positively autoregulated Saget BM,1994; Nakamura T,1988and controls the transcription of the genes involved in the process of reparation of alkylated DNA Saget BM,1994; Landini P,1995; Volkert MR,1994; Nakabeppu Y,1986; Landini P,1999; Saget BM,1994 also called the adaptive response Takahashi K,1988; Nieminuszczy J,2007; Landini P,2000 O6-methylguanine and O4-methylthymine are the major mutagenic lesions resulting from exposure of DNA to simple alkylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-methyl-N-nitrosourea (MNU) and, to a lesser degree, methane methanesulfonate (MMS) Takahashi K,1988; Saget BM,1994; Nieminuszczy J,2007 The O6-methylguanine and O4-methylthymine alkylation products constitute potentially mutagenic lesions due to their tendency to mispair with thymine and with guanine, respectively, forming transition mutations; In Escherichia coli there are two separate direct repair mechanisms for the reversal of these types of alkylating lesions through the involvement of two methyltransferases, Ada and Ogt Nieminuszczy J,2007This regulator contains two functional domains: an N-terminal domain, which contains a motif for DNA binding, and the C-terminal domain, which is involved in the interaction with the RNA polymerase Landini P,2000; Demple B,1985; Teo I,1984; Shevell DE,1991; Shevell DE,1988; Sakumi K,1993; Landini P,1998 This regulator removes methyl groups (as well as larger groups) from the guanine and thymine substrates and transfers them to its own cysteine residue (Cys-321) in the C-terminal domain; The Ada protein also transfers methyl groups to a second cysteine residue (Cys-69) in the N-terminal domain, from alkylphosphotriesters in DNA Lindahl T,1982; Landini P,2000; Sakashita H,1995; Yoshikai T,1988; Takano K,1988 This reaction converts the Ada protein into a strong transcriptional activator of several genes; This regulator acts as an activator by binding to cis-acting elements that overlap the upstream elements (UP) of the promoters regulated Landini P,1995; Sakumi K,1989A model of the mechanism of action of Ada has been proposed Landini P,2000; Landini P,1998The solution structure of the methylated N-terminal domain of Ada has been determined by NMR and mass spectrometry Takinowaki H,2006We have modified the reported length of the binding site of this protein to 13 bp, according to the proposal by Teo et al Teo I,1986; Other authors have proposed different lengths and consensus sequences for Ada Sakumi K,1989; Landini P,1995, but Nakamura et al showed that deletions in this consensus sequence (AAANNAAAGCGCA) decrease the activity of β-galactosidase Nakamura T,1988.; DNA repair; methylated-DNA—[protein]-cysteine S-methyltransferase; operon; activator; Transcription related; cytoplasm; methylation; metabolic process; sequence-specific DNA binding; transferase activity; zinc ion binding; methyltransferase activity; response to DNA damage stimulus; regulation of transcription, DNA-dependent; intracellular; catalytic activity; sequence-specific DNA binding transcription factor activity; DNA binding; methylated-DNA-[protein]-cysteine S-methyltransferase activity; transcription, DNA-dependent; transcription activator activity; transcription repressor activity; repressor

cluster, which is involved in transport and catabolism of N-acetylgalactosamine and d-galactosamine Ray WK,2004; Brinkkotter A,2000 It is negatively autoregulated and coordinately represses transcription of the divergent agaZVWEFA operon, which is related to transport and degradation of N-acetylgalactosamine Ray WK,2004 This repressor responds to N-acetylgalactosamine and d-galactosamine in the medium.As a member of the DeoR/GlpR family of transcriptional regulators Ray WK,2004 AgaR features an N-terminal domain containing a helix-turn-helix motif and a C-terminal domain that includes the key residues involved in co-inducer recognition and oligomerization Ray WK,2004 In accordance with other helix-turn-helix DNA-binding repressors, AgaR may bind to DNA as a tetramer; AgaR binds in tandem to several repeat sequences in the intergenic regions of agaZp, agaRp, and agaSp to repress transcription by overlapping the - 35 and -10 boxes; The binding targets for AgaR consist of 24-nucleotide-long repeat sequences that possess conserved motifs Ray WK,2004agaR: N-acetylglactosamine degradation Reizer J,1996; repressor; Transcription related; amino sugar conversions; regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent

of several genes and operons involved in arabinose catabolism and transport; It coregulates with another transcriptional regulator, CRP; both are transcription factors involved in l-arabinose degradation; These regulators bind cooperatively to activate transcription of five operons related to transport, catabolism, and autoregulation of l-arabinose; Transcription of these operons is induced when E. coli is grown in the absence of glucose and when the physiological inducer, l-arabinose, binds to the AraC regulator; In the absence of glucose, cellular cyclic AMP levels are high and cyclic AMP forms a dimeric complex with CRP to coregulate with AraC Gallegos MT,1997; Reeder T,1991; Stoner C,1983; Hendrickson W,1992; Seabold RR,1998; Hendrickson W,1990; Miyada CG,1984AraC binds to five target sites in the araBp region; AraC binds to the less-conserved site (-42.5) with less strength; this binding occurs only in the presence of arabinose, and it is absolutely required for expression of araBp Lobell RB,1990; Hamilton EP,1988; Lee N,1987; Martin K,1986; Carra JH,1993 AraC binding to the distal site (-123.5) has been shown to down-regulate expression of araBp and araCp Lee DH,1992; Hamilton EP,1988 In the absence of arabinose, AraC is unable to activate araBp, but it regulates its own expression by repressing araCp and araBp simultaneously Lobell RB,1990; Martin K,1986 Arabinose triggers AraC-dependent activation of araBp and relieves AraC-dependent repression of araCp Hamilton EP,1988; Martin K,1986 The araBAD operon is located upstream of araC and in the opposite direction.In the presence of arabinose, this regulator activates transcription by overlapping the -35 box of the core promoters, and the central position of the binding site is located near bp -41.5; The binding targets for AraC consist of 17-nucleotide-long direct repeat sequences that possess conserved motifs; each monomer binds to one of these conserved sequences Gallegos MT,1997; Niland P,1996 The AraC regulator belongs to the AraC/XylS family and occurs as both a monomer and a homodimer; It is composed of two domains; The solution structure of the C-terminal DNA-binding domain has been solved; It consists of two helix-turn-helix regions connected by an α-helix Rodgers ME,2009 The N-terminal domain is responsible for dimerization and L-arabinose binding Gallegos MT,1997; Gallegos MT,1993 Its crystal structure Soisson SM,1997; Soisson SM,1997reveals that the sugar molecule is bound within a β-barrel, buried by the N-terminal arm of the protein; It has been suggested that this N-terminal arm plays a key role in the regulation of the arabinose-dependent DNA-binding properties of the protein; In the absence of arabinose it interacts with the DNA-binding domain and constrains this domain, and it releases it in the presence of arabinose Soisson SM,1997; Rodgers ME,2009 This interaction appears to be affected by a mutation in the interdomain linker Seedorff J,2011.; Transcription related; repressor; activator; operon; carbon compounds; cytoplasm; sequence-specific DNA binding; arabinose catabolic process; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent; regulation of transcription, DNA-dependent

Transcription related; cytoplasm; intracellular signal transduction; sequence-specific DNA binding transcription factor activity; negative regulation of transcription, DNA-dependent; positive regulation of transcription, DNA-dependent; intracellular; regulation of transcription, DNA-dependent; two-component signal transduction system (phosphorelay); two-component response regulator activity; transcription activator activity; two component regulatory systems (external signal)

DNA replication; specific transcriptional repressor activity; positive regulation of transcription, DNA-dependent; negative regulation of DNA-dependent DNA replication initiation; negative regulation of transcription, DNA-dependent; transcription activator activity; sequence-specific DNA binding transcription factor activity; sequence-specific DNA binding; nucleoproteins, basic proteins

DNA binding; sequence-specific DNA binding transcription factor activity; regulation of transcription, DNA-dependent; cellular amino acid biosynthetic process; plasmid recombination; transcription regulatory region DNA binding; negative regulation of transcription initiation, DNA-dependent

operon (ascFB) whose genes are involved in transport and utilization of the β-glucoside sugars arbutin, salicin, and cellibiose; This operon is activated only when the repressor is inactivated through the interruption of the gene by an insertion sequence Hall BG,1992 AscG also regulates prpBC for propionate catabolism Ishida Y,2009 AscG is a GalR-type transcription factor and has a helix-turn-helix motif Hall BG,1992; Ishida Y,2009 AscG recognizes and binds the consensus palindromic sequence TGAAACCGGTTTCA Ishida Y,2009The ascG gene is transcribed divergently from the operon it regulates Hall BG,1992 ascG is paralogous to galR Ishida Y,2009 A high level of AscG is always present in wild-type Escherichia coli cells Ishida Y,2009; carbon compounds; repressor; operon; Transcription related; cytoplasm; specific transcriptional repressor activity; negative regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; carbohydrate catabolic process; transcription, DNA-dependent; sequence-specific DNA binding

DNA-dependent; response to amino acid stimulus; amino acid binding; sequence-specific DNA binding; intracellular; sequence-specific DNA binding transcription factor activity; transcription activator activity; asparagine; Transcription related; activator; repressor; specific transcriptional repressor activity

DNA binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; two component regulatory systems (external signal); activator; Transcription related

carnitine metabolic process; transcription, DNA-dependent; activator; operon; amines; cytoplasm

binding transcription factor activity; cytoplasm; two-component signal transduction system (phosphorelay); two-component response regulator activity; transcription activator activity; proteins/peptides/glycopeptides; detoxification; Transcription related; two component regulatory systems (external signal); repressor; activator; intracellular signal transduction; positive regulation of transcription, DNA-dependent

regulation of transcription, DNA-dependent; intracellular; response to fructose stimulus; cytoplasm; regulon; activator; repressor; Transcription related

DNA-dependent; cAMP binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; nucleotide binding; transcription, DNA-dependent; transcription activator activity; transcription repressor activity; activator

regulator Hammar M,1995that regulates a number of genes involved in the Curli assembly, transport, and structural components Loferer H,1997; Hammar M,1995 which are important for biofilm formation Brombacher E,2003 In addition, it also regulates genes related to cell surface-associated structures Brombacher E,2003; Gualdi L,2008; Brombacher E,2006 It may also have the capability to respond to starvation and high cell density Brombacher E,2003and positively controls σS expression Bougdour A,2006; Gualdi L,2007 In general the environmental conditions, such as low osmolarity, low growth temperature (csgD and the production of the biofilm and cellulose Gualdi L,2008; Prigent-Combaret C,2001; Olsen A,1993Since csgD is induced during the mid-exponential phase of growth and the CsgD-dependent activation of csg genes is detected in the stationary phase, it has been suggested that CsgD is posttranscriptionally activated in the stationary phase Brombacher E,2003CsgD might activate transcription through two different mechanisms, as suggested by the different locations of its binding sites in the regulatory regions of the genes it activates; In one regulatory region, the protein binds to a single site, whereas it binds to two sites arranged as inverted repeats in another region Brombacher E,2003 CsgD belongs to the FixJ/LuxR/UhpA family, which is characterized by a C-terminal domain that contains a potential helix-turn-helix DNA-binding motif and a receiver domain in the N-terminal region Volz K.,1993Five different small RNAs are known to regulate expression of CsgD at the post-transcriptional level; reviewed in Boehm A,2012.; plasma membrane; two-component response regulator activity; two-component signal transduction system (phosphorelay); membrane; intracellular signal transduction; Transcription related; activator; repressor; sequence-specific DNA binding; transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity; intracellular; regulation of transcription, DNA-dependent

G,1981; Jovanovic M,2003 this regulator also controls the transcription of the operon involved in novobiocin resistance Lilic M,2003; Jovanovic M,2003and transcription of genes involved in sulfur utilization and sulfonate-sulfur catabolism via cysteine biosynthesis Jagura-Burdzy G,1981; van der Ploeg JR,1997; Monroe RS,1990; Lochowska A,2001; Lochowska A,2004; Kredich NM.,1992; Leyh TS,1988; van der Ploeg JR,2001; Rakonjac J,1991 In the presense of N-acetylserine, the inducer molecule of this regulator, DNA binding by CysB tetramers to the target sequences is facilitated Lochowska A,2001; Jovanovic M,2003 The amino acid sequence of CysB shows homology to members of the LysR family of transcriptional regulators Tei H,1990; Ostrowski J,1987; Tyrrell R,1997; Jovanovic M,2003 The N-terminal region of this protein comprises a helix-turn-helix DNA-binding motif; CysB has a central region, suggesting that it may be important for inducer recognition Tyrrell R,1997 and the carboxy-terminal domain is involved in homo-oligomerization, stability, and DNA binding Lamark T,1991; Tyrrel et al; proposed that this regulator has an unusual mechanism of binding to DNA Tyrrell R,1997; cysteine; Transcription related; activator; repressor; regulon; cytoplasm; cellular amino acid biosynthetic process; regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; DNA binding; cysteine biosynthetic process; transcription, DNA-dependent; negative regulation of transcription, DNA-dependent

compound metabolic process; regulation of transcription, DNA-dependent; intracellular; protein binding; sequence-specific DNA binding transcription factor activity; DNA binding; transcription activator activity; transcription, DNA-dependent; transcription repressor activity; Transcription related

transcription activator activity; positive regulation of transcription, DNA-dependent; repressor; activator

transcription activator activity; DNA binding; Transcription related; regulation of transcription, DNA-dependent; cytoplasm; activator; two component regulatory systems (external signal); anaerobic respiration; intracellular signal transduction; response to external stimulus; nucleic acid binding transcription factor activity

negative expression of genes related to transport and catabolism of deoxyribonucleoside nucleotides Hammer-Jespersen K,1975; Short SA,1984; Barbier CS,1985; Valentin-Hansen P,1986; Bremer E,1988; Bremer E,1990; Amouyal M,1989; Dandanell G,1991; Munch-Petersen A,1990 DeoR belongs to the DeoR family of transcriptional regulators Valentin-Hansen P,1985; Zeng G,1996 This protein consists of two domains, an amino-terminal domain that contains a potential helix-turn-helix DNA-binding motif and a carboxy-terminal domain involved in the oligomerization and the recognition of a possible co-inducer Valentin-Hansen P,1985; Zeng G,1996; Garces F,2008 DeoR is an octamer in solution Mortensen L,1989and it forms multiple complexes (oligomers) in its target promoters; the cooperative binding of this regulator to different tandem inverted repeat sequences generates a repression DNA loop Mochul'skaia NA,1994; Dandanell G,1985; Valentin- Hansen P,1982; Mortensen L,1989; Dandanell G.,1992 The binding targets for DeoR consist of 16-nucleotide inverted repeat sequences that possess conserved motifs Hammer K,1993; Dandanell G.,1992; operon; repressor; transcription, DNA-dependent; DNA binding; Transcription related; intracellular; regulation of transcription, DNA-dependent; cytoplasm; nucleotide and nucleoside conversions; sequence-specific DNA binding transcription factor activity

transcriptional dualregulator that controls the expression of a number of genes encoding enzymes of the Escherichia coliphosphotransferase (PTS) and phosphoenolpyruvate (PEP) systems Plumbridge J.,2002; Pradhanang V,2005 It also regulates genesinvolved in the uptake of glucose Plumbridge J.,2001 It is considered a global regulator of carbohydrate metabolismDecker K,1998; Kimata K,1998; In addition, Mlc regulates expression of the MalT transcriptional regulator, the activator of themaltose regulon Decker K,1998; Mlc repressor function is disabled by binding of Mlc to an actively-transported and dephosphorylated form of PtsG(EIICBGlc) Lee SJ,2000; Nam TW,2001 The membrane-bound part of EIICBGlc is essential forMlc inactivation Nam TW,2001; Seitz S,2003; Analysis of the crystal structures of the tetrameric Mlc/EIIB complex shows amolecular mechanism of Mlc inactivation by membrane sequestration, in which Mlc loss its DNA binding ability in vivodue to the conformational obstruction by EIIB molecules Nam TW,2008The crystal structure of Mlc has been determined Gerber K,2005; Schiefner A,2005to 2.85 and 2.7 Å resolution and Mlc incomplex with four molecules of enzyme IIBGlc (EIIB) Nam TW,2008 to 2.85 Å resolution; Mlc forms stable dimersand binds to palindromic operator sites; The N-terminal region has a helix-turn-helix domain, and a C-terminal helix is implicated in EIICBGlc binding Seitz S,2003; Mlc forms tetramers in solution Gerber K,2005; Nam TW,2001 The Mlc monomer is composed of three domains: a DNA-binding motif (D-domain), an EIICBGlc-binding motif (E-domain), and an oligomerization domain (O-domain) Nam TW,2008.Mlc is autoregulated Decker K,1998; Shin D,2001 but it is also repressed and activated by CRP Shin D,2001 Mlc binds to sites with a length of 23 bp; Its consensus sequence has been determined Plumbridge J.,2001The intracellular concentration of Mlc is very limited Nam TW,2001 Zinc mediates the Mlc repressor function Schiefner A,2005 Mlc has a high homology with the NagC transcriptional dual regulator (40% identity and 80% similarity) Hosono K,1995; Cho S,2005 At the post-transcriptional level, Mlc interacts with MtfA, which is involved in the regulation of the ptsG Becker AK,2006Mlc is a member of the ROK (repressor, ORFs, kinases) (NagC/XylR) family of proteins, which contains at least two distinct classes of proteins: xylose repressor (XylR) and a series of glucose/fructose kinases Titgemeyer F,1994; Hansen T,2002.; global; repressor; operon; Transcription related; cytoplasmic polysaccharides; polysaccharide biosynthetic process; metal ion binding; carbohydrate metabolic process; DNA binding; transcription, DNA-dependent; cytoplasm

in E. coli; It initiates the process of replication by binding the the origin of replication (oriC); This opens the origin to provide access to single-stranded DNA for the replicative helicase DnaB and its associated loading protein, DnaC, creating the two replication forks that will move outward as DNA polymerase synthesizes new DNA; DnaA is a central focus for regulation of this initiation process, maintaining the critical ratio of one initiation of DNA replication per cell division; As a consequence, a number of factors feed into the regulation of both DnaA abundance and activity, yielding an integrated control over this core cellular process.DnaA interacts with oriC via binding at short DNA sequences known as DnaA boxes |CITS: [7615570][2542031][6091903][6310593][9297181]|; Prior to the start of the replication initiation process, DnaA monomers are bound to three high-affinity sites within oriC; As the replication initiation process begins, DnaA oligomerizes, apparently spidering out from these high-affinity sites to facilitate binding of the low-affinity DnaA boxes |CITS: [19833870][10234818][9351837]|; IHF binds at the same time as this shift from high- to low-affinity sites occurs, enhancing binding by DnaA to these low-affinity boxes |CITS: [10692160][12366835]|; DnaA-ATP binds with somewhat greater affinity to the general oriC region than DnaA-ADP |CITS: [11250912]|; This appears to be the consequence of a handful of initiator or DnaA boxes within oriC which have a four-fold higher affinity for DnaA-ATP over DnaA-ADP |CITS: [14978287][16298387]|; In line with the model of these particular DnaA boxes being gatekeepers for initiation of replication, E. coli win which normal DnaA boxes have been replaced with additional initiator sequences are subject to asynchronous and overly frequent replication initiation |CITS: [17850252]|; More generally, all the DnaA boxes in oriC play a role in proper regulation of initiation, as does their spacing and orientation |CITS: [8858585][7667087][8022267][1603077][1291230][2830261]|; The transition between the closed and open origin is made sharper by the coordinated action of Fis, IHF, and DnaA; Fis initially blocks access by both IHF and DnaA, but as DnaA abundance increases, Fis is kicked off and IHF and DnaA bind the remaining DnaA boxes en masse, starting the opening process |CITS: [14982629]|; Once oriC has begun to unwind, DnaA-ATP binds with significantly higher affinity to the newly revealed single-stranded DNA than to the remaining double-stranded DNA, whereas DnaA-ADP shows no difference in affinity |CITS: [11250912]|.After unwinding the double helix at oriC, DnaA faciliates the loading of the replicative helicase DnaB onto two nascent replication forks; DnaA binds to DnaB, bringing it into the area of the unwound oriC |CITS: [8106460][627535]|; The complete prepriming complex involves 10 DnaA monomers and 2 DnaB hexamers per oriC, meaning that there is one replicative helicase (DnaB hexamer) per new replication fork |CITS: [11551962]|; Although the binding of DnaB and its loader to the oriC region depends on having available single-stranded DNA from the newly unwound helix, DnaA binding does not, meaning that in the prepriming complex DnaA monomers are bound to both the wound and unwound regions of the origin |CITS: [12161435]|; Although there will eventually be a helicase loaded onto each replication fork, loading that is directly attributable to the DnaA-DnaB interaction only occurs on one of the two strands |CITS: [12421318]|; Presumably the replication bubble is effectively held open by the first helicase loaded, allowing access for a second one; Following the generation of this oriC-DnaB prepriming complex, DnaA's role in initiation is complete and it is no longer required |CITS: [2153124]|.DnaA oligomerizes extensively as part of carrying out its role in initiating replication |CITS: [15878847]|; The final prepriming complex has been reported to comprise 10-30 DnaA monomers, with complete occupancy of all oriC DnaA boxes |CITS: [11551962][8663334][12864864]|; As described above, this oligomerization process appears to start with binding at high-affinity DnaA boxes followed by spidering out to lower-affinity sites across the whole of oriC; Proper oligomerization and subsequent opening of oriC depends on DiaA, which forms a tetramer that binds multiple DnaA monomers, suggesting that DiaA may act as a coordinator of DnaA oligomers |CITS: [15326179][17699754]|; DiaA appears unlikely to be part of some sort of DnaA-DiaA complex, as DiaA blocks DnaB loading, implying that at some point after oligomerization of DnaA, DiaA exits the picture |CITS: [19632993]|.Initiation of DNA replication has been proposed to be regulated by several mechanisms that operate through DnaA and oriC; These include control over the ATP/ADP status of DnaA, sequestering of the origin of replication, and titration of available DnaA.The ATP- versus ADP-bound status of DnaA has a major impact on its ability to operate as an initiator of DNA replication; Although DnaA binds both ATP and ADP with high affinity, only the ATP-bound form is able to initiate replication under normal circumstances, as described above |CITS: [3036372][9125116][2835363]|; This difference is not due to binding, as both forms can bind at oriC, but instead is a function of DnaA-ATP being the only form with the ability to prompt unwinding of the double helix |CITS: [8377183]|; Averaged across the entire cell cycle, some 15-30% of all DnaA is typically in ATP-bound form; This abundance rises across the course of the cell cycle, topping out at about 80% just ahead of DNA division and cell division |CITS: [10581238]|.The primary limiter of the abundance of DnaA-ATP is the DnaA regulator Hda, acting in concert with the beta clamp of DNA Pol III |CITS: [7721846][9473485][9674428][10581238][16882985]|; Hda acts as a bridge between the beta clamp of the polymerase and DnaA; Two Hda homodimers bind per clamp via the Hda amino-terminus, and then Hda interacts with DnaA via the DnaA amino-terminus; When this complexing occurs, ATP hydrolysis is stimulated, converting DnaA-ATP to DnaA-ADP |CITS: [15150238][15611053][11254969]|; ATP hydrolysis is inhibited when DnaA is bound to a DnaA box, but this inhibition is overcome by Hda-clamp binding and active DNA synthesis |CITS: [15189445][11309120]|; This suggests that either this interaction is tethering DnaA to non-DnaA-box DNA, or that it may let the DNA polymerase complex drag DnaA off of a DnaA box; This conversion of DnaA-ATP to its ADP state is required to prevent premature or asynchronous initiation of DNA replication |CITS: [15939703][16041320][16321957][12730188][11483528]|.DnaA-ADP is regenerated to its ATP-bound form via an interaction with phospholipids; Cardiolipin and various unsaturated fatty acids in relatively fluid membranes dissociate ADP from DnaA, leaving DnaA available for binding by new ATP |CITS: [2835364][8227025]|; Phospholipids lacking unsaturated fatty acids only poorly promote the release of ADP |CITS: [2845401]|; DnaA binding to oriC is important for stabilizing the protein during this process |CITS: [1512219]|; Conversely, the presence of various phospholipids in advance of binding blocks oriC binding by DnaA |CITS: [12366847]|; The carboxy-terminal portion of DnaA appears to actually enter the membrane during this regeneration process |CITS: [9478970]|; This aligns well with the observation that DnaA localizes to the cell membrane |CITS: [10762265]|.The regeneration of DnaA-ADP to DnaA-ATP is also promoted by two intergenic regions on the chromosome labeled DARS1 and DARS2; Each of these regions contains many DnaA sites, promoting the oligomerization of DnaA in such a manner as to enhance the release of ADP |CITS: [19401329]|.Newly synthesized DNA within oriC and the nearby dnaA locus remains hemimethylated significantly longer than other newly synthesized DNA; This was originally proposed as a mechanism of delaying initiation of new DNA replication, as hemimethylated DNA is not transcription competent |CITS: [1697508]|; Based on analyses carried out using oriC DNA on a plasmid SeqA was observed to bind this hemimethylated DNA and inhibit DnaA binding |CITS: [11122375]|; However, mutants lacking any seqA activity see only a modest increase in initiation of replication, and methylation state of sites within the dnaA promoter region has no impact on replication timing |CITS: [16041320][16740964]|; It does appear that SeqA facilitates oriC reset by blocking access of DnaA to the low-affinity DnaA boxes that are typically only occupied during the initiation of replication |CITS: [17114060]|.There are a number of other DnaA boxes throughout the E. coli genome beyond those within contained oriC and the DARS regions; One theory of regulation of DnaA activity as an initiator of DNA replication is that DnaA monomers are titrated out by binding to many of these alternate DnaA boxes; The major proposed DnaA titration site is datA; The datA site contains multiple DnaA boxes, and titrates out DnaA in a box- dependent manner; Mutations within this site lead to asynchronous and overly frequent initiation of DNA replicatio|CITS: [9765205][11690638][12068813]|; When additional datA sites are introduced into E. coli, DNA replication and cell division are delayed, followed by an induced SOS response and incomplete replication at especially high doses of datA |CITS: [14507385]|; However, given that cells are viable and DNA replication can be initiated in the absence of a datA site, it has been suggested that the role of datA titration of DnaA is in timing of initiation relative to cell growth, rather than in blocking incorrect initiation completely |CITS: [15939703][16041320]|; The DnaA boxes involved in titrating DnaA are structurally distinct from those involved in binding of oligomeric DnaA to oriC |CITS: [17316685]|; However, much like oriC, the DnaA boxes within datA contain an interstitial IHF binding region which must be intact to allow proper function of datA in regulating replication initiation |CITS: [ 19170757]|.DnaA is presented at approximately 800-2,100 molecules per cell; Although this number varies across different E. coli strains, it appears to be fairly consistent across differing growth conditions within a given strain |CITS: [1860829]|.DnaA is involved in a number of processes beyond cellular DNA replication; DnaA is required for replication of many plasmids, including pSC101, pBR322, ColE1, F plasmid, R1, RK2, and mini-F plasmids such as pSC183, pKP1013, and pKV513 |CITS: [6091903][3020005][3931918][3037524][2820940][2844794]|; Mutations in dnaA can also lead to a decrease in linking number in resident plasmids |CITS: [8573119]|; It is also involved in the life cycle of phages such as f1, lambda, and Coliphage 186, as well as being required for robust Tn5 transposition |CITS: [4601460][7033562][2820938][7867947][9819062]|.DnaA is subject to autoregulation, as increased abundance of DnaA represses transcription of dnaA |CITS: [2995766][2981626][3025553][2828882][8407830]|; This occurs via binding of DnaA to DnaA boxes at the dnaA locus, where the DnaA-DnaA box complex directly blocks transcription |CITS: [2854096][2548849][2088506][8995231]|; An internal DnaA box within the actual dnaA gene appears to play no role in modulating transcription, however, and it has been suggested that at least one other DnaA box at the locus is also dispensible for autoregulation |CITS: [7896719][9106220]|.Binding of DnaA to other DnaA boxes can similarly impact regulation of other genes, including rpoH and guaA |CITS: [2540187][1736096]|.The structure of DnaA has been examined in great detail, with an emphasis on how it relates to DnaA's function within the cell.The amino-terminal portion of DnaA is required for replication, but not for ATP or oriC binding |CITS: [9852089]|; This requirement for replication is likely due to the fact that the amino-terminal domain is both necessary and sufficient for oligomerization of DnaA, and is required for the interaction between DnaA and DnaB |CITS: [10540285][10972842]|; The amino-terminal region contains a number of residues whose hydrophobicity is required for proper DnaA function |CITS: [12132668]|; The flexible linker Domain II within DnaA has been evaluated via systematic deletion, revealing a minimum length requirement of 21-27 residues |CITS: [18957591]|; This domain is required for recruiting DnaB to oriC |CITS: [19546317]|; The Box VII domain within DnaA is required for oligomerization |CITS: [15371441]|; Phospholipid binding occurs via the region comprising residues 115-381 |CITS: [8670850][11102450]|; This region is an amphipathic helix that inserts into the membrane to activate the release of ADP |CITS: [9786858]|; ATP binding takes place near K415, R328, and K372 |CITS: [11700030][11853554]|; The carboxy-terminal 94 amino acids are both necessary and sufficient for binding to DnaA boxes in general and oriC in particular; This binding domain contains three α helices |CITS: [7744016][9417934][10844646]|; Circular dichroism and NMR analysis of the DNA-binding domain of DnaA has been carried out |CITS: [12435387]|; NMR analysis has also identified the specific binding surface within this DNA binding domain |CITS: [14523560]|; The DnaA amino-terminal region has also been evaluated via NMR |CITS: [17420252]|.The crystal structure of DnaA's DNA-binding domain complexed with an example DnaA box has been resolved to 2.1 Å resolution |CITS: [12682358]|.An experimental molecular weight of 48 kD has also been reported for DnaA |CITS: [6258023]|.; DNA replication; cytoplasm; regulon; activator; Transcription related; nucleoproteins, basic proteins; sequence-specific DNA binding; nucleoside-triphosphatase activity; regulation of DNA replication; DNA-dependent DNA replication initiation; ATP binding; DNA replication origin binding; DNA binding; nucleotide binding; DNA-dependent DNA replication; repressor

signal transduction; sequence-specific DNA binding; two-component response regulator activity; transcription, DNA-dependent; intracellular; two-component signal transduction system (phosphorelay); DNA binding; sequence-specific DNA binding transcription factor activity; regulation of transcription, DNA-dependent

its own synthesis and represses transcription of the operons involved in transport and catabolism of galacturonate and glucuronate Hugovieux-Cotte-Pattat N,1982; Rodionov DA,2000; Ritzenthaler P,1981; Robert-Baudouy J,1981; Hugouvieux-Cotte-Pattat N,1981; Nemoz G,1976; On the other hand, ExuR is similar to UxuR ARRAY(0x245a4c0) , and apparently both act together and are capable of cross-talk to regulate expression of the uxu operon Rodionov DA,2000; Ritzenthaler P,1983; Ritzenthaler P,1985 ; For this reason, there is the possibility that these regulators bind the same sites with different affinities; Currently, no DNA-binding sites for this regulator have been reported in the literature, and although little is known about the regulating mechanism of ExuR, it has been shown to act as a repressor that binds to a putative inverted repeat sequence Rodionov DA,2000 ; Comparative analysis of intergenic DNA sequences showed the consistent occurrence of ExuR possible binding sites upstream of the genes related to the transport of gluconate ARRAY(0x245cc80) and with the transport and degradation of glucuronides ARRAY(0x24335f8) Rodionov DA,2000 ."; carbon compounds; repressor; regulon; Transcription related; cytoplasm; regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; DNA binding; carbohydrate catabolic process; transcription, DNA-dependent; transcription repressor activity; intracellular

regulator DiRusso CC.,1988that exerts negative control over the fatty acid degradative regulon Simons RW,1980; Simons RW,1980and acetate metabolism Maloy SR,1981 whereas it is responsible for the maximal expression of unsaturated fatty acid biosynthesis Nunn WD,1983 FadR regulates coordinately fatty acid biosynthesis and fatty acid degradation at the level of transcription DiRusso CC,1993 In this way, FadR functions as switch between fatty acid β-oxidation and fatty acid biosynthesis Xu Y,2001br>FadR belongs to the GntR family van Aalten DM,2000; Haydon DJ,1991 However, Xu et al; (2001) reported that homologies to CAP and the Tet repressor based on structure are more relevant and they have categorized FadR as a chimera of two motifs Xu Y,2001FadR appears to be a two-domain dimeric molecule in which the N-terminal domains Raman N,1995; Raman N,1997; DiRusso CC,1992; DiRusso CC.,1988 bind to DNA whereas the C-terminal domain binds the fatty acyl coenzyme A (acyl-CoA) Xu Y,2001 In addition, there is a linker which links both the N terminal and C terminal; The binding of the acyl-CoA disrupts a buried network of charged and polar residues in the C-terminal domain, and the resulting conformational change is transmitted to the N-terminal domain via a domain-spanning α-helix CoA Xu Y,2001 in this way there is loss of DNA binding van Aalten DM,2000 since acyl-CoA regulates DNA binding by FadR DiRusso CC,1992; Cronan JE.,1997The α/β N-terminal domain (α1-β1-α2-α3-β2-β3) has a winged-helix motif, and the α-helical C-terminal domain (α6-α7-α8-α9-α10-α11-α12) resembles the sensor domain of the Tet repressor Xu Y,2001and PAS domain, in particular the photoactive yellow protein van Aalten DM,2000 and finally the linker comprising two short α-helices (α4-α5) Xu Y,2001The binding of FadR to DNA is determined by the localization of the α3 recognition helices that are paired together at the dimer interface Xu Y,2001The DNA-binding domain is very highly conserved among FadR-containing bacteria, whereas the C-terminal acyl-CoA-binding domain shows only weak conservation Iram SH,2005A FadR-type regulator has been identified in Vibrio vulnificus Brown RN,2008 Corynebacterium glutamicum Georgi T,2008 Salmonella enterica, Vibrio cholerae, Pasteurella multocida, and Hemophilus influenzae Iram SH,2005FadR is a homodimer Raman N,1997; Xu Y,2001that recognizes a palindromic sequence, 5'-TGGNNNNNCCA-3' Xu Y,2001Review: Marrakchi H,2002; Cronan JE,1998.; fatty acid metabolic process; lipid metabolic process; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; fatty-acyl-CoA binding; transcription, DNA-dependent; transcription activator activity; transcription repressor activity; regulation of fatty acid metabolic process; regulation of transcription, DNA-dependent; positive regulation of transcription, DNA-dependent; negative regulation of transcription, DNA-dependent; fatty acid oxidation; cytoplasm; Transcription related; operon; regulon; repressor; fatty acids; activator

DNA binding transcription factor activity; DNA binding; nucleotide binding; two-component signal transduction system (phosphorelay); transcription, DNA-dependent; fermentation; operon; activator; Transcription related; cytoplasm; nucleoside-triphosphatase activity

DNA-dependent; cytoplasmic nucleosome; sequence-specific DNA binding; regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; DNA binding; regulation of transcription by chromatin organization

motility, chemotaxis, energytaxis (aerotaxis, redoxtaxis etc); flagella; positive regulation of transcription, DNA-dependent; transcription activator activity; DNA binding; transcription repressor activity; flagellum organization

oxide; 4 iron, 4 sulfur cluster binding; iron-sulfur cluster binding; metal ion binding; regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent

binding transcription factor activity; DNA binding; transcription activator activity; transcription, DNA-dependent; negative regulation of transcription, DNA-dependent; transcription repressor activity; regulation of transcription, DNA-dependent

Ma Z,2004; Hommais F,2004and controls the transcription of genes involved in the maintenance of pH homeostasis, including the principal acid resistance system Tramonti A,2003; Tramonti A,2002; Shin S,2001; Hommais F,2004; Ma Z,2003; Masuda N,2002; Masuda N,2003; Tucker DL,2002 glutamate dependent (GAD), also referred as the GAD system, and genes involved in multidrug efflux, among others Ma Z,2002; Tramonti A,2008; Tucker DL,2003; Tramonti A,2006; Nishino K,2008; Hommais F,2004 GadE also controls the expression of two transcription factors related to acid resistance, GadW and GadX, and for this reason it is considered the central activator of the acid response system Hommais F,2004; Ma Z,2003 GadE is encoded by the gadE-mdtEF operon, inducible by low pH Tucker DL,2002 which is located in the region called the acid fitness island Tramonti A,2008 Expression of gadE is controlled by an unusually large 798- bp upstream intergenic region, termed the sensory integration locus Sayed AK,2009 At least six regulators related to the acid resistance system, GadE, GadX, GadW, EvgA, YdeO, and MnmE, are involved in the direct regulation of gadE Sayed AK,2009; Sayed AK,2007; Hommais F,2004Ma et al; proposed that the binding targets for GadE consist of 20-nucleotide sequences that possess nonconserved motifs, called the GAD box, and suggested that it is a regulator that may form a complex with GadX Ma Z,2003 As a member of the LysR family, this transcription factor is composed of two domains: the N-terminal domain, which has a potential helix-turn-helix DNA-binding motif in the DNA-binding region, and the C-terminal inducer-binding domain Senda T,2005; Schell MA.,1993; pH; activator; Transcription related; intracellular signal transduction; two-component response regulator activity; regulation of transcription, DNA-dependent; sequence-specific DNA binding; transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity; intracellular; two-component signal transduction system (phosphorelay)

and controls the transcription of the genes involved in the principal acid resistance system, is glutamate dependent (GAD), and is also referred to as the GAD system Ma Z,2002; Tramonti A,2008; Tucker DL,2003; Tramonti A,2006; Sayed AK,2007 In addition, GadW also activates the transcription of the central activator involved in the acid response Sayed AK,2007 The physiological inducer is unknown; Richard et al; proposed that GadW can sense intracellular Na+ concentrations, but the mechanism is not known Richard H,2007GadW is one of the regulators in the acid resistance system and is encoded by the unusual gadXW operon, which is located in the region called the acid fitness island Tramonti A,2008 This operon encodes two transcriptional regulators, GadX and GadW, both of which are members of the AraC/XylS family of transcriptional regulators Gallegos MT,1997; Martin RG,2001; Tramonti A,2008 The activities of GadW and GadX are indispensable upon entry into the stationary phase in response to acid pH Tramonti A,2002; Ma Z,2002 In addition, Tramonti et al; provided evidence that the transcription of the gadXW operon is regulated to a posttranscriptional level by a gadY small RNA Tramonti A,2008; Opdyke JA,2004GadW is highly homologous to GadX (42%), and apparently both are capable of cross talk to regulate expression of the genes of this system Tramonti A,2008 Although little is known about the regulating mechanism of GadW, Tucker et al; proposed that this regulator and GadX have distinct molecular mechanisms Tucker DL,2003; Tramonti A,2006 These regulators form homodimers Gallegos MT,1997 and heterodimers Ma Z,2002in vivo.Currently, the GadW/GadX-dependent circuit, involved in the GAD system, is under discussion and study; Tramonti et al; showed that GadX alone activates gadA and gadB promoters Tramonti A,2002 Ma et al; added to this regulatory interaction with the GadW protein, showing that it inhibits GadX and that in some cases it activates in the absence of GadX Ma Z,2002 Trucker et al; gave evidence that GadW can work as a coactivator of GadX or it can inhibit the GadX-dependent activation; they also provided evidence of more target genes for GadX/GadW regulation Tucker DL,2003 Regarding these interactions, Tramonti et al; showed the direct GadX binding at promoters of the gadB (two sites) and gadA (four sites) operons Tramonti A,2002 also, Ma et al; showed that GadW forms a homodimer and that it also binds to the DNA of the gadA and gadB promoters Ma Z,2002 As a member of the AraC/XylS family, this transcription factor is composed of two domains: the C-terminal domain (60% homologous to the C terminal of GadX), which contains two potential helix-turn-helix DNA-binding motifs in the DNA-binding region, and the amino-terminal domain (30% homologous to the N terminal of GadX), which is responsible for dimerization Gallegos MT,1997; Gallegos MT,1993; Ma Z,2002 Tramonti et al; speculated that GadW binds in tandem to two directed repeat sequences, in the same orientation, in the intergenic regions to activate or repress the transcription of the genes regulated Tramonti A,2008 The binding targets for GadW consist of 21-nucleotide-long directed repeat sequences that possess conserved motifs, called the GAD box, which is proposed to be the binding site for GadW and GadX Tucker DL,2003; Tramonti A,2008 This proposal was not unexpected, because the identity and similarity of the C-terminal domains are 41% and 66%, respectively Tramonti A,2008 Each monomer of GadW binds to one of these conserved sequences Tramonti A,2008; sequence-specific DNA binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent; protein-DNA complex; regulation of transcription, DNA-dependent; Transcription related; repressor

and controls the transcription of pH-inducible genes, including the principal acid resistance system Tramonti A,2003; Tramonti A,2002; Shin S,2001 is glutamate dependent (GAD), is also referred to as the GAD system, and its genes are involved in multidrug efflux Ma Z,2002; Tramonti A,2008; Tucker DL,2003; Tramonti A,2006; Nishino K,2008 In addition GadX also activates the transcription of the central activator involved in the acid response Sayed AK,2007 The physiological inducer is unknown; Richard et al; proposed that GadX can sense intracellular Na+ concentrations, but the mechanism is not known Richard H,2007GadX is one of the regulators of the acid resistance system and is encoded by the unusual gadXW operon, which is located in the region called the acid fitness island Tramonti A,2008 This operon encodes two transcriptional regulators, GadX and GadW, both of which are members of the AraC/XylS family of transcriptional regulators Gallegos MT,1997; Martin RG,2001; Tramonti A,2008 The activities of GadX and GadW are indispensable upon entry into the stationary phase in response to acid pH Tramonti A,2002; Ma Z,2002 In addition Tramonti et al; provided evidence that the transcription of the gadXW operon is regulated to a posttranscriptional level by a gadY small RNA Tramonti A,2008; Opdyke JA,2004GadX is highly homologous to GadW (42%), and apparently both are capable of cross talk to regulate expression of the genes of this system Tramonti A,2008 Although little is known about the regulating mechanism of GadX, Tucker et al; proposed that this regulator and GadW have distinct molecular mechanisms Tucker DL,2003; Tramonti A,2006 These regulators form homodimers Gallegos MT,1997 and heterodimers Ma Z,2002in vivo.Currently, the GadW/GadX-dependent circuit, involved in the GAD system, is under discussion and study; Tramonti et al; showed that GadX alone activates the gadA and gadB promoters Tramonti A,2002 Ma et al; added to this regulatory interaction the GadW protein, showing that it inhibits GadX and that in some cases it activates in the absence of GadX Ma Z,2002 Trucker et al; provided evidence that GadW can work as a coactivator of GadX or it can inhibit the GadX-dependent activation, along with evidence of more target genes for GadX/GadW regulation Tucker DL,2003 About their interactions, Tramonti et al; showed the direct GadX binding at the promoters of the gadB (two sites) and gadA (four sites) operons Tramonti A,2002 also, Ma et al; showed that GadW forms a homodimer and that it also binds to the DNA of the gadA and gadB promoters Ma Z,2002 As a member of the AraC/XylS family, this transcription factor is composed of two domains: the C-terminal domain (60% homologous to the C terminal of GadW), which contains two potential helix-turn-helix DNA-binding motifs in the DNA-binding region, and the amino-terminal domain (30% homologous to the N terminal of GadW), which is responsible for dimerization Gallegos MT,1997; Gallegos MT,1993; Ma Z,2002 Tramonti et al; speculated that GadX binds in tandem to two directed repeat sequences, in the same orientation, in the intergenic regions to activate or represses the transcription of the genes regulated Tramonti A,2008 The binding targets for GadX consist of 21-nucleotide-long directed repeat sequences that possess conserved motifs, called the GAD box, which is proposed to be the binding site for GadX and GadW Tucker DL,2003; Tramonti A,2008 This proposal was not unexpected, because the identity and similarity of the C-terminal domains are 41% and 66%, respectively Tramonti A,2008 Each monomer of GadX binds to one of these conserved sequences Tramonti A,2008; activator; Transcription related; regulation of transcription, DNA-dependent; sequence-specific DNA binding; sequence-specific DNA binding transcription factor activity; transcription activator activity; transcription, DNA-dependent; DNA binding; intracellular

transcription of the operons involved in transport and catabolism of D-galactose Semsey S,2007; Weickert MJ,1993; Geanacopoulos M,1997; Synthesis of these operons is induced when E. coli is grown in the presence of inducer (D-galactose) and the absence glucose Geanacopoulos M,1997; Weickert MJ,1992; Weickert MJ,1993 The expression of galR is increased only in the presence of inducer Weickert MJ,1993; Geanacopoulos M,1997 In particular, in the absence of D-galactose, GalR represses the galETKM operon Aki T,1997 In this repression system, GalR binds to two operators in the presence of HU, resulting in the formation of a repressor loop Aki T,1997; Semsey S,2002; Semsey S,2004 This repressor binds in tandem to inverted repeat sequences that are 16 nucleotides long and possess conserved motifs; each dimer binds to one of these conserved sequences Weickert MJ,1993; Weickert MJ,1993 On the other hand, GalR is highly homologous in its amino acid sequence to GalS (55% identical and 88% similar); apparently both act together and are capable of cross-talk to regulate expression of the gal regulon Weickert MJ,1992; Geanacopoulos M,1997 For this reason these regulators bind the same operators, in the cis regulatory regions, with different affinities Brown MP,1994 In the presence of inductor, GalR undergoes a conformational change that reduces its affinity for the operator; Golding et al; showed that GalR is the major repressor of the gal operon Golding A,1991GalR belongs to the GalR/LacI family of transcriptional regulators; Accordingly, this transcriptional repressor family protein is composed of two domains: a conserved N-terminal domain which contains the DNA-binding region, and the carboxy-terminal domain, which is involved in effector binding and dimerization Weickert MJ,1992; Geanacopoulos M,1997 GalR and GalS have only two substitutions in the first helix of the N-terminal domain Weickert MJ,1992; carbon compounds; repressor; operon; Transcription related; cytoplasm; transcription, DNA-dependent; carbohydrate metabolic process; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; regulation of transcription, DNA-dependent

transcription of the operons involved in transport and catabolism of D-galactose Semsey S,2007; Weickert MJ,1993; Weickert MJ,1992; Geanacopoulos M,1997; Synthesis of these operons is induced when E. coli is grown in the presence of the inducer (D-galactose) and the absence glucose Geanacopoulos M,1997; Weickert MJ,1993 GalS is negatively autoregulated, and its expression is increased in the presence of inducer and glucose Weickert MJ,1993; Geanacopoulos M,1997 On the other hand, GalS is highly homologous in its amino acid sequence to GalR (55% identical and 88% similar); apparently both act together and are capable of cross-talking to regulate expression of the gal regulon Weickert MJ,1992; Geanacopoulos M,1997 For this reason these regulators bind the same operators, in the cis regulatory regions, with different affinities; In the presence of an inductor, GalS undergoes a conformational change that reduces its affinity for the operator; Golding et al; showed that GalR is the major repressor of the gal operon Golding A,1991 This repressor binds in tandem to inverted repeat sequences that are 16 nucleotides long and possess conserved motifs; each dimer binds to one of these conserved sequences Weickert MJ,1993; Weickert MJ,1993 GalS belongs to the GalR/LacI family of transcriptional regulators; Accordingly, this transcriptional repressor family protein is composed of two domains: a conserved N-terminal domain which contains the DNA-binding region, and the carboxy-terminal domain, which is involved in effector binding and dimerization Weickert MJ,1992; Geanacopoulos M,1997 GalS and GalR have only two substitutions in the first helix of the N-terminal domain Weickert MJ,1992; carbon compounds; repressor; operon; Transcription related; transcription, DNA-dependent; regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; cytoplasm

enzyme system, which is a secondary pathway for production of C1 units Wilson RL,1994 It is negatively autoregulated, and it coordinately activates transcription of a small-RNA divergent gene Wilson RL,1995; Urbanowski ML,2000In the absence of glycine and the presence of GcvR, GcvA represses operons involved in the glycine cleavage system Wilson RL,1995; Urbanowski ML,2000; Ghrist AC,2001 GcvR is an accessory protein that binds directly to GcvA, bending DNA to form a repression complex (GcvA/GcvR) in the regulatory region of the gcvT operon Ghrist AC,2001 Glycine binds directly to GcvR to disrupt or block the association of the GcvA/GcvR complex, whereas purines appear to promote the formation of the repression complex through an unknown mechanism Heil G,2002; Ghrist AC,2001 GcvA also activates transcription of the gcv genes, via interaction with the α or σ subunits of RNA polymerase Stauffer LT,2005This transcriptional dual regulator, which belongs to the LysR-family Wilson RL,1994 has two domains: the amino-terminal domain, which appears to be involved in transcription activation and in DNA binding through its helix-turn-helix subdomain, and the carboxy-terminal domain, involved in GcvR interaction Jourdan AD,1998; Ghrist AC,2001The GcvA binding sites do not show a clear conservation in their sequences except for a short 5'-CTAAT-3' region Wilson RL,1995; repressor; cytoplasm; transcription repressor activity; transcription activator activity; transcription, DNA-dependent; cellular amino acid catabolic process; 10-formyltetrahydrofolate biosynthetic process; DNA binding; sequence-specific DNA binding transcription factor activity; regulation of transcription, DNA-dependent; amino acids; formyl-THF biosynthesis; operon; activator; Transcription related

which is organized in different operons Larson TJ,1987; Lin EC.,1976; Larson TJ,1992; Yang B,1997; Truniger V,1992; Weissenborn DL,1992; Yang B,1996 ; This regulator is part of the glpEGR operon, yet it can also be constitutively expressed as an independent ARRAY(0x2433490) transcription unit Yang B,1998; Schweizer H,1985 ; In addition, the operons regulated are induced when Escherichia coli is grown in the presence of inductor, glycerol, or glycerol-3-phosphate ARRAY(0x24161c0) , and the absence of glucose Lin EC.,1976; In the absence of inductor, this repressor binds in tandem to inverted repeat sequences that consist of 20-nucleotide-long DNA target sites Zhao N,1994; Lin EC.,1976 ; Binding of GlpR to DNA is diminished in the presence of the inducers glycerol or G3P; GlpR belongs to the DeoR family of transcriptional regulators Zeng G,1996 ; Accordingly, this transcriptional repressor family protein is composed of two domains: a conserved N-terminal domain which contains the DNA-binding region, and the carboxy-terminal domain, which is involved in oligomerization and binding of the inducer Zeng G,1996 ; Resequencing of multiple isolates of the MG1655 strain has identified several genetic variations compared to the reference sequence, including a 1-bp deletion in glpR in strain ATCC700926 Freddolino PL,2012 ; This EcoliWiki page summarizes these sequence differences."; repressor; anaerobic respiration; sequence-specific DNA binding transcription factor activity; intracellular; glycerol metabolic process; regulation of transcription, DNA-dependent; cytoplasm; Transcription related; operon; DNA binding; transcription, DNA-dependent

operon involved in the catabolism of d-gluconate via the Entner-Doudoroff pathway and also represses genes involved in two different systems related to d-gluconate uptake: gluconate I and gluconate II Rodionov DA,2000; Tsunedomi R,2003; Bausch C,1998; This regulator is part of the gntRKU operon, yet it can also be constitutively expressed as an independent ARRAY(0x2431180) transcription unit Izu H,1997; Tong S,1996; Gluconate I is considered the main system for transport of d-gluconate and contains genes that encode high- and low-affinity gluconate transporters Rodionov DA,2000; Porco A,1997; Porco A,1998; Izu H,1997; Peekhaus N,1998; The d-gluconate II system is capable of transport of l-idonate and also is regulated by IdnR; the genes involved in this system encode another high-affinity gluconate transporter Rodionov DA,2000; In addition, the genes regulated are induced when Escherichia coli is grown in the presence of the inductor, d-gloconate, and in the absence of glucose; In the absence of inductor, this repressor binds in tandem to inverted repeat sequences that consist of 20-nucleotide-long DNA target sites Rodionov DA,2000; Binding of GntR to DNA is diminished in the presence of the inducer d-gluconate; GntR is closely homologous to IdnR ARRAY(0x2409e78) and belongs to the LacI/GalR family of transcriptional regulators Rodionov DA,2000; Accordingly, this transcriptional repressor family protein is composed of two domains: a conserved N-terminal domain which contains the DNA-binding region, and the carboxy-terminal domain, which is involved in effector binding and oligomerization Izu H,1997."; intracellular; transcription repressor activity; sequence-specific DNA binding transcription factor activity; DNA binding; regulation of transcription, DNA-dependent; cytoplasm; operon; repressor; Transcription related; transcription, DNA-dependent

activity

multifunctional protein that is capable of condensing Dame RT,2000and supercoiling DNA Zimmerman SB.,2006; Dame RT.,2005; McLeod SM,2001; Tupper AE,1994 It is a global transcriptional silencer of genes with high AT content Dorman CJ.,2004; Fang FC,2008 regulates 5% of all Escherichia coli genes Hommais F,2001 and plays a key role in global chromosome organization in bacteria Wang W,2011 This protein acts as a pleiotropic transcriptional factor with a strong preference for horizontally acquired genes among the 250 loci to which it binds Yamada H,1990; Oshima T,2006 H-NS functions almost exclusively as a transcriptional repressor, although there is no clear evidence that this regulator is an activator; Currently, no inducer for this regulator has been reported in the literature, although Reush et al; proposed that this regulator can form a complex with a short chain of polyhydroxybutyrate Reusch RN,2002 Additional genes might be identified by high-throughput analysis Uyar E,2009H-NS plays an important role in the regulation of many genes in response to environmental changes and adaptation to stress; therefore, it is capable of controlling its own synthesis Falconi M,1993; Falconi M,1996 It also regulates transcription of many other genes that participate in a variety of cellular functions, including genes involved in the following processes or responses: biogenesis of flagella Bertin P,1994; Soutourina O,1999; Landini P,2002 transcription control of the type I fimbria structural genes Donato GM,1999; Donato GM,1997; Olsen PB,1998; Olsen PB,1994; Schembri MA,1998 acid resistance Shin M,2005 the functional glutamic acid-dependent system De Biase D,1999 osmotically inducible genes Bouvier J,1998 the glutamate decarboxylase-dependent acid resistance system Giangrossi M,2005; Ma Z,2002; Tramonti A,2002; Hommais F,2001 osmotic control Lucht JM,1994; Rajkumari K,2001 the type II secretion pathway Francetic O,2000 carbon sources Rimsky S,1990 genes involved in the RNA component of the small subunit (30S subunit) Afflerbach H,1998; Gralla JD.,2005 and proteases Forns N,2005 among others.H-NS is capable of inducing severe bends in the DNA, interacting with a large number of DNA regions that contain a planar curvature Yamada H,1990; Yamada H,1991; Jauregui R,2003 It has been suggested that H-NS binds strongly to sites carrying a 10-bp AT-rich consensus sequence, which functions as a nucleation site for the formation of a repressive higher-order nucleoprotein complex Lang B,2007; Sette M,2009 H-NS binds to intergenic regions as well as regions within genes, but not all genes that bind H-NS are affected by this protein, a fact that is in agreement with the primary role assigned to HN-S in maintenance of nucleoid structure; Currently, there are different models for the formation of DNA-H-NS-DNA bridges which show that this protein binds in tandem to sequences in the genome, forming multimers Dame RT.,2005; Dorman CJ.,2007; Luijsterburg MS,2006As expected for a gene involved in the modulation of many cellular processes, the expression of hns is regulated by several systems and at different levels; At the transcription level, hns is autoregulated, and it is controlled by different transcription factors; hns is induced by high hydrostatic pressure Welch TJ,1993 and DNA synthesis Free A,1995 At the posttranscriptional level, it is subject to regulation by the sRNAs Hfq and DsrA Lease RA,2000; Brescia CC,2003; Majdalani N,2005; Brescia CC,2004; Repoila F,2003It is a DNA-binding protein with similarity to StpA Shi X,1994; Zhang A,1992and these two proteins can have similar functions Ali Azam T,1999; Azam TA,2000 It has an approximately fivefold-lower affinity for DNA than StpA and has a major preference for curved DNA Sonnenfield JM,2001 Expression of stpA from a plasmid can complement an hns mutant phenotype and StpA is able to repress and activate a subset of H-NS-regulated genes, but the specific mechanisms remain to be determined Shi X,1994; Sonnenfield JM,2001; Sonden B,1996; Zhang A,1996; Uyar E,2009; Sonden B,1996 A dominant negative form of StpA can disrupt H-NS activity and vice versa, and H-NS can interact with StpA at two distinct domains to form heterodimers in vitro; also, there is evidence that these proteins can form homodimers Johansson J,2001; Williams RM,1996; Dorman CJ,1999; Williams RM,1996 For this reason, in the absence of H-NS the StpA protein is rapidly degraded in a Lon protease-dependent manner Johansson J,2001; Johansson J,1999 protection from proteolytic degradation appears to be mediated by a direct interaction between StpA and H-NS Johansson J,2001 On the other hand H-NS also may form heterotrimeric complexes with Hha and YdgT Madrid C,2007; Paytubi S,2004H-NS is a small protein and it is an abundant nucleic acid protein in the genome, with about 20,000 copies per cell; This regulator belongs to the histone-like family of transcriptional regulators and the structure of the protein consists of two structured domains which are separated by a flexible linker Dorman CJ.,2004 The N-terminal domain is required for oligomerization and it is involved in protein-protein interactions, while the purified C-terminal domain is involved in DNA binding Dorman CJ.,2004; Rimsky S.,2004; Sette M,2009 H-NS forms two compact clusters associated with each copy of the chromosome; These clusters are located near the one-quarter and three-quarter positions along the long axis of the cell Wang W,2011 In cells with three clusters, the additional cluster tends to appear in the middle Wang W,2011 The two cluster formations are induced by the N-terminal domain-driven oligomerization of the protein Wang W,2011 H-NS sequesters the regulated genes and operons into these clusters and juxtaposed numerous DNA segments broadly distributed throughout the chromosome Wang W,2011 Wang et al; (2011) reported that H-NS clusters could thus serve as anchoring points for numerous DNA loci distributed throughout the genome, creating DNA loops connecting the anchored loci Wang W,2011 Reviews: Luijsterburg MS,2006; Williams RM,1997; Dorman CJ.,2004; Repoila F,2003; repressor; activator; Transcription related; nucleoproteins, basic proteins; cytoplasm; bent DNA binding; membrane; intracellular; DNA binding; transcription activator activity; transcription repressor activity; regulation of transcription, DNA-dependent; transcription, DNA-dependent

Gui L,1996and it regulates the expression of the glyoxylate bypass operon Peskov K,2008; Resnik E,1996; Galinier A,1991; Cortay JC,1989; Maloy SR,1982; Cortay JC,1991 Transcription of this operon is induced when E. coli is grown during acetate accumulation in the exponential phase; Glyoxylate and pyruvate have been identified as effectors of IclR and show antagonistic effects; While glyoxylate favors the inactive dimeric state of IclR, pyruvate increases the binding of IclR to the aceBp promoter by stabilizing the active tetrameric form of the protein Lorca GL,2007On other hand, the genes of the aceBAK operon are expressed to varied degrees due to two facts: first, they are differentially regulated at the translational level, and second, there is a putative premature transcriptional termination in the region preceding the aceK gene Cozzone AJ,2005 IclR represses aceBAK transcription through two mechanisms Yamamoto K,2003 (1) binding to the proximal site, overlapping the -35 promoter box, and preventing RNA polymerase binding Pan B,1996; Negre D,1992; Cortay JC,1991 and (2) binding to the distal site after the RNA polymerase has bound to the promoter and formed the open complex, avoiding the polymerase escape of the promoter through its interaction with the α-subunits; Perhaps the IclR binding at both sites forms an intermolecular bridge that leads to a DNA loop structure and thus enhances the aceBAK repression Yamamoto K,2003This regulator belongs to the IclR family of repressors; IclR is composed of two domains: the amino-terminal domain, which contains the DNA-binding region, and the carboxy-terminal domain, which is responsible for inducer binding Negre D,1992; Sunnarborg A,1990; Lorca GL,2007; Donald LJ,1996; Negre D,1991The crystal structure of the C-terminal domain of IclR (2.3Å) has been solved Lorca GL,2007An iclR mutation affects the carbon flow in the metabolism Lin H,2005; Sanchez AM, 2005 Under glucose-abundant conditions, a double mutant of IclR and ArcA causes an increase in biomass yield (47%) and reduction of acetate (70%) and CO2 (16%) production; Under glucose-limited conditions, this double mutant exhibits an increase of biomass of only 13% Waegeman H,2011.; glyoxylate bypass; repressor; Transcription related; operon; transcription, DNA-dependent; regulation of transcription, DNA-dependent; DNA binding; glyoxylate cycle; cytoplasm

transcription repressor activity; transcription activator activity; DNA binding; activator; Transcription related; repressor; nucleoproteins, basic proteins; regulation of translation; regulation of transcription, DNA-dependent; chromosome

and it contains an iron-sulfur cluster that could act as a sensor of iron-sulfur cluster assembly Schwartz CJ,2001; Giel JL,2006 This protein regulates the expression of the operons that encode components of a secondary pathway of iron-sulfur cluster assembly, iron-sulfur proteins, anaerobic respiration enzymes, and biofilm formation Tokumoto U,2001; Schwartz CJ,2001; Giel JL,2006; Lee KC,2008; Yeo WS,2006; Wu Y,2009IscR is a member of the Rrf2 family Nesbit AD,2009and carries a predicted N-terminal helix-turn-helix DNA-binding motif and three conserved cysteines in its C terminus; IscR is a dimer in solution Nesbit AD,2009 and it contains the [2Fe-2S]1+ cluster when purified under anaerobic conditions Schwartz CJ,2001Two types of DNA-binding sites have been described for IscR: type 1 and type 2. Both sites resemble 25-bp imperfect palindromes but differ in their sequence Giel JL,2006; Nesbit AD,2009 IscR requires the iron-sulfur cluster for its activity when bound to type 1 sites; PiscR contains two type 1 sites Giel JL,2006 Therefore, under conditions when Fe-S cluster assembly becomes rate limiting, levels of [2Fe-2S]-containing IscR may decrease due to a lower rate of its synthesis, thus relieving repression of the iscRSUA operon for the biogenesis of the iron-sulfur cluster Schwartz CJ,2001; Frazzon J,2001 In contrast, for the regulation of promoters containing type 2 sites, such as PsufA, the [2Fe-2S] cluster of IscR is dispensable Yeo WS,2006; Lee KC,2008IscR binds cooperatively to DNA, and four protomers bind to one palindromic site Nesbit AD,2009; Transcription related; repressor; activator; operon; 2 iron, 2 sulfur cluster binding; iron-sulfur cluster binding; metal ion binding; response to stress; regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; double-stranded DNA binding; DNA binding; transcription activator activity; transcription, DNA- dependent; transcription repressor activity

leucine biosynthesis Chen CC,2005; Hertzberg KM,1980, genes involved in the utilization of certain β-glucosides Ueguchi C,1998; Madhusudan S,2005 and genes encoding LuxR-type transcription factors Stratmann T,2008 It is also involved in the bacterial stringent response Majumder A,2001.LeuO is one of the transcription factors that counteract H-NS-mediated repression of specific loci Chen CC,2005; Madhusudan S,2005; Ueguchi C,1998 Overproduction of LeuO causes the phenotype Bgl+, since LeuO can unsilence the bglGFB operon, which is silenced (phenotypically Bgl ) under laboratory conditions Ueguchi C,1998LeuO is part of the RpoS/H-NS/Hfq/LeuO/DsrA RNA regulatory cascade that controls the bglGFH operon Madhusudan S,2005and translation of rpoS, particularly at low temperatures Klauck E,1997; Repoila F,2003.LeuO belongs to the LysR transcriptional regulator family and contains a helix-turn-helix DNA-binding domain Ueguchi C, 1998; Henikoff S,1988 No LeuO consensus binding sequence is known Stratmann T,2008.LeuO activates transcription of the divergent leuLABCD operon Chen CC,2001.An in vivo genetic selection (SELEX) and phenotype microarray analysis revealed several multidrug resistance genes as targets for LeuO, including acrEF, ygcLKJIH-ygbTF, and mdtNOP (sdsRQP); mdtNOP (sdsRQP) is involved in sensitivity control against sulfa drugs Shimada T,2009; activator; regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent; leucine; operon; cytoplasm; Transcription related

chromatin; serine-type endopeptidase activity; regulation of transcription, DNA-dependent; hydrolase activity; response to DNA damage stimulus; proteolysis; DNA replication; DNA binding; DNA repair

least 10% of the genes in Escherichia coli Tani TH,2002 These genes are involved in amino acid biosynthesis and catabolism, nutrient transport, pili synthesis, and other cellular functions, including 1-carbon metabolism Ernsting BR,1992; Brinkman AB,2003; Calvo JM,1994 In addition, Lrp affects nearly three-fourths of the genes induced upon entry into stationary phase Tani TH,2002; Cho BK,2008 Lrp might also play a topological role in dynamic DNA packaging D'Ari R,1993Lrp can act as a repressor or activator for its target genes; Binding of leucine can affect these activities in three different ways: leucine either potentiates, antagonizes, or has no discernible effect upon Lrp action Lin R,1992; Platko JV,1993; Newman EB,1995 It is believed that Lrp senses the presence of rich nutrition based on the concentration of leucine and positively regulates genes that function during famine and negatively regulates genes that function during a feast Calvo JM,1994Lrp forms a mixture of octamers and hexadecamers Chen S,2001 In the presence of leucine, the octamer configuration is favored; It is believed that the switch between the octameric and hexadecameric states modulated by leucine affects the binding and the activity of Lrp at its target genes Chen S,2002 The structure of Lrp from Escherichia coli bound to DNA as an octamer has been solved de los Rios S,2007 Lrp forms an open ring structure, in which the DNA is wrapped around the octamer in a nucleosome-like structure; The monomer chain contains two domains, an N-terminal helix-turn-helix motif and a C-terminal αβ-sandwich fold; The N-terminal is responsible for the specificity and function among members of the Lrp regulon across the Enterobacteriaceae; The N-terminal tail plays a significant role in modulating Lrp function, similar to what has been reported for a number of other transcriptional regulators Hart BR,2011N-terminal diversity is responsible for some of the differences between orthologs in terms of DNA binding and multimerization Hart BR,2011Lrp-regulated promoters commonly contain multiple adjacent binding sites for the protein with low sequence specificity; A consensus recognition sequence has been described Cui Y,1996 The identified 15-bp sequence motif is structured with flanking CAG/CTG triplets and a central AT-rich signal; Leucine has two effects upon binding to DNA in vitro: the affinity of Lrp is reduced but the cooperativity of binding to multiple sites is increased Chen S,2005Lrp belongs to the Lrp/AsnC family of transcriptional regulatory proteins, which is widely distributed throughout the eubacterial and archaeal domains; Lrp appears to be very well conserved in members of the γ-proteobacteria Brinkman AB,2003A microarray analysis for Lrp of Escherichia coli was done by Hung SP,2002.; regulation of transcription, DNA-dependent; sequence-specific DNA binding; response to leucine; cytoplasm; nucleoproteins, basic proteins; Transcription related; intracellular; operon; repressor; isoleucine/valine; leucine; leucine biosynthetic process; sequence-specific DNA binding transcription factor activity; activator

binding; trisaccharide binding; two-component response regulator activity; two-component signal transduction system (phosphorelay); sequence-specific DNA binding; regulation of transcription, DNA-dependent; transcription, DNA-dependent; carbohydrate metabolic process; intracellular; ATP binding; binding; sequence-specific DNA binding transcription factor activity; DNA binding; carbon compounds

involved in resistance to antibiotics, oxidative stress Alekshun MN,1999 organic solvents White DG,1997; Alekshun MN,1999; Asako H,1997 and heavy metals Alekshun MN,1999MarA, SoxS, and Rob are paralogous transcriptional regulators that show 45% amino acid identity between them Cohen SP,1993 the crystal structures for Rob Kwon HJ,2000and MarA Rhee S,1998confirm this similarity between them; They activate a common set of genes, but the expression and activity of each one of these proteins are induced by different signals: the activity of Rob is increased with dipyridyl, bile salts, or decanoate Rosner JL,2002; Rosenberg EY,2003, and the transcription of MarA and SoxS is increased by the aromatic weak acid salicylate Martin RG,2002and oxidative stress Demple B.,1996 respectively.Many genes are regulated by all three proteins; however, some genes are regulated only by one of them; The differential regulation of these genes might be caused by the degeneracy of their DNA-binding sites Pomposiello PJ,2003These three monomer proteins bind to the same DNA site, a degenerate 19-bp sequence known as the sox-mar-rob box, which has to be in a specific orientation and distance relative to the -35 and -10 boxes of the promoter Martin RG,1999; Wood TI,1999 In class I promoters, the activators bind upstream of the -35 box and are generally oriented in a backwards direction, while in class II promoters the proteins overlap the -35 promoter hexamer and generally are oriented in the forward direction Martin RG,1999; Wood TI,1999 In a subset of the class I promoters the sox-mar-rob box is separated by ~30 bp from the -10 hexamer but can be functional in either orientation Martin RG,1999; Wood TI,1999For MarA it was shown that the extent of activation at different promoters is only poorly correlated with the strength of MarA binding to the specific mar box Martin RG,2008 By using a computational model of transcriptional activation it was proposed that at the class I promoter of mar MarA increases the binding of RNA polymerase but not the occupancy; At the class II promoters of sodA and micF MarA can even decrease both RNA polymerase affinity and occupancy at the promoter; The model predicts that MarA increases the rate of transcription initiation while decreasing the overall presence of the transcription machinery at the promoter Wall ME,2009The sox-mar-rob box contains an invariant A at position 1, two recognition elements, the RE1 at postion 4-7 and RE2 at position 15-18, and a 7-bp A/T-rich spacer separating these elements Kwon HJ,2000; Dangi B,2001; Griffith KL,2001; There are more than 10,000 such binding sites per genome Griffith KL,2002 However, the majority of these sites are not functional because they are not in the proper orientation or distance relative to the promoter Martin RG,2002 Based on these findings, it was proposed that these proteins activate the transcription by a mechanism named DNA scanning or prerecruitment, which consists of the formation of the complex RNA polymerase transcriptional regulator in the absence of DNA, and then this complex scans the DNA to bind to appropriate sites Martin RG,2002; Griffith KL,2002These three proteins belong to the AraC/XylS family of transcriptional regulators Gallegos MT,1997 and as with other members of this family they have two helix-turn-helix (HTH) motifs for DNA binding, one of them, located in the N-terminal region, interacts with the element RE1 of the mar box, and the HTH located in the C-terminal region interacts with the element RE2 Griffith KL,2002; Rhee S,1998; Dangi B,2001 In the case of Rob, it appears that only one of two HTH motifs makes base-specific contact with DNA; this was observed for the micF promoter Kwon HJ,2000Cells carrying a MarA mutation in a glutamic acid residue (E89A) were able to express higher resistance to superoxides than those harboring wild-type MarA Martin RG,2011 Thus, MarA E89A acts more like SoxS than MarA in exhibiting greater activation and binding at the class I promoter Martin RG,2011marA is the second gene of the marRAB operon, which encodes an autorepressor (MarR) and an autoactivator (MarA) Cohen SP,1993 MarR is inactivated by salicylate, and then the operon is induced; Upon removal of the inducer (salicylate), MarA is degraded by the Lon protease Griffith KL,2004 and the binding of MarA with DNA or RNA polymerase protects it from degradation Shah IM,2006Reviews: Alekshun MN,1999; Demple B.,1996; Randall LP,2002; sequence-specific DNA binding transcription factor activity; DNA binding; transcription repressor activity; response to drug; xenobiotic metabolic process; transcription, DNA-dependent; transcription activator activity; cytoplasm; Transcription related; activator; repressor; operon; detoxification; drug resistance/sensitivity; response to antibiotic; regulation of transcription, DNA-dependent; sequence-specific DNA binding; intracellular

binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; regulation of transcription, DNA-dependent

binding transcription factor activity; repressor; cellular amino acid biosynthetic process; regulation of transcription, DNA-dependent; Transcription related; operon; methionine metabolic process