World J Microbiol Biotechnol (2017) 33:162
DOI 10.1007/s11274-017-2328-0
REVIEW
Carbon catabolite regulation in Streptomyces: new insights
and lessons learned
Alba Romero‑Rodríguez1 · Diana Rocha1 · Beatriz Ruiz‑Villafán1 · Silvia Guzmán‑Trampe1 ·
Nidia Maldonado‑Carmona1 · Melissa Vázquez‑Hernández1 · Augusto Zelarayán1 · Romina Rodríguez‑Sanoja1 ·
Sergio Sánchez1 
Received: 3 June 2017 / Accepted: 30 July 2017
© Springer Science+Business Media B.V. 2017
Abstract  One of the most significant control mechanisms
of the physiological processes in the genus Streptomyces
is carbon catabolite repression (CCR). This mechanism
controls the expression of genes involved in the uptake
and utilization of alternative carbon sources in Streptomy-
ces and is mostly independent of the phosphoenolpyruvate
phosphotransferase system (PTS). CCR also affects mor-
phological differentiation and the synthesis of secondary
metabolites, although not all secondary metabolite genes
are equally sensitive to the control by the carbon source.
Even when the outcome effect of CCR in bacteria is the
same, their essential mechanisms can be rather different.
Although usually, glucose elicits this phenomenon, other
rapidly metabolized carbon sources can also cause CCR.
Multiple efforts have been put through to the understanding
of the mechanism of CCR in this genus. However, a rea-
sonable mechanism to explain the nature of this process in
Streptomyces does not yet exist. Several examples of pri-
mary and secondary metabolites subject to CCR will be
examined in this review. Additionally, recent advances in
the metabolites and protein factors involved in the Strepto-
myces CCR, as well as their mechanisms will be described
and discussed in this review.
Alba Romero-Rodríguez and Diana Rocha have contributed
equally to this work.
* Sergio Sánchez
sersan@biomedicas.unam.mx
1 Glucose, usually an excellent carbon source for growth,
Instituto de Investigaciones Biomédicas, Universidad
Nacional Autónoma de México, Tercer Circuito Exterior de
Ciudad Universitaria, Mexico City 04510, Mexico
Keywords  Streptomyces · Regulatory mechanisms ·
Repression · Gene expression · Secondary metabolites ·
Morphological differentiation
Introduction
Importance of carbon catabolite repression
In Streptomyces and other microorganisms, carbon source
regulation, commonly known as carbon catabolite repres-
sion (CCR), is one of the most conserved mechanisms pro-
tecting the cells against wasting the protein-synthesizing
machinery. CCR is an important mechanism for competi-
tion in natural environments, since the selection of pre-
ferred carbon sources is a major determining factor in the
microbial growth rate and therefore, supports successful
competition with other microorganisms (Gorke and Stülke
2008). This mechanism regulates the expression of genes
involved in the uptake and utilization of alternative carbon
sources and operates when more than one utilizable sub-
strate is present in the environment. As many as 5–10%
of all bacterial genes are subject to this type of regulation.
While the cell produces specific enzymes to catabolize the
rapidly assimilated carbon sources, the enzymes involved
in other substrates utilization are repressed until the pri-
mary substrate is exhausted, and it is at that moment that
the second best starts to be utilized. Although CCR is usu-
ally exerted by glucose, in different microorganisms other
rapidly metabolized carbon sources can cause repression
and, even, can repress the catabolism of glucose (Demain
1989).
when used in high concentrations also interferes with
the formation of many compounds, including secondary
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metabolites, and delays morphological differentiation: ‘too
much of a good thing can be bad’ (Demain 1989).
Diverse mechanisms have been described in bacteria to
explain the undesirable carbon catabolite effects on pri-
mary metabolites utilization and secondary metabolite pro-
duction. These mechanisms show substantial differences
depending on the type of bacteria being considered. For
a long time, glucose kinase has been associated to CCR
(Angell et al. 1992). However, new molecules or transcrip-
tional regulators have emerged as potential performers of
this puzzling mechanism (Romero-Rodríguez et al. 2016a).
In this review, aside from describing the physiological pro-
cesses and metabolic pathways influenced by glucose in
several Streptomyces models, several unexplored transcrip-
tional regulators involved in the CCR mechanism and new
putative regulatory proteins possibly involved or control-
ling CCR, will be described and discussed.
Regulation by the carbon source in Streptomyces
species
Primary metabolism
Streptomycetes are widely distributed on the planet,
although the soil has been the niche most studied. Depend-
ing on the sampled region the soil could be rich in insolu-
ble polymers such as proteins, starch, cellulose, and chitin.
The source of most of these insoluble polymeric nutrients
are the plants. The use of these substrates for the bacte-
rial growth requires secretion of extracellular enzymes and
incorporation of the soluble breakdown products. The vari-
ety and multiplicity of carbohydrate and protein degrading
pathways harbored by Streptomyces reflect the diversity
and multiplicity of these polymers in the soil. Therefore,
control of the primary metabolism in Streptomyces depends
on the nutrients availability. Glucose affects the expres-
sion of genes involved in the utilization of glycerol (Hin-
dle and Smith 1994), galactose (Brawner et  al. 1997),
sucrose, mannose (Kayali et  al. 2011), arabinose, fructose
(Hodgson 1982), maltose (van Wezel et al. 1997) and cel-
lobiose (Schlösser et al. 2000). In addition to carbohydrate
transport systems, CCR of intracellular and extracellular
catabolic enzymes have been reported in different strepto-
mycetes. As such, glucose influences production of glyco-
side-hydrolases such as cellulases (Marushima et al. 2009),
α-amylases (Mellouli et  al. 2002), xylanases (Arhin et  al.
1994), β-galactosidases (Pérez-Pons et  al. 1995), agarases
(Servin-Gonzalez et  al. 1994) and chitinases (Saito et  al.
2000). A repressive effect of glucose was also reported for
bacteriolytic- and proteolytic enzymes in several Strepto-
myces strains (Zhernosekova and Kilochek 2000; Abdelwa-
hed et  al. 2014). Also in the metabolism of some amino
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World J Microbiol Biotechnol (2017) 33:162
acids (Tang and Hutchinson 1995) and nucleotides (Ohe
and Watanabe 1977), respectively.
The regulatory mechanisms involved in these processes
in Streptomyces will be described in detail in the following
paragraphs.
Regulation of secondary metabolites production
Secondary metabolism comprises a group of metabolic
pathways whose products are synthesized from a precur-
sor derived from primary metabolism (Demain and Fang
2001). These products are known as secondary metabolites,
and they display an extensive range of activities of human
interest including antibacterial effects. Among bacteria, the
most prolific antibiotic producers are Streptomyces bacte-
ria. The antibiotic synthesis begins at the idiophase, and
their production is highly regulated genetically as well as
by the nutritional intake of phosphate, nitrogen and carbon
sources (Liu et  al. 2013; Romero-Rodríguez et  al. 2015,
2016a) (Fig. 1). The carbon regulation initiates when high
concentrations of glucose and other carbohydrates are fed
into the culture media, resulting in most cases in downregu-
lation effects on antibiotic production by lowering or even
abolishing its production (Ruiz et  al. 2010; Romero-Rod-
ríguez et al. 2016b).
It has been reported that glucose plays the major role
as a suppressor over secondary metabolism by modulat-
ing the primary metabolism and thus limiting the avail-
ability of its precursors as occurs with actinorhodin (ACT)
and undecylprodigiosin (RED) production in Streptomyces
coelicolor (Ruiz et al. 2010). In addition to glucose, other
carbon sources like glycerol display suppressive effects on
the production of secondary metabolites like actinomycin
by Streptomyces parvulus or cycloserine in Streptomyces
garyphalus (Demain and Fang 1995). The suppressive
effects are also seen in non-antibiotic metabolites like geo-
smin in Streptomyces halstedii. In this case, several carbon
sources like citrate, fructose or sucrose decrease its pro-
duction levels when compared to mannitol (Schrader and
Blevins 2001). The negative influence of several carbon
sources over the synthesis of antibiotics, most of them with
clinical application, are displayed in Table 1.
While earlier studies have focused on how carbon
sources such as monosaccharides affect the production of
select metabolites, the current research investigates the
molecular factors implicated in these phenotypical changes.
Morphological differentiation
Streptomycetes exhibit a complex developmental biology,
involving mycelial growth, multicellular behavior, inter-
cellular communication, and morphological differentia-
tion. These biological processes are accurately regulated by
World J Microbiol Biotechnol (2017) 33:162 Page 3 of 11  162
Fig.  1  a Regulation of secondary metabolism by the nutritional
intake/availability of phosphate (P), nitrogen (N) and carbon sources
(CS). Regulation can occur by modifying the activity of enzymes
of primary (PM) or secondary metabolism (SM), as well as through
the effect of pleiotropic and carbon source regulators. A high con-
centration of glucose and other carbohydrates results in most cases
in down-regulation effects on antibiotic production. b Effect of
SCO2127 and phosphorylated intermediates of the glycolisis on sec-
ondary metabolism in Streptomyces peucetius var. caesius. While the
ATP-Glk is necessary for CCR, its function on the anthracycline for-
several regulatory mechanisms, including the regulation
by the carbon source. The morphological differentiation of
Streptomyces assures the survival of the cell under differ-
ent types of stress. However, due to its metabolic cost, it
is a top regulated process in the cell. Like most processes
in Streptomyces, a high concentration of glucose or other
favorable carbon source prevents its morphological differ-
entiation, but the molecular mechanism used in the process
remain elusive (McCormick and Flärdh 2012). Morpholog-
ical differentiation is repressed by glucose in several strep-
tomycetes like Streptomyces albidoflavus (Kang and Lee
1997), Streptomyces griseus (Seo et al. 2002), and S. coeli-
color (Colson et al. 2008; Romero-Rodríguez et al. 2016b).
Several proteins have been found to be involved in the
CCR of morphological development. Among them, the
most studied is the operon DasABC, a protein complex
mation is currently unclear. Red arrows indicate a negative effect. c
DasR repression of target genes expression in secondary metabolites
formation. Regulators such as AtrA, ROK7B7 and ArgR seem to have
a positive effect. A direct interaction between Glk with transcriptional
factors has not been yet demonstrated. Red arrows indicate a negative
effect; solid black arrows indicate a positive effect, dashed lines indi-
cate a possible indirect effect. Illustrated secondary metabolites are
ACT (actinorhodin), RED (undecylprodigiosin), CPK (yellow type I
polyketide), CDA (calcium-dependent antibiotic)
encoding an ABC transporter, probably involved in sugar
import (Seo et al. 2002). Disruption of dasA gene in in the
S. griseus wild-type strain resulted in ectopic sporulation of
substrate mycelium in the presence of glucose, suggesting
an additional role of this gene in aerial mycelium forma-
tion. Introduction of a multicopy plasmid containing the
gene dasA into the wild-type strain caused ectopic sporu-
lation independent of the presence of the butyrolactone A
factor (Seo et al. 2002).
Historically, bldB mutants have been recognized for
their incapacity to develop aerial mycelium. Unlike the
other bld mutants as bldD or bldA, bldB mutants are
insensitive to glucose repression (Pope et  al. 1998),
which probably means a limited relationship between
primary metabolism and morphological differentiation
through GlkA. The latter was demonstrated in recent
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Table 1  Examples of antibiotics repressed by the carbon source and the producer microorganism
Strain Antibiotic Repressor System References

Streptomyces lincolnensis L1245
Streptomyces parvalus
Streptomyces garyphalus
Streptomyces griseus
Streptomyces peucetius var.
caesius
Streptomyces venezuelae
Streptomyces coelicolor, Strepto-
myces lividans
Streptomyces lactamdurans
Streptomyces clavuligerus
Lincomycin Glucose Glucose diminish Ln production. Majerčíková et al. (2015)
When added to a 7 day precul-
ture enhances Ln production
Actinomycin Glucose, glycerol Both represses tryptophan pyr- Brown et al. (1983)
rolase and kynurenine formami-
dase
Cycloserine Glycerol Demain and Fang (1995)
Streptomycin Glucose Glucose repression of mannosi- Demain and Inamine (1970)
dostreptomycinase decreases
streptomycin yields obtained
from mannosidostreptomycin
breakdown
Anthracyclines Glucose Over 100 mM glucose exhibits a Escalante et al. (1999)
negative effect on anthracycline
synthesis
Chloramphenicol Glucose Glucose has a negative effect Bhatnagar et al. (1988)
over antibiotic depending on
the nitrogen source supplied or
reducing arylamine synthetase
expression
Actinorhodin ACT/ Glucose Glucose acts as repressor of ACT Borodina et al. (2008)
undecylprodigiosin Xylose and RED by activating pfkA2 Park et al. (2009)
RED Using xylose, ROK7B7 activates
the production of ACT but
represses RED
Cephamycin Glucose Glucose represses expandase Cortés et al. (1984)
Glycerol biosynthesis Lebrihi et al. (1988)
Glycerol exerts repression of
cephamycin C synthase and
expandase

proteomic studies on a glkA null mutant, on which a clear
repression on bld genes was observed in the presence of
glucose (van Wezel and McDowall 2011).
In S. coelicolor, our research group has discovered that
high concentration of glucose (100 mM) arrests sporula-
tion on solid media in the wild-type strain (M145). How-
ever, a null Δsco2127 mutant dodges this effect and its
sporulation is unaffected by glucose, suggesting a role of
this protein in the regulatory process. In support of this
view, an interaction between SCO2127 and BldKB has
been demonstrated in vitro (Chávez et al. 2009, 2011).
Mutants on the RNA polymerase sigma factor SigN
had shown a delay in development when were grown
on minimal media with 1% glucose. Interestingly, sigN
mutants still produce actinorhodin and undecylprodi-
gionin, implying that SigN regulates sporulation but not
antibiotic production, even though the processes are usu-
ally tied together (Dalton et al. 2007). This detachment of
the two regulons can prove beneficial for the bacteria in
this case because it allows microbial protection even in
the absence of differentiation.
While most of the knowledge acquired of CCR on mor-
phological development is a direct consequence of the
study of transcriptional factors, it remains incomplete as
few studies have tried to elucidate the whole framework of
interactions between transcriptional factors and their targets
in various growth conditions.
Advances in the mechanism of carbon source
regulation
The role of glucose kinase (Glk)
In Streptomyces, glucose is mainly transported through
the GlcP transporter of the MFS family (van Wezel et  al.
2005) and phosphorylated by glucose kinase (GlkA), form-
ing glucose 6-phosphate. In this genus, GlkA is involved
globally in regulating the CCR phenomenon. Mutants
from S. coelicolor A3(2) and Streptomyces peucetius var.
caesius, resistant to the glucose analogue, 2-deoxyglucose
(2-dog), are not subject to glucose repression (Hodgson

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World J Microbiol Biotechnol (2017) 33:162 Page 5 of 11  162
1982; Segura et al. 1996). The lack of glucose repression in
such mutants correlates with the loss of the ATP-dependent
glucose kinase activity (Hodgson 1982). Complementation
of S. coelicolor mutants with the Zymomonas mobilis glk
gene restores Glk activity; growth on glucose, 2-dog sensi-
tivity, but not sensitivity to glucose repression (Angell et al.
1994). These results suggest that Glk plays a determinant
role in CCR beyond restoring the metabolic flux (Angell
et  al. 1994). This glucose insensitivity was extended to
other repressor carbon sources that are not metabolized via
GlkA (Kwakman and Postma 1994).
GlkA shares identity with the ROK family proteins,
comprising transcriptional regulators that have the classic
DNA binding site (helix-turn-helix), and kinases, involved
in regulatory processes. However, the S. coelicolor GlkA,
as well as the ROK family kinases, lack this DNA bind-
ing domain, so they cannot exert their regulatory role by
directly binding to the promoter regions of the repressed
genes (Titgemeyer et al. 1994).
It has been speculated that Glk acts interacting with
other proteins and the formed complex exerts this regula-
tion. Interaction of GlkA with other proteins was detected
in the cytosolic fraction of S. coelicolor when analyzed by
surface plasmon resonance, but the target protein has not
been identified (Mahr et al. 2000). Nevertheless, van Wezel
et  al. (2007) demonstrated the interaction between GlkA
and GlcP, necessary for the efficient transport and phospho-
rylation of glucose from the culture medium.
For the doxorubicin producer, S. peucetius var. caesius,
DogR mutants were obtained, which presented insensitiv-
ity to CCR. These mutants showed decreased GlcP and Glk
activity (Escalante et al. 1999). Both activities are restored
or even increased when the mutants are complemented
with glkA and sco2127 genes. The sco2127 gene is located
upstream of glkA, but its function is unknown (Guzmán
et al. 2005a, b).
Recent studies in a S. coelicolor ΔglkA mutant sug-
gested that CCR operates through two different mecha-
nisms, one is GlkA-dependent and the other is glucose
dependent (Romero-Rodríguez et  al. 2016a). Proteomic
and transcriptomic studies showed that the higher change
in gene expression was due to the glucose itself compared
to the absence of GlkA. It was observed that glucose stimu-
lated glycolysis and the pentose phosphate pathway, signal
mediated by GlcP. It also affects negatively the enzymes
involved in the metabolism and transport of amino acids.
Unlike other transporters, the xylose transport system
is strongly activated in the presence of glucose and do
not depends on GlkA, as well as its regulator Rok7B7
(Swiatek et  al. 2013). As expected, the inducer exclusion
of different carbohydrates and amino acids transporters
are also dependent of GlkA regulation. A strong influence
of GlkA over the synthesis of prodigionins (RED) and
calcium-dependent antibiotic (CDA) was observed (Gub-
bens et al. 2012; Romero-Rodríguez et al. 2016a).
Transcriptome studies showed a change in the expres-
sion of 91 genes in the presence of glucose and absence
of glkA. About 500 genes changed their expression solely
due to glucose and only the expression of 43 genes is modi-
fied by the absence of the glkA gene. Therefore, contrary to
the previous hypothesis, GlkA does not seem to have such
a broad global effect on CCR (Fig.  1b). GlkA also modi-
fies the expression of 40 DNA binding protein genes, sug-
gesting that the CCR effect observed during all these years
of study is probably due to the combined action of GlkA
and some transcription factors to exert CCR (Romero-Rod-
ríguez et al. 2016b). These studies demonstrate how com-
plex is the process of regulation of CCR in Streptomyces,
and opens the way to study multiple regulators of unknown
function that could be involved in the process.
Regulation by additional proteins
As previously mentioned, the pioneer studies on Streptomy-
ces CCR identified the Glk as a transcendental masterpiece
of this mechanism. Nonetheless, the complementation of
DogR mutants with Glk only partially restores the CCR
(Angell et al. 1992). Total recovery can be observed when
using a 2.9 kb DNA fragment containing the sco2127 gene.
This effect is also detected in the anthracycline producer S.
peucetius var. caesius (Guzmán et al. 2005a) (Fig. 1c).
It has been predicted that the sco2127 gene product,
which is located directly upstream of glkA, may interact
with other proteins to stimulate either glkA transcription or
enzyme activity (Guzmán et al. 2005a, Chavez et al. 2011).
However, these hypotheses have not been experimentally
validated yet.
The sco2127 gene codes for a soluble protein detected
during the late growth phase of S. coelicolor grown in a
complex medium supplemented with 100  mM glucose
(Chávez et  al. 2011). When comparing the Glk activ-
ity in S. coelicolor M145 and its sco2127 null mutant in
cells grown in a chemically defined medium, the glucose
consumption and Glk activity show the same profile in
both strains (Forero et  al. 2012). However, the primary
Glk activity remains higher in the sco2127 mutant when
compared with its parenteral strain. It was suggested that
sco2127 gene could prevent actinorhodin formation during
early stages of fermentation (Forero et al. 2012). Recently,
a proteomic approach showed the comparison between the
sco2127 deleted strain and its parenteral strain. The mutant
displayed a reduction in the production of actinorhodin,
an altered expression of the mycothiol and hydroxyec-
toine biosynthetic enzymes, as well as the accumulation
of nitrite (Tierrafría et  al. 2016). Additionally, deletion of
sco2127 also resulted in an increased abundance of the
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 162   Page 6 of 11
gluconeogenic enzymes glyceraldehyde-3-phosphate dehy-
drogenase (SCO7040) and fructose 1,6-bisphosphatase
(SCO5047) (Tierrafría et al. 2016).
As mentioned, several studies have been performed to
determine the activity/function, if any, of the expression
product of the gene sco2127, but despite the efforts, to our
knowledge, the participation of the sco2127 on CCR, at
least in S. coelicolor, is unclear.
The role of transcriptional regulators
Transcriptional factors are involved in regulation of pri-
mary and secondary metabolism. Mutants in pathway-
specific regulators are also deregulated in glucose repres-
sion. Hindle and Smith (1994) first reported a catabolic
regulator, GylR, necessary for both, substrate induction and
CCR of glycerol utilization. In the same line, mutants in
the master regulator of the cellulose/cellooligosaccharide
catabolism (CebR), exhibit a deficient glucose repression
of β-galactosidase in a minimal medium containing lactose,
indicating that CebR is required for the glucose repression
of this enzyme (Marushima et  al. 2009). A homologous
repressor of the LacI/GalR family, MalR, from S. coeli-
color is required for maltose utilization, and hence it is
required for substrate induction and glucose repression of
maltose utilization (vanWezel et al. 1997).
Recently, the probable LacI-family transcriptional reg-
ulator encoded by sco3485 has been proposed to be the
regulator of agar utilization in S. coelicolor. Transcription
of the dag gene is not affected either by glucose or glkA
(Gubbens et  al. 2012; Romero-Rodríguez et  al. 2016a),
but instead SCO3485 may act as a repressor, binding to its
target and allosterically regulating by its ligand, probably
neoagarobiose.
AtrA, is a transcription factor that belongs to the TetR
family, which is required for the transcription of actIII-
ORF4 in S. coelicolor (Uguru et  al. 2005). Furthermore,
strR is the pathway specific activator of ACT and strepto-
mycin production in S. griseus (Hong et al. 2007) (Fig. 1c).
The above examples of substrate induction and CCR
mediated by specific regulators may imply a protein–pro-
tein interaction or allosteric inhibition controlling the activ-
ity of specific transcriptional regulators. However, how this
regulation is orchestrated or affected by Glk is unknown.
The direct interaction of Glk with transcriptional factors
have been tested showing inconclusive results (Mahr et al.
2000; van Wezel et al. 2007). Nevertheless, it is clear that
operon specific regulators are necessary not only for the
control of their own operons but also for CCR.
Besides local regulation of operons, CCR may also
be mediated by global regulators. As Martin and Liras
(2010) proposed, the interactions between the global nutri-
tional regulators are a promising ground to understand the
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World J Microbiol Biotechnol (2017) 33:162
coordination of metabolism and the response to different
nutritional factors in Streptomyces, including CCR.
One of the best-studied regulators related to car-
bon metabolism on the Streptomyces genus is DasR, a
GntR-family transcriptional factor (Romero-Rodríguez
et  al. 2015). Through different approximations, it has
been revealed its significant role on RCC in S. griseus
(SGR_2282) (Seo et  al. 2002) and S. coelicolor (gene
sco5231). On both organisms, DasR represses expression
of its target genes accordingly to N-acetylglucosamine-
6-phosphate (GlcNAc-6P) or glucosamine-6-phosphate
(Glc-6P) availability on the media (Fig. 2). These substrates
are products of chitin degradation, but also a byproduct of
cell wall lysis, indicating the DasR capability to differenti-
ate between nutrients provided by the surrounding media
or by autolysis (Świątek et al. 2012). Lately, by a genomic-
wide approximation, it was confirmed not only its ability
to bind the dre-sites of genes related to morphological dif-
ferentiation and primary metabolism but also to discov-
ered novel binding sites (Świątek-Połatyńska et  al. 2015).
Interestingly, these novel binding sites include the upstream
regions of genes directly related to the production of the
Calcium-Dependent Antibiotic (cdaPSI and cdaPSII), to
actinorhodin (actII-4), undecylprodigiosin (redD, redZ)
and the cryptic polyketide (cpkC, cpkB, cpkA). This discov-
ery indicates a direct link between primary metabolism and
cryptic clusters, providing a tool for metabolic engineer-
ing in the expression of cryptic clusters of other actino-
mycetes (Świątek et  al. 2012). Also, the possible interac-
tion between DasR and other regulatory proteins leads to
new studies that will extend the knowledge on CCR and
its molecular mechanisms, as DasR appears to be the best-
known link between primary metabolism, morphological
differentiation, and antibiotic production.
ROK7B7 is a member of the ROK family, a group of
sugar-responsive transcriptional regulators whose partici-
pation on CCR has just recently noted. Initially, ROK7B7
was identified as a protein capable of bind to the upstream
region of red genes (Park et  al. 2009). This finding was
later verified in a transcriptomic and proteomic evalua-
tion of the null mutant of ROK7B7, where prodigionins
expression was largely induced, as well as other secondary
metabolites. Remarkably, GlkA expression was enhanced
in this mutant, suggesting a correlation between ROK7B7
and CCR (Fig. 2c). A reduction in the agarase production
by the mutant ROk7B7 in several carbon sources confirmed
this view. However, the amplitude of its function as regulon
is still unknown (Swiatek et al. 2013).
A comparison between the S. coelicolor wild-type strain
and its derivative argR mutant demonstrated that this regu-
lator is not only involved in the arginine metabolism. Actu-
ally, nitrogen metabolism, antibiotics production, synthesis
of membrane proteins, morphology, sporulation, multiple
World J Microbiol Biotechnol (2017) 33:162 Page 7 of 11  162
Fig. 2  Model of the DasR
effect on antibiotic formation,
morphological differentiation
and the influence of GlcNAc-6P
and Glc-6P on its formation
two-component systems and the lipid and carbohydrate
metabolism are also affected (Pérez-Redondo et al. 2012).
Interestingly, the transcription and protein expression of
ArgR seems to be affected by the carbon source and GlkA
(Gubbens et al. 2012; Romero-Rodríguez et al. 2016a).
Participation of single and phosphorylated metabolites
in CCR
The participation of several metabolite types in catabolic
repression has been signposted since the elucidation of the
mechanism in Escherichia coli. cAMP was pinpointed as
relevant in such mechanism as it binds to the cyclic AMP
receptor protein (CRP) to exert activation of several cata-
bolic genes and operons (Escalante et al. 2012). Neverthe-
less, unlike enterobacteria, in Streptomyces the CRP does
not have any role on CCR; conversely, CRP protein has
been involved as a regulator in morphological differentia-
tion and antibiotic production in S. coelicolor (Derouaux
et al. 2004; Gao et al. 2012).
Several phosphorylated metabolites derived from the
glucose metabolism, like glucose 6-phosphate, fructose
2,6-diphosphate, fructose 1,6-diphosphate and even inor-
ganic phosphate exert a negative influence on the cephamy-
cin C biosynthesis in Streptomyces lactamdurans (Cortés
et al. 1986).
The levels of glycerol 3-phosphate, inducer of the
glycerol operon (gylCABX) in S. coelicolor, determine
the degree of repression that can exert the repressor GylR
on the promotor of gylCABX. As the addition of glucose
to the medium diminishes the glycerol operon expres-
sion, it has been postulated that GlkA might modulate the
intracellular levels of glycerol 3-phosphate (Hindle and
Smith 1994).
The relevance of glucose uptake/Glk ratio for the CCR
onset was proved in the doxorubicin overproducer S.
peucetius var. caesius, which suggested the importance of
the intracellular concentration of glycolytic intermediates
for the CCR in this strain (Ramos et al. 2004). Taking the
latter into account, two single and two phosphorylated
compounds were added in a chemically defined medium,
and the anthracycline concentration was measured. The
results showed an 81% decrease in anthracycline pro-
duction when using fructose-1,6-bis-phosphate and 55%
with phosphoenolpyruvate in the wild type strain of S.
peucetius var. caesius and one mutant insensitive to CCR.
However, pyruvate and acetate had no effect on anthracy-
cline formation (Ramos et  al. 2004). These results sup-
port the participation of glycolytic phosphorylated inter-
mediates in the CCR (Fig.  1b). An integral view of the
mechanisms involved in CCR is presented in Fig. 3.
13
 162   Page 8 of 11
Fig. 3  Regulators that have been described and their possible impli-
cation in different physiological processes of Streptomyces. MalR
is necessary for induction and repression of maltose utilization, and
likely interacts with Glk (pink line). Similarly, GylR is required for
induction and repression of glycerol transport. CebR is required for
induction and repression of β-galactosidase. Rok7b7 is activated by
the presence of xylose or any product of its metabolism, the absence
of Rok7B7 increases expression of Glk and GlcP, therefore, it is
The PTS mechanism
Streptomyces can use a great variety of carbon sources
for growth and secondary metabolites production (Hodg-
son 1982). However, there is limited knowledge about
the transport and metabolism of different carbon sources
(Bertram et  al. 2004). The complex bacterial PTS con-
sists of a chain of phosphorylation reactions across dif-
ferent enzymes, where carbohydrates are the ultimate
receptor of the phosphate group. It involves complex pro-
cesses as carbohydrates transport, CCR, and chemotaxis
(Saier 2015). Although well understood in enterobacteria
and Gram-positive bacteria with low guanine-cytosine
content, very little is known about PTS and its implica-
tions in Streptomyces. The PTS system has been studied
13
World J Microbiol Biotechnol (2017) 33:162
implicated indirectly in CCR. Glucose or some product of its metabo-
lism exert an effect on GlcP and CCR, independently of Glk. DasR
has an effect on different processes and responds to different signals
such as hydrolysis of the cell wall or the presence of chitin as carbon
source. It has been observed that Glk, ArgR and DasR have pleio-
tropic effects on different cellular processes and although it has not
been possible to demonstrate a direct interaction between these pro-
teins, a regulation network cannot be ruled out
in several streptomycetes (Novotna and Hostalek 1985).
It seems to play a relevant role in the phosphorylation,
transport, and CCR of d-fructose and N-acetylglucosa-
mine (GlcNAc). PTS is inducible in S. coelicolor, S.
lividans and constitutive in S. griseofuscus (Titgemeyer
et  al. 1995). Null ptsH mutants of S. coelicolor are
impaired in fructose utilization, and their growth in this
carbohydrate is severely affected (Nothaft et  al. 2003).
Also, the fructose repression over glycerol kinase enzyme
is lost in these mutants (Nothaft et  al. 2003). However,
contrary to previous reports in other bacteria, the HPr
system does not have an overall effect on the CCR in
Streptomyces, since no changes are observed in the fruc-
tose-CCR over agarase and galactokinase expression in S.
lividans in ∆ptsH mutants (Butler et  al. 1999). Besides,
World J Microbiol Biotechnol (2017) 33:162 Page 9 of 11  162
glucose is neither transported nor phosphorylated by this
system (van Wezel et al. 2005; Romero et al. 2015b).
Concluding remarks
Even though CCR has been studied for decades, our
knowledge on the role of different transcriptional regu-
lators and proteins involved in it remains scarce. The
regulatory nutritional network involved in CCR, which
assures the survival of the cell in response to a series of
nutritious states, is still unclear.
The Streptomyces responsive capability is directly
reflected in its genome size, in which up to 12% of the
total chromosome are regulatory genes. Thus, it is an
enormous task to understand the totality of regulatory
networks influencing the Streptomyces metabolism.
Although different approaches of various research
groups have been done for several years, it is a fact that
many results are hard to compare due to differences in
culture media and conditions used, making tough to
integrate the available information. The smart combina-
tion of bench work and bioinformatics offers a possibil-
ity to expand, in a rational way, our knowledge on CCR.
There are databases and programs, such as the colombos
expression compendia (Engelen et  al. 2011), that unify
different transcriptome assays (http://www.colombos.
org). Thus, making possible to identify co-transcribed
genes on different conditions and serve as a convenient
expression analysis tool to extract useful biological infor-
mation. Unfortunately, up to this moment this database is
only available for S. coelicolor with only nine different
experiments, therefore limiting its analysis capacity.
Interestingly, Ishihama et  al. (2016) have taken the
colossal work of characterizing the binding sites of each
transcriptional regulator and sigma factors of E. coli,
creating the database, ‘Transcription Profile of E. coli’
(http://www.shigen.nig.ac.jp/ecoli/tec/). This approach
has allowed the recognition of uncharacterized binding
sites, boosting the known binding sites up to 18 times for
some already studied regulators. This procedure invites
us to use genome-wide approaches and its rational anal-
ysis to achieve a better understanding about the role of
DNA-binding proteins, not only for CCR, but also for dif-
ferent cellular aspects of the Streptomyces.
Acknowledgements  This work was supported by the Grant
CB-219686 from CONACYT, Mexico. We thank Corina Ceapa for
critical reading this manuscript. We acknowledge Marco A. Ortíz-
Jiménez and Betsabe Linares for manuscript preparation.
References
Abdelwahed NAM, Danial EN, El-Naggar NEl-A, Mohamed AA
(2014) Optimization of alkaline protease production by Strep-
tomyces ambofaciens in free and immobilized form. Am J Bio-
chem Biotechnol 10(1):1–13
Angell S, Schwarz E, Bibb MJ (1992) The glucose kinase gene of
Streptomyces coelicolor A3(2): its nucleotide sequence, tran-
scriptional analysis and role in glucose repression. Mol Micro-
biol 6:2833–2844
Angell S, Lewis CG, Buttner MJ, Bibb MJ (1994) Glucose repression
in Streptomyces coelicolor A3(2) a likely regulatory role for glu-
cose kinase. Mol Gen Genet 244:135–143
Arhin FF, Shareck E, Kluepfel D, Morosoli R (1994) Effects of dis-
ruption of xylanase-encoding genes on the xylanolytic system of
Streptomyces lividans. J Bacteriol 176:4924–4930
Bertram R, Schlicht M, Mahr K, Nothaft H, Saier MH Jr, Tietmeyer
F (2004) In silico and transcriptional analysis of carbohydrate
uptake systems of Streptomyces coelicolor A3(2). J Bacteriol
186:1362–1373
Bhatnagar RK, Doull JL, Vining LC (1988) Role of the carbon source
in regulating chloramphenicol production by Streptomyces vene-
zuelae: studies in batch and continuous cultures. Can J Microbiol
34:1217–1223
Borodina I, Siebring J, Zhang J, Smith CP, van Keulen G, Dijkhuizen
L, Nielsen J (2008) Antibiotic overproduction in Streptomyces
coelicolor A3(2) mediated by phosphofructokinase deletion. J
Biol Chem 283:25186–25199
Brawner ME, Mattern SG, Babcock MJ, Westpheling J (1997) The
Streptomyces galP1 promoter has a novel RNA polymerase rec-
ognition sequence and is transcribed by a new form of RNA pol-
ymerase in vitro. J Bacteriol 179:3222–3231
Brown D, Foster J, Hitchcock MJ, Ochi K, Troost T, Katz E (1983)
Regulation of tryptophan metabolism and its relationship to
actinomycin D synthesis. In: Ikeda Y, Beppu T (eds) Genetics of
industrial microorganisms. Kodansha, Tokyo, pp 85–91
Butler MJ, Deutscher J, Postma PW, Wilson TJ, Galinier A, Bibb MJ
(1999) Analysis of a ptsH homologue from Streptomyces coeli-
color A3(2). FEMS Microbiol Lett 177:279–288
Chávez A, García-Huante Y, Ruiz B, Langley E, Rodríguez-Sanoja R,
Sanchez S (2009) Cloning and expression of the sco2127 gene
from Streptomyces coelicolor M145. J Ind Microbiol Biotechnol
36:649–654
Chávez A, Forero A, Sánchez M, Rodríguez-Sanoja R, Mendoza-
Hernández, G, Servín-Gonzalez L, Sánchez S (2011) Interaction
of SCO2127 with BldKB and its possible connection to carbon
catabolite regulation of morphological differentiation in Strepto-
myces coelicolor. Appl Microbiol Biotechnol 89:799–806
Colson S, van Wezel G, Craig M, Noens E, Nothaft H, Mommaas
M, Titgemeyer F, Joris B, Rigali S (2008) The chitobiose-
binding protein, DasA, acts as a link between chitin utilization
and morphogenesis in Streptomyces coelicolor. Microbiology
154:373–382
Cortés J, Liras P, Castro JM, Romero J, Martín JF (1984) Regulation
of the biosynthesis of cephamycin C by Streptomyces lactam-
durans. Biochem Soc Trans 12:863–864
Cortés J, Liras P, Castro JM, Martín JF (1986) Glucose regulation
of cephamycin biosynthesis in Streptomyces lactamdurans is
exerted on the formation of alfa-aminoadipyl-cysteinyl-valine
and deacetoxycephalosporin C synthase. J Gen Microbiol
132:1805–1814
Dalton KA, Thibessard A, Hunter JIB, Kelemen GH (2007) A novel
compartment, the “subapical stem” of the aerial hyphae, is the
location of a sigN-dependent, developmentally distinct transcrip-
tion in Streptomyces coelicolor. Mol Microbiol 64:719–737
13
 162   Page 10 of 11
Demain AL (1989) Carbon source regulation of idiolite biosynthesis.
In: Shapiro S (ed) Regulation of secondary metabolism in actin-
omycetes. CRC Press, Boca Raton, pp 127–134
Demain A, Fang A (1995) Emerging concepts of secondary metabo-
lism in actinomycetes. Actinomycetology 9:98–117
Demain AL, Fang A (2001) The natural functions of secondary
metabolites. Adv Biochem Eng Biotechnol 69:1–39
Demain AL, Inamine E (1970) Biochemistry and regulation of strep-
tomycin and mannosidostreptomycinase (α-d-mannosidase) for-
mation. Bacteriol Rev 34:1–19
Derouaux A, Halici S, Nothaft H, Neutelings T, Moutzourelis G,
Dusart J, Titgemeyer F, Rigali S (2004) Deletion of a cyclic
AMP receptor protein homologue diminishes germination and
affects morphological development of Streptomyces coelicolor. J
Bacteriol 186:1893–1897
Engelen K, Fu Q, Meysman P et al (2011) COLOMBOS: access port
for cross-platform bacterial expression compendia. PLoS ONE
6:e20938
Escalante L, Ramos I, Imriskova I, Langley E, Sanchez S (1999)
Glucose repression of anthracycline formation in Streptomyces
peucetius var. caesius. Appl Microbiol Biotechnol 52:572–578
Escalante A, Cervantes AS, Gosset G, Bolívar F (2012) Current
knowledge of the Escherichia coli phosphoenolpyruvate-carbo-
hydrate phosphotransferase system: peculiarities of regulation
and impact on growth and product formation. Appl Microbiol
Biotechnol 94:1483–1494
Forero A, Sánchez M, Chávez A, Ruiz B, Rodríguez-Sanoja R,
Servín-González L, Sánchez S (2012) Possible involvement of
the sco2127 gene product in glucose repression of actinorho-
din production in Streptomyces coelicolor. Can J Microbiol
58:1195–1201
Gao C, Hindra, Mulder D, Yin C, Elliot MA. (2012) Crp is a global
regulator of antibiotic production in Streptomyces. MBio
3:e00407–12
Gorke B, Stülke J (2008) Carbon catabolite repression in bacteria:
many ways to make the most out of nutrients. Nat Rev Microbiol
6:613–624
Gubbens J, Janus M, Florea BI, Overkleeft HS, van Wezel GP (2012)
Identification of glucose kinase-dependent and -independent
pathways for carbon control of primary metabolism, develop-
ment and antibiotic production in Streptomyces coelicolor by
quantitative proteomics. Mol Microbiol 86:1490–1507
Guzmán S, Ramos I, Moreno E, Ruiz B, Rodríguez-Sanoja R, Esca-
lante L, Langley E, Sánchez S (2005a) Pleiotropic effect of the
SC02127 gene on the glucose uptake, glucose kinase activity and
carbon catabolite repression in Streptomyces peucetius var. cae-
sius. Microbiol. SGM 151:1717–1723
Guzmán S, Carmona A, López R, Escalante L, Ruiz B, Rodríguez-
Sanoja R, Sánchez S, Langley E (2005b) Sugar uptake and sen-
sitivity to carbon catabolite regulation in Streptomyces peucetius
var. caesius. Appl Microbiol Biotechnol 69:200–206
Hindle Z, Smith CP (1994) Substrate induction and catabolite repres-
sion of Streptomyces coelicolor glycerol operon are mediated
through the GylR protein. Mol Microbiol 12:737–745
Hodgson DA (1982) Glucose repression of carbon source uptake and
metabolism in Streptomyces coelicolor A3(2) and its perturba-
tion in mutants resistant to 2-deoxyglucose. J Gen Microbiol
128:2417–2430
Hong B, Phornphisutthimas S, Tilley E, Baumberg S, McDowall KJ
(2007) Streptomycin production by Streptomyces griseus can
be modulated by a mechanism not associated with change in
the adpA component of the A-factor cascade. Biotechnol Lett
29:57–64
Ishihama A, Shimada T, Yamazaki Y (2016) Transcription profile of
Escherichia coli: Genomic SELEX search for regulatory targets
of transcription factors. Nucleic Acids Res 44:2058–2074
13
World J Microbiol Biotechnol (2017) 33:162
Kang SG, Lee KJ (1997) Kinetic analysis of morphological differ-
entiation and protease production in Streptomyces albidoflavus
SMF301. Microbiology 143:2709–2714
Kayali HA, Tarhan L, Sazak A, Sahin N (2011) Carbohydrate
metabolite pathways and antibiotic production variations
of a novel Streptomyces sp. M3004 depending on the con-
centrations of carbon sources. Appl Biochem Biotechnol
165:369–381
Kwakman JH, Postma PW (1994) Glucose kinase has a regulatory
role in carbon catabolite repression in Streptomyces coelicolor. J
Bacteriol 176:2694–2698
Lebrihi A, Lefebvre G, Germain P (1988) Carbon catabolite regula-
tion of cephamycin C and expandase biosynthesis in Streptomy-
ces clavuligerus. Appl Microbiol Biotechnol 28:44–51
Liu G, Chater KF, Chandra G, Niu G, Tan H (2013) Molecular regu-
lation of antibiotic biosynthesis in Streptomyces. Microbiol Mol
Biol Rev 77:112–143
Mahr K, van Wezel GP, Svensson C, Krengel U, Bibb MJ, Titgemeyer
F (2000) Glucose kinase of Streptomyces coelicolor A3(2):
large-scale purification and biochemical analysis. Anton Leeuw
Int JG 78:253–261
Majerčíková K, Labuda R, Jaunecker G, Javoreková S (2015) The glu-
cose effect on lincomycin production by Streptomyces lincolnen-
sis var. lincolnensis DMS 40 355 on synthetic media. J Microb
Biotech Food Sci Nitra 4:306–309
Martín JF, Liras P (2010) Engineering of regulatory cascades and net-
works controlling antibiotic biosynthesis in Streptomyces. Curr
Opin Microbiol 13:263–273
Marushima K, Ohnishi Y, Horinouchi S (2009) CebR as a master
regulator for cellulose/cellooligosaccharide catabolism affects
morphological development in Streptomyces griseus. J Bacteriol
191:5930–5940
McCormick JR, Flärdh K (2012) Signals and regulators that govern
Streptomyces development. FEMS Microbiol Rev 36:206–231
Mellouli L, Karray-Rebai I, Bejar S (2002) Construction of alpha-
amylase-producing strains not subject to carbon catabolite
repression. FEMS Microbiol Lett 206:157–162
Nothaft H, Dresel D, Willimek A, Mahr K, Niederweis M, Tit-
gemeyer F (2003) The phosphotransferase system of Streptomy-
ces coelicolor is biased for N-acetylglucosamine metabolism. J
Bacteriol 185:7019–7023
Novotna J, Hostalek Z (1985) Phosphorylation of hex-
oses in Streptomyces aureofaciens: evidence that the
phosphoenolpyruvate:sugar phosphotransferase system is not
operative. FEMS Microbiol Lett 28:347–350
Ohe T, Watanabe Y, (1977) Effects of glucose and ammonium on the
formation of xanthine dehydrogenase of Streptomyces sp. Agric
Biol Chem 41(7):1161–1170
Park SS, Yang YH, Song E et al (2009) Mass spectrometric screening
of transcriptional regulators involved in antibiotic biosynthesis
in Streptomyces coelicolor A3(2). J Ind Microbiol Biotechnol
36:1073–1083
Pérez-Pons JA, Rebordosa X, Querol E (1995) Properties of a novel
glucose-enhanced beta-glucosidae purified from Streptomyces
sp. (ATCC11238). Biochim Biophys Acta 1251:145–153
Pérez-Redondo R, Rodríguez-García A, Botas A, Santamarta I, Mar-
tín JF, Liras P (2012) ArgR of Streptomyces coelicolor is a versa-
tile regulator. PLoS ONE 7(3):e32697
Pope MK, Green B, Westpheling J (1998) The bldB gene encodes a
small protein required for morphogenesis, antibiotic production,
and catabolite control in Streptomyces coelicolor. J Bacteriol
180:1556–1562
Ramos I, Guzmán S, Escalante L, Imriskova I, Rodríguez-Sanoja R,
Sánchez S, Langley E (2004) Glucose kinase alone cannot be
responsible for carbon source regulation in Streptomyces peuce-
tius var. caesius. Res Microbiol 155:267–274
World J Microbiol Biotechnol (2017) 33:162 Page 11 of 11  162
Romero A, Ruiz B, Sohng JK, Koirala N, Rodríguez-Sanoja R,
Sanchez S (2015) Functional analysis of the GlcP promoter in
Streptomyces peucetius var. caesius. Appl Biochem Biotechnol
175:3207–3217
Romero-Rodríguez A, Robledo-Casados I, Sanchez S (2015) An over-
view on transcriptional regulators in Streptomyces. Biochim Bio-
phys Acta 1849:1017–1039
Romero-Rodríguez A, Rocha D, Tierrafría V, Ruiz-Villafán B, Rod-
ríguez-Sanoja R, Segura-González D, Sánchez S (2016a) Tran-
scriptomic analysis of a classical model of carbon catabolite
regulation in Streptomyces coelicolor. BMC Microbiol 16:77
Romero-Rodríguez A, Ruiz-Villafán B, Tierrafría V, Rodríguez-
Sanoja R, Sánchez S (2016b) Carbon catabolite regulation of
secondary metabolite formation and morphological differen-
tiation in Streptomyces coelicolor. Appl Biochem Biotechnol
180:1152–1166
Ruiz B, Chávez A, Forero A, García-Huante Y, Romero A, Sánchez
M, Rocha D, Sánchez B, Rodríguez-Sanoja R, Sánchez S, Lang-
ley E (2010) Production of microbial secondary metabolites: reg-
ulation by the carbon source. Crit Rev Microbiol 36(2):146–167
Saier MH (2015) The bacterial phosphotransferase system: new fron-
tiers 50 years after its discovery. J Mol Microbiol Biotechnol
25:73–78
Saito A, Ishizaka M, Francisco PB, Fujii T, Miyashita K (2000) Tran-
scriptional co-regulation of five chitinase genes scattered on
the Streptomyces coelicolor A3(2) chromosome. Microbiology
146:2937–2946
Schlösser A, Aldekamp T, Schrempf H (2000) Binding characteristics
of CebR, the regulator of the ceb operon required for cellobiose/
cellotriose uptake in Streptomyces reticuli. FEMS Microbiol Lett
190:127–132
Schrader KK, Blevins WT (2001) Effects of carbon source, phospho-
rus concentration, and several micronutrients on biomass and
geosmin production by Streptomyces halstedii. J Ind Microbiol
Biotechnol 26:241–247
Segura D, González R, Rodríguez R, Sandoval T, Escalante L,
Sánchez S (1996) Streptomyces mutants insensitive to glu-
cose repression showed deregulation of primary and secondary
metabolism. Asia Pac J Mol Biol Biotechnol 4:30–36
Seo J, Ohnishi Y, Hirata A, Horinouchi S (2002) ATP-binding cas-
sette transport system involved in regulation of morphological
differentiation in response to glucose in Streptomyces griseus. J
Bacteriol 184:91–103
Servin-Gonzalez L, Jensen MR, White J, Bibb M (1994) Transcrip-
tional regulation of the four promoters of the agarase gene (dagA)
of Streptomyees coelicolor A3(2). Microbiology 140:2555–2565
Swiatek MA, Gubbens J, Bucca G et al (2013) The ROK family regu-
lator Rok7B7 pleiotropically affects xylose utilization, carbon
catabolite repression, and antibiotic production in Streptomyces
coelicolor. J Bacteriol 195:1236–1248
Świątek MA, Tenconi E, Rigali S et al (2012) Functional analysis of
the N-acetylglucosamine metabolic genes of Streptomyces coeli-
color and role in control of development and antibiotic produc-
tion. J Bacteriol 194:1136–1144
Świątek-Połatyńska MA, Bucca G, Laing E et  al (2015) Genome-
wide analysis of in  vivo binding of the master regulator DasR
in Streptomyces coelicolor identifies novel non-canonical targets.
PLoS ONE 10:1–24
Tang L, Hutchinson CR (1995) Regulation of expression of the valine
(branched chain amino acid) dehydrogenase-encoding gene from
Streptomyces coelicolor. Gene 162:69–74
Tierrafría V, Licona-Cassani C, Maldonado-Carmona N, Romero-
Rodríguez A, Centeno-Leija S, Marcellin E, Rodríguez-Sanoja
R, Ruiz B, Nielsen L, Sánchez S (2016) Deletion of the hypo-
thetical protein SCO2127 of Streptomyces coelicolor allowed
identification of a new regulator of actinorhodin production.
Appl Microbiol Biotechnol 100:9229–9237
Titgemeyer F, Reizer J, Reizer A, Saier MH Jr (1994) Evolutionary
relationships between sugar kinases and transcriptional repres-
sors in bacteria. Microbiology 140:2349–2354
Titgemeyer F, Walkenhorst J, Reizer J, Stuiver MH, Cui X, Saier
MH Jr (1995) Identification and characterization of phosphoe-
nolpyruvate: fructose phosphotransferase systems in three Strep-
tomyces species. Microbiol SGM. 141:51–58
Uguru GC, Stephens KE, Stead JA, Towle JE, Baumberg S, McDow-
all KJ (2005) Transcriptional activation of the pathway-specific
regulator of the actinorhodin biosynthetic genes in Streptomyces
coelicolor. Mol Microbiol 58:131–150
van Wezel GP, McDowall KJ (2011) The regulation of the second-
ary metabolism of Streptomyces: new links and experimental
advances. Nat Prod Rep 28:1311–1333
van Wezel GP, While J, Young P Postma PW, Bibb MJ (1997) Sub-
strate induction and glucose repression of maltose utilization by
Streptomyces coelicolor A3(2) is controlled by malR a mem-
ber of the lacl-galR family of regulatory genes. Mol Microbiol
23:537–549
van Wezel GP, Mahr K, König M, Traag BA, Pimentel-Schmitt EF,
Willimek A, Titgemeyer F (2005) GlcP constitutes the major
glucose uptake system of Streptomyces coelicolor A3(2). Mol
Microbiol 55:624–636
van Wezel GP, König M, Mahr K, Nothaft H, Thomae AW, Bibb
MJ, Titgemeyer F (2007) A new piece of an old jigsaw: glu-
cose kinase is activated posttranslationally in a glucose trans-
port–dependent manner in Streptomyces coelicolor A3(2). J Mol
Microbiol Biotechnol 12:67–74
Zhernosekova IV, Kilochek TP (2000) The effect of glucose on the
biosynthesis of extracellular enzymes by Streptomyces recifensis
var. lyticus 2435 and its mutants. Mikrobiol Z 62(2):19–26
13