Riboflavin Production by Roseoflavin-resistant Strains of Some Bacteria

Matsui, Kunihiko; Wang, Hsiu-Chuan; Hirota, Takako; Matsukawa, Hirokazu; Kasai, Shinji; Shinagawa, Kunihiro; Otani, Shuzo

doi:10.1080/00021369.1982.10865390

Cited by 11 publications

(10 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In B. subtilis some roseoflavin-resistant strains were found to overproduce riboflavin (28). In these strains, accumulating riboflavin dilutes roseoflavin and prevents the formation of toxic levels of RoFMN and RoFAD.…”

Section: Discussionmentioning

confidence: 99%

The Bifunctional Flavokinase/Flavin Adenine Dinucleotide Synthetase from Streptomyces davawensis Produces Inactive Flavin Cofactors and Is Not Involved in Resistance to the Antibiotic Roseoflavin

et al. 2008

View full text Add to dashboard Cite

Streptomyces davawensis synthesizes the antibiotic roseoflavin, one of the few known natural riboflavin analogs, and is roseoflavin resistant. It is thought that the endogenous flavokinase (EC 2.7.1.26)/flavin adenine dinucleotide (FAD) synthetase (EC 2.7.7.2) activities of roseoflavin-sensitive organisms are responsible for the antibiotic effect of roseoflavin, producing the inactive cofactors roseoflavin-5-monophosphate (RoFMN) and roseoflavin adenine dinucleotide (RoFAD) from roseoflavin. To confirm this, the FAD-dependent Sus scrofa D-amino acid oxidase (EC 1.4.3.3) was tested with RoFAD as a cofactor and found to be inactive. It was hypothesized that a flavokinase/FAD synthetase (RibC) highly specific for riboflavin may be present in S. davawensis, which would not allow the formation of toxic RoFMN/RoFAD. The gene ribC from S. davawensis was cloned. RibC from S. davawensis was overproduced in Escherichia coli and purified. ). Both RibC enzymes synthesized RoFAD and RoFMN. The functional expression of S. davawensis ribC did not confer roseoflavin resistance to a ribC-defective B. subtilis strain.Riboflavin (vitamin B 2 ) analogs have the potential to serve as basic structures for the development of novel anti-infectives (3). Consequently, both the mode of action of riboflavin analogs and the mechanism of resistance to these compounds are of substantial interest. Only very few natural riboflavin analogs are known (24). Moreover, the only known organism to produce a riboflavin analog with antibiotic activity is the grampositive bacterium Streptomyces davawensis (32).S. davawensis synthesizes the anti-vitamin 8-dimethyl-amino-8-demethyl-D-riboflavin, or roseoflavin ( Fig. 1), from riboflavin (27) via 8-amino-and 8-methylamino-8-demethyl-D-riboflavin (22). Roseoflavin is toxic to gram-positive but also to gramnegative bacteria if the compound is able to enter the cell (16). The molecular basis for roseoflavin toxicity is not clear. In all organisms, riboflavin serves as the direct precursor for the cofactors (ribo)flavin-5Ј-monophosphate (FMN) and flavin adenine dinucleotide (FAD) (12). FAD and (to a lesser extent) FMN are active components of flavoproteins, being involved in a wide range of redox and other reactions (15). FMN is synthesized from riboflavin by flavokinase (EC 2.7.1.26), and FAD is produced from FMN by FAD synthetase (EC 2.7.7.2) (2). In microorganisms, both enzymatic activities seem to be present in sufficient amounts, since only traces of free riboflavin are detectable in the cytoplasm (11). Accordingly, cytoplasmic roseoflavin may quickly be converted to the corresponding FMN/ FAD analogs roseoflavin-5Ј-monophosphate (RoFMN) and roseoflavin adenine dinucleotide (RoFAD). The synthesis of these inactive cofactors may explain the antibiotic activity of roseoflavin ( Fig. 1) (31, 36).S. davawensis is roseoflavin resistant, and the mechanism of self-resistance could involve a flavokinase/FAD synthetase with a high substrate specificity for riboflavin. Such an enzyme would not accept roseoflavin as...

show abstract

Section: Discussionmentioning

confidence: 99%

The Bifunctional Flavokinase/Flavin Adenine Dinucleotide Synthetase from Streptomyces davawensis Produces Inactive Flavin Cofactors and Is Not Involved in Resistance to the Antibiotic Roseoflavin

et al. 2008

View full text Add to dashboard Cite

show abstract

“…28 Some roseoflavin resistant strains are deregulated with respect to riboflavin biosynthesis and overproduce riboflavin. 20 These strains carry mutations in either ribC or within the RFN riboswitch: The riboflavin overproducing phenotype in RibC deficient strains can be explained by the reduced synthesis of FMN. 14 Mutations in RFN may prevent FMN from binding to RFN and producing the terminator structure.…”

Section: Discussionmentioning

confidence: 99%

The RFN riboswitch ofBacillus subtilisis a target for the antibiotic roseoflavin produced byStreptomyces davawensis

Ott

Stolz²,

Lehmann³

et al. 2009

RNA Biology

View full text Add to dashboard Cite

The riboflavin (vitamin B 2 ) biosynthetic genes in Bacillus subtilis are transcribed simultaneously from the riboflavin promoter (P rib ). The 5'-end of the nascent rib-mRNA carries a flavin mononucleotide (FMN) binding riboswitch, which regulates gene expression. The antibiotic roseoflavin from Streptomyces davawensis is a naturally occurring riboflavin analog, its mechanism of action is largely unknown. A recombinant B. subtilis strain carrying a copy of P rib -RFN fused to a promoterless lacZ reporter gene in the chromosomal amyE locus was grown in a minimal medium. Upon addition of roseoflavin to the growth medium the apparent LacZ activity in this strain was not significantly reduced. Similar experiments carried out on recombinant B. subtilis strains oversynthesizing the flavin transporters RibU (B. subtilis) or RibM (S. davawensis) produced still other results. In these strains, roseoflavin (as well as riboflavin) repressed LacZ synthesis indicating that the RFN riboswitch is a target for roseoflavin (or roseoflavin mononucleotide), which may at least in part explain its antibiotic activity.

show abstract

“…[152] Because of its similarity in structure with FMN, roseoflavin might potentially target the FMN riboswitch and control the operon involved in riboflavin biosynthesis. [35,41] It was recently reported that roseoflavin is able to bind FMN riboswitch in vitro.…”

Section: Riboswitches As Antibacterial Targetsmentioning

confidence: 99%

Riboswitches: Ancient and Promising Genetic Regulators

et al. 2009

View full text Add to dashboard Cite

Bait and switch: Metabolite‐sensing riboswitches make use of RNA structural modulation to regulate gene expression, as illustrated in the scheme, in response to subtle changes in metabolite concentrations. This review describes the current knowledge about naturally occurring riboswitches and their growing potential as antibacterial cellular targets and as molecular biosensors.magnified imageNewly discovered metabolite‐sensing riboswitches have revealed that cellular processes extensively make use of RNA structural modulation to regulate gene expression in response to subtle changes in metabolite concentrations. Riboswitches are involved at various regulation levels of gene expression, such as transcription attenuation, translation initiation, mRNA splicing and mRNA processing. Riboswitches are found in the three kingdoms of life, and in various cases, are involved in the regulation of essential genes, which makes their regulation an essential part of cell survival. Because riboswitches operate without the assistance of accessory proteins, they are believed to be remnants of an ancient time, when gene regulation was strictly based on RNA, from which are left numerous “living molecular fossils”, as exemplified by ribozymes, and more spectacularly, by the ribosome. Due to their nature, riboswitches hold high expectations for the manipulation of gene expression and the detection of small metabolites, and also offer an unprecedented potential for the discovery of novel classes of antimicrobial agents.

show abstract

Riboflavin Production by Roseoflavin-resistant Strains of Some Bacteria

Cited by 11 publications

References 5 publications

The Bifunctional Flavokinase/Flavin Adenine Dinucleotide Synthetase from Streptomyces davawensis Produces Inactive Flavin Cofactors and Is Not Involved in Resistance to the Antibiotic Roseoflavin

The Bifunctional Flavokinase/Flavin Adenine Dinucleotide Synthetase from Streptomyces davawensis Produces Inactive Flavin Cofactors and Is Not Involved in Resistance to the Antibiotic Roseoflavin

The RFN riboswitch ofBacillus subtilisis a target for the antibiotic roseoflavin produced byStreptomyces davawensis

Riboswitches: Ancient and Promising Genetic Regulators

Contact Info

Product

Resources

About