Control of Proteobacterial Central Carbon Metabolism by the HexR Transcriptional Regulator

Leyn, Semen A.; Li, Xiaoqing; Zheng, Qing-Xiang; Novichkov, Pavel S.; Reed, Samantha B.; Romine, Margaret F.; Fredrickson, James K.; Yang, Chen; Osterman, Andrei L.; Rodionov, Dmitry A.

doi:10.1074/jbc.m111.267963

Cited by 48 publications

(59 citation statements)

References 42 publications

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“…Experimental testing of selected bioinformatic predictions (binding sites) provides an additional validation strategy that was used by us in some of the previous studies on genomic reconstruction of regulatory networks (16,(29)(30)(31). In this study, we chose to test the novel Rex regulon in T. maritima because of its several unique features.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Central Carbon and Energy Metabolism in Bacteria by Redox-Responsive Repressor Rex

Ravcheev

Latif

et al. 2011

Journal of Bacteriology

122

213

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Redox-sensing repressor Rex was previously implicated in the control of anaerobic respiration in response to the cellular NADH/NAD ؉ levels in Gram-positive bacteria. We utilized the comparative genomics approach to infer candidate Rex-binding DNA motifs and assess the Rex regulon content in 119 genomes from 11 taxonomic groups. Both DNA-binding and NADsensing domains are broadly conserved in Rex orthologs identified in the phyla Firmicutes, Thermotogales, Actinobacteria, Chloroflexi, Deinococcus-Thermus, and Proteobacteria. The identified DNA-binding motifs showed significant conservation in these species, with the only exception detected in Clostridia, where the Rex motif deviates in two positions from the generalized consensus, TTGTGAANNNNTTCACAA. Comparative analysis of candidate Rex sites revealed remarkable variations in functional repertoires of candidate Rex-regulated genes in various microorganisms. Most of the reconstructed regulatory interactions are lineage specific, suggesting frequent events of gain and loss of regulator binding sites in the evolution of Rex regulons. We identified more than 50 novel Rex-regulated operons encoding functions that are essential for resumption of the NADH:NAD ؉ balance. The novel functional role of Rex in the control of the central carbon metabolism and hydrogen production genes was validated by in vitro DNA binding assays using the TM0169 protein in the hydrogen-producing bacterium Thermotoga maritima. Bacteria can adapt to changes in their environment by utilizing a range of transcription factors that receive an appropriate intra-or extracellular signal and trigger the specific transcriptional response. The Rex regulator is a transcription factor that responds to intracellular redox potential and negatively controls expression of genes involved in energy metabolism and fermentative growth in Gram-positive bacteria, including the actinobacterium Streptomyces coelicolor (4) and various Firmicutes, such as Bacillus subtilis (35), Staphylococcus aureus (25), and Streptococcus mutans (3). NAD plays an important role in different biological processes, including redox cellular balance. During the catabolism of carbohydrates, NAD ϩ is reduced to NADH by glycolytic enzymes. The NADH formed is reoxidized back either by respiratory electron transport chains or by NADH-linked fermentative enzymes. The DNA-binding activity of Rex is modulated by the intracellular ratio of NADH:NAD ϩ . Under the low NADH:NAD ϩ ratio, the Rex protein binds to the target sites and represses transcription of genes involved in NADH reoxidation, while the increase of NADH concentration results in the dissociation of Rex from DNA and derepression of its target genes (4, 25, 35).Rex was initially described in S. coelicolor, where it controls the cytochrome bd terminal oxidase operon cydABCD and the heme biosynthesis genes hemACD, as well as the membrane-bound proton-translocating NADH dehydrogenase operon nuoA-nuoN (4). The Rex-regulated promoters contain a common DNA motif with consensus 5=-TGTGNNCNNNT...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Central Carbon and Energy Metabolism in Bacteria by Redox-Responsive Repressor Rex

Ravcheev

Latif

et al. 2011

Journal of Bacteriology

122

213

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“…Finally, the knowledge-driven comparative-genomics approach (14), which uses a combination of the motif identification computational algorithms, the genome context techniques, and available experimental data from the literature, was successfully applied to the analysis of various regulatory systems in several groups of microorganisms (15,16). The combined reconstruction of certain metabolic pathways and transcriptional regulons was previously used to infer regulons involved in the central metabolism of sugars, amino acids, nucleotides, metals, and cofactors and resulted in the prediction of numerous novel functions for previously uncharacterized genes (17)(18)(19).…”

mentioning

confidence: 99%

Genomic Reconstruction of the Transcriptional Regulatory Network in Bacillus subtilis

et al. 2013

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“…In gammaproteobacteria, the KDPG metabolic intermediate of glycolysis was reported to abrogate the affinity of HexR for its target DNA (43,44). Therefore, we tested several metabolic intermediates (KDPG, glucose-6-phosphate, fructose-1,6-biphosphate, and 6-phosphogluconic acid) as putative effectors for N. meningitidis HexR binding in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…HexR contains two domains, namely, a helix-turn-helix (HTH) binding domain in the N-terminal region and a sugar isomerase (SIS) domain in the C-terminal region that is predicted to bind phosphosugars. In the gammaproteobacteria P. putida and Shewanella oneidensis, binding of the 2-dehydro-3-deoxyphosphogluconate (KDPG) metabolic intermediate of glycolysis was reported to dissociate HexR from its target DNA (43,44). The NMB1389 (hexR) nucleotide sequence is highly conserved (Ͼ98%) among the available N. meningitidis genome sequences, and it is present in all species of the Neisseria genus, such as Neisseria gonorrhoeae, Neisseria lactamica, Neisseria cinerea, Neisseria flavescens, Neisseria mucosa, Neisseria sicca, and Neisseria subflava.…”

Section: Resultsmentioning

confidence: 99%

“…The NMB1389 gene encodes a protein with 41% amino acid identity and 58% amino acid similarity to the HexR protein of Pseudomonas putida (43). HexR-like transcriptional regulators from the RpiR family are often involved in sugar catabolism regulation in proteobacteria (43,44). HexR contains two domains, namely, a helix-turn-helix (HTH) binding domain in the N-terminal region and a sugar isomerase (SIS) domain in the C-terminal region that is predicted to bind phosphosugars.…”

Section: Resultsmentioning

confidence: 99%

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HexR Controls Glucose-Responsive Genes and Central Carbon Metabolism in Neisseria meningitidis

Antunes¹,

Golfieri²,

Ferlicca³

et al. 2016

J Bacteriol

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Neisseria meningitidis, an exclusively human pathogen and the leading cause of bacterial meningitis, must adapt to different host niches during human infection. N. meningitidis can utilize a restricted range of carbon sources, including lactate, glucose, and pyruvate, whose concentrations vary in host niches. Microarray analysis of N. meningitidis grown in a chemically defined medium in the presence or absence of glucose allowed us to identify genes regulated by carbon source availability. Most such genes are implicated in energy metabolism and transport, and some are implicated in virulence. In particular, genes involved in glucose catabolism were upregulated, whereas genes involved in the tricarboxylic acid cycle were downregulated. Several genes encoding surface-exposed proteins, including the MafA adhesins and Neisseria surface protein A, were upregulated in the presence of glucose. Our microarray analysis led to the identification of a glucose-responsive hexR-like transcriptional regulator that controls genes of the central carbon metabolism of N. meningitidis in response to glucose. We characterized the HexR regulon and showed that the hexR gene is accountable for some of the glucose-responsive regulation; in vitro assays with the purified protein showed that HexR binds to the promoters of the central metabolic operons of the bacterium. Based on DNA sequence alignment of the target sites, we propose a 17-bp pseudopalindromic consensus HexR binding motif. Furthermore, N. meningitidis strains lacking hexR expression were deficient in establishing successful bacteremia in an infant rat model of infection, indicating the importance of this regulator for the survival of this pathogen in vivo. IMPORTANCENeisseria meningitidis grows on a limited range of nutrients during infection. We analyzed the gene expression of N. meningitidis in response to glucose, the main energy source available in human blood, and we found that glucose regulates many genes implicated in energy metabolism and nutrient transport, as well as some implicated in virulence. We identified and characterized a transcriptional regulator (HexR) that controls metabolic genes of N. meningitidis in response to glucose. We generated a mutant lacking HexR and found that the mutant was impaired in causing systemic infection in animal models. Since N. meningitidis lacks known bacterial regulators of energy metabolism, our findings suggest that HexR plays a major role in its biology by regulating metabolism in response to environmental signals.

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Control of Proteobacterial Central Carbon Metabolism by the HexR Transcriptional Regulator

Cited by 48 publications

References 42 publications

Transcriptional Regulation of Central Carbon and Energy Metabolism in Bacteria by Redox-Responsive Repressor Rex

Transcriptional Regulation of Central Carbon and Energy Metabolism in Bacteria by Redox-Responsive Repressor Rex

Genomic Reconstruction of the Transcriptional Regulatory Network in Bacillus subtilis

HexR Controls Glucose-Responsive Genes and Central Carbon Metabolism in Neisseria meningitidis

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