 1998), directly influences the autophosphorylation activity of EI and in turn the phosphorylation
state of HPr and IIAGlc, the general regulatory output
protein of the PTS (Brückner & Titgemeyer, 2002).
Glucose flux considerations
Different approaches have been adopted using the glucosePTS to develop a computer model of bacterial growth under
various conditions. A comprehensive model on glucose/
lactose diauxic growth behaviour was presented for example
by Kremling et al. (2001) and has been extended recently
(Bettenbrock et al., 2006). This model perfectly reproduces
biomass yield, glucose and lactose consumption, the preferential use of glucose, and the induction of the lac operon
over time. This is a first step on the way to a complex
computer model of the whole bacterial metabolism, which
takes both metabolic fluxes and their regulation into
account.
Alternatives
Besides PTS-dependent glucose transport systems, enteric
bacteria can also internalize glucose by two different galactose-induced uptake systems: the galactose permease GalP
and the methyl-galactoside permease MglBAC (Ferenci,
1996). Escherichia coli or Salmonella strains lacking both EI
and HPr regain the ability to utilize glucose by constitutive
expression of one of the two galactose systems (Saier et al.,
1973). It was also found that under glucose limitation in a
chemostat, the mgl system is induced by endogenous
galactose synthesis (Death & Ferenci, 1994). Especially the
ATP-driven ABC transporter MglBAC exhibits a very high
affinity for glucose with a Km of about 10 mM, whereas the
proton-symporter GalP has a Km for glucose in the 100 mM
range (Lengeler, 1993). GalP has been characterized further
with a Km for galactose of 45 mM and a rather broad
specificity for galactose, glucose, mannose, fucose, 2-deoxygalactose, and 2-deoxyglucose (Postma, 1977). In contrast to
PTSs, growth on glucose transported via MglBAC or GalP
permeases requires subsequent phosphorylation by glucokinase. Interestingly, such a setting can already have a drastic
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K. Jahreis et al.
impact on glucose metabolism. Replacement of the glucosePTS by the galactose permease in genetically engineered
strains reduced acetate accumulation and improved bioprocess formation probably by increasing the glycolytic flux to
fermentation products (Hernandez-Montalvo et al., 2003;
De Anda et al., 2006).
Vibrio species
Vibrionaceae are closely related to the above-described
enteric bacteria. For the facultatively anaerobic, pathogenic
species of Vibrio furnissii, three different PTS-dependent
permeases have been described, which complement an
E. coli mutant deficient in glucose transport (Bouma &
Roseman, 1996a, b). The first permease, designated as MalX,
exhibits 38% identical residues with the IICBGlc from E. coli
and 37% with the IICBAGlc from B. subtilis. However, the
highest similarity was observed to MalX from E. coli (67%
identity), a PTS permease of unknown substrate specificity
(Postma et al., 1993). The second permease was termed
NagE, because it shows with 47% identical residues the
highest similarity to the N-terminal, hydrophobic domain
IIC of the N-acetyl-glucosamine-PTS IICBANag (gene nagE)
from E. coli. Both MalX and NagE lack the IIA domain
and require an additional IIAGlc factor for transport and
phosphorylation. For NagE, it was demonstrated that both
N-acetylglucosamine and glucose were transported and
phosphorylated. The third glucose-transporting system was
described as a mannose/glucose-specific PTS (Bouma &
Roseman, 1996b). The corresponding genes were similar to
the manXYZ (IIC, IID, IIABMan) genes of E. coli with the
difference that in V. furnissii, the IIA and IIB proteins are
encoded by two individual genes: manZ and manW. By
heterologous expression in E. coli, it was shown that these
four proteins are sufficient for the phosphoryl transfer and
transport of mannose and glucose in vivo and in vitro.
Unlike the E. coli mannose-PTS, V. furnissii IIMan is not
capable of transporting N-acetylglucosamine or fructose.
However, it should be noted that the manXYZW genes of
V. furnissii have the highest similarity to an N-acetylgalactosamine PTS (aga gene locus) of E. coli (Brinkkötter et al.,
2000). In addition, both gene loci comprise a gene for an
N-acetylgalactosamine deacetylase. Hence, the identified
IIMan of V. furnissii may transport N-acetylgalactosamine as
the main substrate. A V. furnissii equivalent of E. coli IICBGlc
has not yet been found.
In the Gram-negative, halophilic marine, pathogenic
bacterium Vibrio parahaemolyticus glucose is taken up by
two systems: a PTS and a sodium-coupled permease (Kubota
et al., 1979; Sarker et al., 1997, 1994). Based on biochemical
data, the V. parahaemolyticus glucose–PTS seems to be
similar to the glucose-PTS of enteric bacteria, while the
other GLT (SglS) is a member of the sodium/glucose
FEMS Microbiol Rev 32 (2008) 891–907
897
Ins and outs of glucose transport systems in eubacteria
transporter family (SGLT) that is typically found in mammalian cells (Wood & Trayhurn, 2003). The energy necessary for
the transport is generated by the electrochemical potential of
Na1 across the cell membrane, which is established by the
respiration-driven Na1 pump and the Na1/H1 antiporter
(Tsuchiya & Shinoda, 1985; Kuroda et al., 1994). SglS
mediates not only the uptake of glucose but also the uptake
of galactose, fucose, salt, and water (Sarker et al., 1997). The
Km for glucose and galactose were determined as 30 and
14 mM, respectively, with a calculated Vmax of 97 and
85 nmol min1 mg1 protein.
Xanthomonas oryzae pv. oryzae
In addition to the symporter system of V. parahaemolyticus,
other members of the SGLT family transporter were identified in X. oryzae pv. oryzae, a plant-pathogenic bacterium
(Tsuge et al., 2001), which belongs to the Gammaproteobacteria. This GLT shares 50% amino acid identity to the Na1/
H1 glucose permease of V. parahaemolyticus and also has an
additional affinity for galactose. However, the rates of
[14C]glucose transported by GLT did not decrease in the
presence or absence of NaCl, or when replaced by KCl. It has
been suggested that GLT does not need Na1 to couple
glucose transport. Because the transport buffer did not
contain additional cations, it was suggested that GLT is a
H1-coupled GLT rather than a Na1/glucose symporter.
Brucella abortus
The facultative intracellular pathogen B. abortus belongs to
the group of Alphaproteobacteria. It is capable of surviving
and growing in macrophages and other phagocytes. This
bacterium has been reported to grow on various carbohydrates including glucose, galactose, and fructose (McCullough
& Beal, 1951). Transport of glucose was determined with a
Km of 160 mM. Interestingly, the only common glucose
analogue transported was 2-deoxyglucose, with an apparent
Ki of 0.73 mM. The observation that the uptake was sensitive
to various inhibitors led to the suggestion of a protoncoupled rather than a PTS-dependent uptake mechanism
(Rest & Robertson, 1974). By heterologous expression in a
glucose transport-deficient E. coli strain, a screen of a
genomic B. abortus library revealed the identification of the
gluP gene (Essenberg et al., 1997). This gene encodes a
glucose/galactose transporter, which belongs to the major
facilitator superfamily with the fucose-transporter FucP of
E. coli as the closest relative (Pao et al., 1998).
Zymomonas mobilis
In terms of glucose transport systems, the Gram-negative
ethanol producer Z. mobilis constitutes an exception. This
bacterium obviously has a glucose facilitator (Glf) that also
FEMS Microbiol Rev 32 (2008) 891–907
mediates the uptake of fructose and xylose (Weisser et al.,
1995). Subsequent phosphorylation of glucose in Z. mobilis
is catalysed by the glucokinase GlkA. Heterologous complementation using appropriate E. coli mutants demonstrated
that the expression of glkA of Z. mobilis restores the
glucokinase phenotype (Snoep et al., 1994). The introduction of glf into glucose transport-negative, glucokinasepositive E. coli derivatives led to the restoration of growth
on glucose. Transport kinetics of heterologous expression of
glf in such E. coli mutants with [14C]substrates demonstrated that Glf has a Km of 2.5 0.3 mM and a Vmax of
92 5 nmol min1 mg1 protein for glucose. Moreover, the
presence or absence of GlkA did not change the apparent Km
of Glf for glucose, whereas the Vmax for glucose transport
went up by 80% in the presence of glucokinase (Parker
et al., 1995). Interestingly, the apparent Km for glucose of
Glf in recombinant E. coli strains is significantly lower than
measurements of the Km for glucose performed with
wild-type Z. mobilis (Struch et al., 1991). An explanation
for this difference is not known. Nevertheless, because
Z. mobilis resides in the glucose-rich juice of Agave americana, the presence of the low-affinity facilitator Glf is very
appropriate.
Cyanobacterium Synechocystis sp.
In photoautotrophic cyanobacterium Synechocystis sp., the
respiratory process to metabolize sugars is utilized besides
their natural photosynthetic process to generate energy
(Joset-Espardellier et al., 1978). By recovery of the glucose
transport capacity of a transport-deficient Synechocystis
strain, a gene for a proton symporter (glcP) has been
characterized that mediates the assimilation of glucose
(Zhang et al., 1989). Further analyses of GlcP revealed that
this transporter belongs to the major facilitator superfamily,
sharing the highest similarity to the glucose permeases Glf
from Z. mobilis and GlcP from Streptomyces coelicolor
(Snoep et al., 1994; van Wezel et al., 2005).
Thermus thermophilus
Glucose uptake systems have also been described from
T. thermophilus that uses two ABC transport systems, designated as a glucose/mannose ABC and a trehalose, maltose,
sucrose, and palatinose (TMSP)–ABC (Chevance et al.,
2006). The glucose/mannose transport system is encoded
by the glcEFG genes. The glcE gene codes for an extracellular
substrate-binding protein, while the two membrane-embedded permeases of the system are encoded by glcF and
glcG. TMSP–ABC is encoded by the malEFG genes, where
malE encodes the binding protein, which has broader sugar
specificity. The two permeases are encoded by malF and
malG. These systems transport glucose with a Km of 0.15 mM
and a Vmax of 4.22 nmol min1 mL1 OD1
600 nm via the
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898
glucose/mannose ABC transporter and with a Km of 1.4 mM
and a Vmax of 7.6 nmol min1 mL1 OD1
600 nm via the
TMSP–ABC transporter. It could be experimentally demonstrated that the presence of glucose induces both systems
and that the glucose/mannose-binding protein specifically
binds to glucose, mannose, and galactose with a determined
KD of 20 mM and binding saturation at 2.1 mM for glucose,
and galactose, and a KD of 134 mM and binding saturation at
4.76 mM for mannose. The ATPase that provides the energy
for both ABC transporters is encoded by the malK1 gene.
Interestingly, the genes are regulated by an Mlc-like
transcription factor. However, in T. thermophilus no evidence for a glucose–PTS could be found, which means that
the induction mechanism must be different compared with
E. coli. Consequently, it could be demonstrated that binding
of glucose by MlcTth eliminates its ability to bind to its
operator (Chevance et al., 2006). In the absence of glucose,
MlcTth represses the expression of a gene locus, which
encompasses the mlc gene itself, the glucose/mannose ABC
transport genes, and two other genes for permeases. BLAST
analysis of the permease genes revealed homology to membrane components of ABC transporters. Further in silico
analysis identified five other ABC transporters in this
organism. It has been suggested that MalK1 is a general
energy provider for these ABC systems.
Low GC gram-positive bacteria
Bacillus subtilis
In B. subtilis, glucose transport is realized by at least two
different systems: a glucose-specific PTS permease (IICBAGlc) and a hexose/H1 symporter (GlcP) (Sutrina et al.,
1990; Paulsen et al., 1998). The glucose permease is the
product of the ptsG gene and is the first gene of the ptsGHI
operon, which in addition encodes the two general PTS
proteins HPr and EI (Stülke et al., 1998). The glucose/H1
symporter is the gene product of glcP, which was originally
described as a single transcriptional unit (Paulsen et al.,
1998).
Glucose uptake measurements in B. subtilis cells that were
grown in the presence of glucose showed that GlcP contributed about 30% of the glucose transport under these
conditions (Paulsen et al., 1998). In a DptsGHI background,
however, GlcP did not contribute significantly to glucose
transport. This result was taken as an indication that glcP
expression relies on a functional PTS (Paulsen et al., 1998).
The study also revealed that there is at least one more uptake
system operative in B. subtilis. A double mutant devoid of
IIGlc and GlcP still transported glucose. Because ptsHI is also
deleted in the IIGlc-deficient strain, residual glucose uptake
must be due to a non-PTS system. The glucose uptake
protein, GlcU, which was first described in Staphylococcus
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K. Jahreis et al.
xylosus (Fiegler et al., 1999), could be a candidate for the
unknown uptake system in B. subtilis. The gene glcU is
encoded upstream of and is cotranscribed with the glucose
dehydrogenase gene gdh (Nakatani et al., 1989). Transcription of this operon has been shown to occur in the forespore
about two hours after the onset of sporulation (Nakatani
et al., 1989), but expression in the early exponential growth
phase has not been tested. Despite the availability of the
B. subtilis genome sequence (Kunst et al., 1997), the complete set of glucose uptake systems in this organism is still
unknown.
Although some details of glucose uptake in B. subtilis are
missing, it is clear that the ptsG-encoded PTS permease is
the major GLT. Expression of the ptsG gene is glucose
inducible by transcriptional antitermination and involves
the antiterminator protein GlcT, an RNA switch, and the
PtsG permease (Stülke et al., 1997) (Fig. 3). The antiterminator protein GlcT, whose gene is located immediately
upstream of ptsG, consists of three domains: an RNAbinding domain, and two PTS regulation domains (PRD-I,
PRD-II) (Stülke et al., 1998). In the absence of glucose,
PRD-I is phosphorylated by the IIB domain of PtsG
(Schmalisch et al., 2003) and the antiterminator protein is
inactivated. Under these conditions, the transcriptional
terminator in the ptsG RNA switch is generated and ptsGmRNA, which is transcribed by a constitutive promoter, is
prematurely terminated. In contrast, if glucose is transported by PtsG, the phosphate-group is transferred to the
carbohydrate. In turn, nonphosphorylated GlcT can bind to
a sequence in the ptsG riboswitch designated RNA antiterminator (RAT) (Aymerich & Steinmetz, 1992). GlcT
Bacillus subtilis
+ glc
(GlcT active)
– glc
(GlcT~P inactive)
Glc
IIC
IIC
IIB P
IIA P
ptsGP
GlcT
ptsG
Terminator
P
Glc-P
ptsGP
IIB
IIA
ptsG
GlcT
RAT
RAT
Fig. 3. Regulation of the major glucose transport system IICBAGlc (encoded by ptsG) in Bacillus subtilis. In the absence of glucose, the
antiterminator protein GlcT is phosphorylated by the IICBAGlc, which
leads to an inactivation of the protein. In the presence of glucose,
GlcTP is dephosphorylated by the PTS transporter and thus activated.
Activated GlcT binds to the RNA-antiterminator sequence (RAT) and
leads to a transcriptional read-through allowing expression of ptsG.
FEMS Microbiol Rev 32 (2008) 891–907
899
Ins and outs of glucose transport systems in eubacteria
binding to RAT prevents formation of the terminator
structure with transcriptional readthrough as a consequence
(Stülke et al., 1998). GlcT can also be phosphorylated at
PRD-II by HPr, but this phosphorylation has only a minor
impact on protein activity (Schmalisch et al., 2003).
In contrast to the detailed knowledge of ptsG regulation,
very few regulatory details have been worked out for
glcP. Relatively recently, it was shown that the gene is
cotranscribed with genes whose gene products act in the
production of the amino-sugar antibiotic compound neotrehalosadiamine (Inaoka & Ochi, 2007). Interestingly, expression of this operon relies on the catabolite control
protein CcpA as a positive effector. While mechanistic
details of this apparent indirect regulation are still missing,
CcpA-mediated activation of glcP expression may offer an
explanation for the reported PTS dependency of glcP
expression mentioned above (Paulsen et al., 1998). Without
HPr, CcpA activity is considerably diminished in B. subtilis
(Brückner & Titgemeyer, 2002).
Streptococcus /Enterococcus /Lactococcus
In many streptococci, a bacterial group consisting of commensal but also pathogenic species, the major glucose
uptake system belongs to the mannose class of PTS permeases (Zuniga et al., 2005). These PTS permeases, quite
often referred to as mannose/glucose (PTSMan) transporters,
can have relatively broad substrate specificity, being able to
transport mannose, glucose, N-acetylglucosamine, fructose,
and 2-deoxyglucose. Transporters of the mannose class
contain an additional IID domain, and PTSMan transporters
characteristically possess fused IIAB domains (Zuniga et al.,
2005). The genes for PTSMan transporters are organized in
operons with the gene order manLMN (IIAB, IIC, IID)
(Lortie et al., 2000; Abranches et al., 2003; Cochu et al.,
2003; Asanuma et al., 2004; Zuniga et al., 2005). In many,
but not all manLMN operons, a fourth gene encoding a
protein of unknown function is located downstream of the
operon. This gene is designated manO. While manO is
found in a number of other firmicutes, it appears to be
absent from Gammaproteobacteria (Zuniga et al., 2005). In
S. salivarius and S. vestibularis, an additional IIAB (IIABMan
H )
is found, which is larger than IIABMan encoded by manL.
is related to but not identical to IIABMan. The
IIABMan
H
function of this protein remains to be determined (Pelletier
et al., 1998). The mannose PTS is also found in Enterococcus
faecalis and Lactococcus lactis (Thompson & Chassy, 1983,
1985; Thompson et al., 1985).
Expression of the manLMN operon is generally considered constitutive at least with regard to the source of
carbohydrates. However, the manLMN promoter has been
shown recently to be under direct negative control by the
two-component regulatory system CiaRH (Halfmann et al.,
FEMS Microbiol Rev 32 (2008) 891–907
2007). The same regulation appears to be realized in
Streptococcus mitis and Streptococcus sanguinis.
At least in Streptococcus mutans and L. lactis, there is clear
evidence that PTS-independent glucose uptake systems exist
(Keevil et al., 1984, 1986; Cvitkovitch et al., 1995; Luesink
et al., 1999), but those have not been identified at the
molecular level.
Lactobacillus
In lactobacilli, fermentative bacteria that are frequently used
in the dairy industry, the above-mentioned mannose/GLT
(PTSMan) is also the main glucose transport system. The
genes encoding PTSMan are organized in operons (Veyrat
et al., 1996; Yebra et al., 2006). In Lactobacillus casei, for
example, the genetic organization manLMN is the same as in
most of the streptococcal species. The gene manO is located
downstream of the PTSMan-encoding genes. Although
manO is cotranscribed with the manLMN genes, insertional
inactivation of the gene did not result in a recognizable
phenotype (Yebra et al., 2006). Thus, the function of the
ManO protein remains enigmatic. The mannose operon in
Lactobacillus curvatus is one of the examples where the IIA
and IIB domains are encoded by separate genes (Veyrat
et al., 1996).
Apart from the function as the main GLT in quite a
number of bacteria, PTSMan has gained considerable attention as a target for the activity of class II bateriocins (Diep
et al., 2007). It has been demonstrated that the membrane
IIC and IID components render bacteria sensitive to these
types of bacteriocins. Thus, while providing a growth
advantage by means of their efficient carbohydrate uptake,
PTSMan-containing bacteria face the disadvantage of being
susceptible to bacteriocins secreted by competitors.
An L. casei mutant deficient in PTSMan can still take up
glucose and mannose (Veyrat et al., 1994; Yebra et al., 2006).
The transport can be blocked in the presence of an uncoupler that increases the proton permeability of the membrane. The same treatment in the wild-type strain had only a
slight effect on glucose uptake (Veyrat et al., 1994). Thus, a
proton motif force-driven permease is also involved in
glucose transport in this organism. Unfortunately, the gene
for this permease is still unknown. Likewise, a glucose/H1
symporter in Lactobacillus brevis has been characterized
biochemically, but the corresponding gene was not isolated
(Ye et al., 1994). In L. casei, mutants deficient in PTSMan or
in the general PTS are still able to take up glucose (Veyrat
et al., 1996), but again, the non-PTS transport system(s)
have not been characterized.
Staphylococcus
Glucose transport systems have been investigated in two
nonpathogenic staphylococcal species, Staphylococcus
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900
xylosus and Staphylococcus carnosus, which are both applied
in meat fermentation. In S. xylosus, a PTS-independent
glucose uptake system, consisting of the glucose uptake
protein GlcU and the glucokinase GlkA, has been described
(Wagner et al., 1995; Fiegler et al., 1999). The system,
encoded by glcU and glkA at different genetic loci, substantially contributes to glucose catabolism in S. xylosus and its
presence sufficiently explains the ability of a ptsI mutant to
utilize glucose as a carbon source (Jankovic et al., 2003). The
mechanism by which GlcU mediates glucose uptake, however, remains to be clarified.
In S. carnosus, which also contains the GlcU/GlkA system
(Brückner & Rosenstein, 2006), two glucose–PTS permeases
were identified (Christiansen & Hengstenberg, 1999). The
genes glcA and glcB, located in tandem, each encode an
enzyme II denominated IICBAGlc1 and IICBAGlc2, which
share 69% amino acid identity. In vitro PTS-dependent
phosphorylation of glucose demonstrated that IICBAGlc1 has
a Km of 12 mM and IICBAGlc2 of 19 mM. Both enzymes
exhibited similar affinities for glucose, but they reacted differently with glucoside analogues. IICBAGlc1was inhibited by 2deoxy-glucose and methyl-b-D-glucoside, whereas IICBAGlc2
was inhibited by methyl-a-D-glucoside, methyl-b-D-glucoside,
r-nitrophenyl-a-D-glucoside, o-nitrophenyl-b-D-glucoside, and
salicin. Moreover, IICBAGlc1 showed a stronger selection for
substitutions at the C-1 position. It seems that IICBAGlc1 and
IICBAGlc2 have different arrangements of the active-site
amino acids involved in substrate binding and, consequently,
in their catalytic affinity. The tandem arrangement of the
glcA/B genes is so far unique to S. carnosus. In other
staphylococcal species, genes encoding glucose-specific PTS
permeases are not encoded in close vicinity (Jankovic &
Brückner, 2001; Brückner & Rosenstein, 2006).
Immediately upstream of glcA, a gene, glcT, was detected,
whose deduced amino acid sequence shows a high degree of
similarity to bacterial regulators involved in antitermination
(Stülke et al., 1998). A putative transcriptional terminator
partially overlapping an inverted repeat, which could be the
target site for the antiterminator protein GlcT, is situated in
the glcT-glcA intergenic region. This organization resembles
the glcT-ptsG region of B. subtilis. Studies of S. carnosus GlcT
activity in the heterologous host B. subtilis indicated that the
protein is indeed able to cause antitermination (Knezevic
et al., 2000). While glcA of S. carnosus is apparently
controlled by antitermination, glcU regulation in S. xylosus
has not yet been elucidated.
High-GC gram-positive bacteria
In high-GC Gram-positive bacteria that are called Actinobacteria, several glucose transport systems have been described at the molecular level. There is information available
from soil-dwelling sporulating streptomycetes, from non2008 Federation of European Microbiological Societies
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K. Jahreis et al.
sporulating corynebacteria and mycobacteria, and from gut
commensals, the probiotic bifidobacteria.
Streptomyces coelicolor
Streptomyces coelicolor is the model organism for sporulating, antibiotic-producing streptomycetes, a genus of major
importance for pharmacological and industrial exploitation
(Chater, 1999; Demain, 2000). These bacteria grow in the
soil as a vegetative fungus-like mycelium, from which they
develop under nutrient-worsening conditions aerial hyphae
and exospores. The glucose permease GlcP, a member of the
major facilitator super family, was detected by similarity
searches with the glucose permease sequences of Z. mobilis
and Synechocystis (Zhang et al., 1989; Weisser et al., 1995;
van Wezel et al., 2005). Two almost identical glucose
permease genes, glcP1 and glcP2, which differ in four
nucleotides but translate to identical proteins, were detected
in the genome of S. coelicolor A3(2) (Bentley et al., 2002).
The kinetic features of GlcP1 were derived from heterologous production in an E. coli glucose transport mutant
strain. The Km could be determined with 41 5 mM and
the Vmax with 23 1 nmol min1 OD1
600 nm, demonstrating
that GlcP is a high-affinity GLT. As substrates, glucose and
2-deoxyglucose were recognized efficiently, indicating narrow substrate specificity. The activity was inhibited by the
ionophore CCCP, which suggests that GlcP operates as a H1
symporter as most permeases of the major facilitator superfamily do (Pao et al., 1998). Transcription analyses demonstrated that expression of glcP1 is induced by the presence of
glucose in the medium and is essential for glucose uptake,
while glcP2 was found to be barely expressed. It has been
suggested that GlcP2 might be important under different
growth conditions. GlcP is also found in Streptomyces
lividans (van Wezel et al., 2005) and Streptomyces avermitilis
(Ikeda et al., 2003). Because the genome of the latter is
known, it was surprising to notice that this species has only
one glcP gene. The promoter region of glcP1 contains a
conserved 16-bp palindromic sequence, which could participate in the regulation. A regulator, however, has not yet
been identified.
Corynebacteria
Corynebacterium glutamicum is a main producer of amino
acids, notably glutamate, methionine, and lysine, yielding
more than 2 million tonnes of flavour compounds and food
additives each year (Eikmanns et al., 1993; Jetten & Sinskey,
1995). Studies on sugar transport revealed that C. glutamicum has PTS permeases for the uptake of glucose, fructose,
and sucrose (Moon et al., 2007). The PTS components EI,
HPr, and IIBCAGlc (ptsG) were identified experimentally
and it was shown that the respective mutants could barely
grow on glucose (Parche et al., 2001a; Moon et al., 2005),
FEMS Microbiol Rev 32 (2008) 891–907
901
Ins and outs of glucose transport systems in eubacteria
Corynebacterium glutamicum
– glc
(SugR active)
+ glc
(SugR•Fru-6-P inactive)
Glc
IIC
IIC
IIB P
IIA P
IIB
IIA
Glc6-P
Fru6-P
SugR
SugR
ptsGOP
ptsG in C. diphtheriae is, as ptsG of B. subtilis (see Fig. 2),
regulated by transcriptional antitermination and thus in a
manner totally different from the regulation found in
C. glutamicum.
ptsG
ptsGOP
ptsG
Fig. 4. Regulation of the major glucose transport system IIBCAGlc
(encoded by ptsG) in Corynebacterium glutamicum. In the absence of
glucose, ptsG expression is repressed by the DeoR-type regulator SugR.
The transport of glucose causes accumulation of the metabolite fructose-6-phosphate (Fru6-P). Its binding to SugR prevents DNA binding of
the regulator to the cognate operator sequence (ptsGop).
suggesting that ptsG encodes the major GLT. The permease
has a Km in the low micromolar range and narrow substrate
specificity for glucose and glucose analogues, as well as a low
affinity for mannose and fructose (E.F. Pimentel-Schmitt,
unpublished results) (Moon et al., 2007). Phylogenetic
analyses showed that IIBCAGlc falls into the subcluster of the
b-glucoside-sucrose–trehalose family of PTS permeases and
not into the subcluster comprising enzymes II specific for
glucose and N-acetylglucosamine (Parche et al., 2001b).
This suggests a different evolution of the glucose-specific
PTS present in corynebacteria. While it was originally
reported that ptsG expression is constitutive (Parche et al.,
2001a; Moon et al., 2007), it turns out that it is regulated by
the DeoR-type regulator SugR (Fig. 4) (Engels & Wendisch,
2007). SugR binds to a 75-bp fragment of the ptsG promoter
region and responds to fructose-6-phosphate. A cometabolization with gluconeogenic substrates such as acetate results
in repression of ptsG, while glucose or any other condition
that deliver high internal fructose-6-phosphate concentrations leads to ptsG expression. The authors observed further
that SugR is involved in the regulation of several genes
including ptsF and ptsS, which encode the PTS permeases
for fructose and sucrose, indicating that SugR serves functions in a higher hierarchic manner.
In Corynebacterium diphtheriae, the causative agent of
diphtheria (Mattos-Guaraldi et al., 2003), bioinformatic
analyses showed the presence of PTS components encoded
by the genes ptsH, ptsI, and ptsG (Parche et al., 2001b).
PtsG shares 42% protein identity and the same IIBCA
domain order as the one of C. glutamicum. Curiously, a
regulatory gene that encodes an antiterminator, designated
glcT, is found downstream of ptsG (Parche et al., 2001b;
Moon et al., 2007). Based on this, it was suggested that
FEMS Microbiol Rev 32 (2008) 891–907
Bifidobacteria
Bifidobacterium species are applied in the dairy industry as
probiotic cultures that beneficially influence the host (Salminen et al., 1998). They can for example stimulate
the immune system, have cholesterol-lowering effects, and
prevent cancer recurrence. For the transport of glucose,
different systems were identified. A glucose–PTS was demonstrated in Bifidobacterium breve (Degnan & Macfarlane,
1993), and a potassium-dependent glucose permease was
characterized in Bifidobacterium bifidum (Krzewinski et al.,
1997). The latter showed characteristics of a low-affinity
transporter with a Km of 9.16 mM. However, these systems
have so far been characterized biochemically without identification of the genes. Recently, a proton symporter system
for glucose transport (GlcP) was described in detail in
Bifidobacterium longum (Parche et al., 2006). This study
demonstrated that the glcP gene complemented an E. coli
glucose-deficient strain. Using the heterologous expression
system in E. coli, the Km and Vmax for glucose uptake were
determined as 70 14 mM and 11 2 nmol min1 OD1
600 nm.
It was further demonstrated that GlcP has the highest
affinity for glucose, followed by 2-deoxy-glucose, mannose,
and galactose, while fructose, arabinose, and xylose were
poorly recognized. The observation that B. longum shows a
‘reverse’ diauxic growth behaviour is quite interesting. It
prefers lactose over glucose. Microarray analysis revealed
that only the glcP gene was the target of this repression when
B. longum was grown in the presence of glucose and lactose
(Parche et al., 2006).
Adjacent to the glcP gene, genes for a PTS-specific glucose
permease (ptsG) and a gene for an antiterminator (glcT) are
located (Parche et al., 2006). Although it has been shown
that the glucose-PTS is functional, its level of expression is
apparently so low that it merely contributes to glucose
transport (Parche et al., 2006, 2007). The genetic setting of
two glucose permease genes with different mechanistic
functions is thus far a unique feature. The gene order ptsG
glcT, however, resembles the situation in C. diphtheriae.
Further analysis is required to describe a possible regulation
of ptsG and/or glcP by GlcT in B. longum.
Mycobacteria
In contrast to the advantageous industrial use of streptomycetes, corynebacteria, and bifidobacteria, the saprophytic
Mycobacterium smegmatis has been used as a model to
understand virulence in mycobacteria. In contrast to previous reports, a PTS for glucose uptake has been identified
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902
recently by in silico analysis (Titgemeyer et al., 2007). In fact,
all components like HPr, EI, IIBC (ptsG), and IIAGlc (crr) are
present in this organism. Additionally, bioinformatic analyses revealed a putative glucose permease encoded by the
gene msmeg4182 (glcP). The deduced protein belongs to the
major facilitator super family and shares 53% amino acid
identity with the main GLT GlcP of S. coelicolor and 34%
with GlcP of B. longum (van Wezel et al., 2005; Parche et al.,
2006). We could confirm by heterologous complementation
in an E. coli GLT-deficient strain that GlcP of
M. smegmatis is a glucose permease with biochemical
features similar to GlcP of S. coelicolor (Pimentel-Schmitt
et al., 2008). Further analysis regarding the function and
regulation of the two M. smegmatis transporters is currently
in progress. Interestingly, both systems are not present in
slow-growing, pathogenic bacteria, notably Mycobacterium
tuberculosis and Mycobacterium leprae (Titgemeyer et al.,
2007). At present, it is not known by which system glucose is
incorporated into these bacteria.
Conclusions
Our overview of bacterial glucose transport systems shows
that the premium carbon source glucose is internalized by
diverse transporter types that use ATP-, PEP-, or ion
gradient-driven mechanisms, or passive diffusion (Fig. 1
and Table 1). We have learned through the comparison of
data from more than forty years of glucose transport
research that (1) the glucose-specific PTSs are most common in Gram-negative and low-GC Gram-positive bacteria,
while (2) high-GC Gram-positive bacteria prefer homologous types of proton-driven permeases with similar biochemical characteristics, although their habitats and their
life cycles differ considerably. (3) Glucose uptake through
ABC porters or facilitators is the exception. (4) Some
bacteria like E. coli have several glucose uptake systems that
may serve as backup transporters, or that are used as
alternative import possibilities under certain environmental
conditions like up-regulation of a high-affinity system when
low amounts of glucose are available or upregulation of lowaffinity porters in glucose-rich environments. (5) Knowledge of the detailed mechanistic function including insights
into the atomic structures of the permeases and the impact
of transport on the metabolic flux will considerably enhance
our capability to pursue beneficial approaches. (6) The
underlying regulatory mechanisms are the same in closely
related species but diverse, and thus nonhomologous, in
distantly related bacteria, although such bacteria could have
homologous glucose uptake systems. This can be explained
by independent evolution events through horizontal gene
transfer. (7) The continual emergence of new aspects in the
complex regulation of glucose transport, which we have seen
in the past few years in E. coli, definitely sheds some light on
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K. Jahreis et al.
what can be expected from bacterial systems that have not
yet been investigated in such detail.
Acknowledgements
This study was financially supported by the Deutsche Forschungsgemeinschaft through grants GK805 and SFB473 to
E.F.P-S. and F.T., and SFB431 to K.J. F.T. and K.J. dedicate
this review to Joseph Lengeler, who has introduced us to this
fascinating area of research.
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