The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase

Pedrolli, Danielle Biscaro; Nakanishi, Satoshi; Barile, Maria; Мansurova, Мadina; Carmona, Eleonora Cano; Lux, Andreas; Gärtner, Wolfgang; Mack, Matthias

doi:10.1016/j.bcp.2011.08.029

Cited by 45 publications

(57 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to a new nomenclature (35), we propose the name RibCF for the bifunctional flavokinase/FAD synthetase Lmo1329 whereby RibC represents the N-terminal FAD synthetase domain and RibF represents the C-terminal flavokinase domain. Lmo1329 (RibCF) produces AFMN, RoFMN, and AFAD but not RoFAD and thus is different from all other flavokinases/FAD synthetases analyzed so far (5,18,36). Lmo0728 (RibC) is an FAD synthetase and is responsible for the formation of toxic RoFAD in L. monocytogenes.…”

Section: Discussionmentioning

confidence: 88%

“…AF was a gift from Peter Macheroux (Technical University of Graz, Austria) and was dissolved in DMSO. Roseoflavin mononucleotide (RoFMN), AFMN, roseoflavin adenine dinucleotide (RoFAD), and 8-demethyl-8-aminoriboflavin adenine dinucleotide (AFAD) were prepared enzymatically using purified recombinant human flavokinase and human FAD synthetase as described previously (18). All other chemicals were from Sigma-Aldrich (Munich, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Riboflavin analogs and/or their degradation products have the potential to negatively interfere with human metabolism (18). The synthesis of RoFMN and AFMN by human hepatocyte cell extracts suggests that cofactor analogs are generated by humans in vivo.…”

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Flavins were analyzed by high performance liquid chromatography (HPLC) coupled to a mass spectrometer (Agilent Technologies, Waldbronn, Germany) as described earlier (15). …”

Section: Methodsmentioning

confidence: 99%

“…Roseoflavin mononucleotide (RoFMN), roseoflavin adenine dinucleotide (RoFAD) and 8-demethyl-8-amino riboflavin mononucleotide (AFMN) were enzymatically synthesized and purified as described earlier (15). …”

Section: Methodsmentioning

confidence: 99%

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

Pedrolli

Matern

Wang

et al. 2012

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

Streptomyces davawensis is the only organism known to synthesize the antibiotic roseoflavin, a riboflavin (vitamin B 2 ) analog. Roseoflavin is converted to roseoflavin mononucleotide (RoFMN) and roseoflavin adenine dinucleotide in the cytoplasm of target cells. (Ribo-)Flavin mononucleotide (FMN) riboswitches are genetic elements, which in many bacteria control genes responsible for the biosynthesis and transport of riboflavin. Streptomyces davawensis is roseoflavin resistant, and the closely related bacterium Streptomyces coelicolor is roseoflavin sensitive. The two bacteria served as models to investigate roseoflavin resistance of S. davawensis and to analyze the mode of action of roseoflavin in S. coelicolor . Our experiments demonstrate that the ribB FMN riboswitch of S. davawensis (in contrast to the corresponding riboswitch of S. coelicolor ) is able to discriminate between the two very similar flavins FMN and RoFMN and shows opposite responses to the latter ligands.

show abstract

Natural Flavins: Occurrence, Role, and Noncanonical Chemistry

Drenth¹,

Fraaije²

2021

Flavin‐Based Catalysis

View full text Add to dashboard Cite

show abstract

The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase

Cited by 45 publications

References 21 publications

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

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

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

Natural Flavins: Occurrence, Role, and Noncanonical Chemistry

Contact Info

Product

Resources

About