A highly specialized flavin mononucleotide riboswitch responds differently to similar ligands and confers roseoflavin resistance to Streptomyces davawensis

Pedrolli, Danielle Biscaro; Matern, Andreas; Wang, Joy; Ester, Miriam; Siedler, Kathrin; Breaker, Ronald R.; Mack, Matthias

doi:10.1093/nar/gks616

Cited by 71 publications

(75 citation statements)

References 25 publications

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“…The functions of the genes ribB-ribM, ribG, and monofunctional ribA have been verified experimentally in an earlier work (18). Moreover, it was recently shown that the ribBMAH genes are controlled at the level of translation by an FMN riboswitch (ribB FMN riboswitch, or RFN element) located directly upstream of ribBMAH (47).…”

Section: Resultsmentioning

confidence: 80%

“…In addition, non-protein cellular targets for RoFMN were discovered. According to these works, RoFMN reduces expression of genes controlled by FMN riboswitches in B. subtilis, Streptomyces coelicolor, and the human pathogen Listeria monocytogenes (33,35,46,47). FMN riboswitches are genetic elements involved in the regulation of riboflavin biosynthesis and transport (62).…”

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confidence: 99%

“…Blocking of FMN riboswitches leads to riboflavin auxotrophy of target cells (33). Notably, S. davawensis carries a highly specialized FMN riboswitch which is not negatively affected by RoFMN and thus confers roseoflavin resistance to S. davawensis (47).…”

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confidence: 99%

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Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

et al. 2012

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Section: Resultsmentioning

confidence: 80%

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confidence: 99%

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Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

et al. 2012

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“…A DNA fragment coding for Rli96 was produced by PCR using the modifying oligonucleotides 5=-CGC AAA GCT TAT AAA TAA AAC CAG CTA ATT-3= and 5=-ATA TAT GCG GCC GCT CAT TGA ATA ATT CTT CAT TG-3=. The PCR product was digested and ligated to linearized pT7-luc (7). Construction of the recombinant strain L. monocytogenes M1 (a L. monocytogenes EGDe derivative) was described earlier (17).…”

Section: Methodsmentioning

confidence: 99%

Uptake and Metabolism of Antibiotics Roseoflavin and 8-Demethyl-8-Aminoriboflavin in Riboflavin-Auxotrophic Listeria monocytogenes

et al. 2016

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The riboflavin analogs roseoflavin (RoF) and 8-demethyl-8-aminoriboflavin (AF) are produced by the bacteria Streptomyces davawensis and Streptomyces cinnabarinus. Riboflavin analogs have the potential to be used as broad-spectrum antibiotics, and we therefore studied the metabolism of riboflavin (vitamin B 2 ), RoF, and AF in the human pathogen Listeria monocytogenes, a bacterium which is a riboflavin auxotroph. We show that the L. monocytogenes protein Lmo1945 is responsible for the uptake of riboflavin, RoF, and AF. Following import, these flavins are phosphorylated/adenylylated by the bifunctional flavokinase/flavin adenine dinucleotide (FAD) synthetase Lmo1329 and adenylylated by the unique FAD synthetase Lmo0728, the first monofunctional FAD synthetase to be described in bacteria. R iboflavin (vitamin B 2 ) is not synthesized by mammals but is synthesized by many microorganisms and by all plants (1).The genomes of the human bacterial pathogens Listeria monocytogenes, Streptococcus pyogenes, and Enterococcus faecalis do not contain genes encoding riboflavin biosynthetic enzymes (2), and thus these microorganisms are riboflavin auxotrophs. L. monocytogenes, Streptococcus pyogenes, and Enterococcus faecalis produce energy-coupling factor (ECF) transporters which combine with a riboflavin-specific binding subunit (subunit EcfS or RibU) (3), and ECF-RibU-mediated uptake is the sole source of riboflavin (4).Riboflavin cannot be detected in cell extracts of bacteria (5-7), indicating that it is completely metabolized by flavokinases (RibF) (EC 2.7.1.26) and FAD synthetases (RibC) (EC 2.7.7.2). These enzymes catalyze the formation of FMN (from riboflavin and ATP) and FAD (from FMN and ATP) (see Fig. S1 in the supplemental material) and play an important role in metabolic trapping of riboflavin (8). In bacteria, bifunctional flavokinases/FAD synthetases have been found, whereas in eukarya and archaea, monofunctional enzymes seem to be the rule (9). FMN and FAD are cofactors of flavoproteins/flavoenzymes, which have a wide variety of different biological functions (10). The number of flavindependent proteins varies greatly in different organisms (and among pathogens) and covers a range from approximately 0.1% to 3.5% of the proteome (11). In Escherichia coli, FMN and FAD are present at levels which are about 30 times lower than those of the highly abundant amino acids or nucleotides (12), whereby FAD (170 M) clearly is present at higher levels than FMN (54

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“…In addition to the FMN riboswitch variant in C. difficile, other FMN riboswitch variants have been identified in a previous study (Pedrolli et al 2012). One such representative appears to have evolved to functionally discriminate against the natural FMN analog called roseoflavin phosphate, a compound that exhibits antibacterial properties.…”

Section: Orphan and Other Riboswitch Candidatesmentioning

confidence: 97%

Riboswitch diversity and distribution

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Riboswitches are commonly used by bacteria to detect a variety of metabolites and ions to regulate gene expression. To date, nearly 40 different classes of riboswitches have been discovered, experimentally validated, and modeled at atomic resolution in complex with their cognate ligands. The research findings produced since the first riboswitch validation reports in 2002 reveal that these noncoding RNA domains exploit many different structural features to create binding pockets that are extremely selective for their target ligands. Some riboswitch classes are very common and are present in bacteria from nearly all lineages, whereas others are exceedingly rare and appear in only a few species whose DNA has been sequenced. Presented herein are the consensus sequences, structural models, and phylogenetic distributions for all validated riboswitch classes. Based on our findings, we predict that there are potentially many thousands of distinct bacterial riboswitch classes remaining to be discovered, but that the rarity of individual undiscovered classes will make it increasingly difficult to find additional examples of this RNA-based sensory and gene control mechanism.

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A highly specialized flavin mononucleotide riboswitch responds differently to similar ligands and confers roseoflavin resistance to Streptomyces davawensis

Cited by 71 publications

References 25 publications

Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

Uptake and Metabolism of Antibiotics Roseoflavin and 8-Demethyl-8-Aminoriboflavin in Riboflavin-Auxotrophic Listeria monocytogenes

Riboswitch diversity and distribution

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