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Pedrolli D.B.,Institute For Technische Mikrobiologie | Nakanishi S.,Institute For Technische Mikrobiologie | Barile M.,University of Bari | Mansurova M.,Max Planck Institute for Chemistry | And 4 more authors.
Biochemical Pharmacology | Year: 2011

The non-pathogenic Gram-positive soil bacterium Streptomyces davawensis synthesizes the riboflavin (vitamin B 2) analogs roseoflavin (RoF) and 8-demethyl-8-amino-riboflavin (AF). Both compounds are antibiotics. Notably, a number of other riboflavin analogs are currently under investigation with regard to the development of novel antiinfectives. As a first step towards understanding the metabolism of riboflavin analogs in humans, the key enzymes flavokinase (EC and FAD synthetase (EC were studied. Human flavokinase efficiently converted RoF and AF to roseoflavin mononucleotide (RoFMN) and 8-demethyl-8-amino-riboflavin mononucleotide (AFMN), respectively. Human FAD synthetase accepted RoFMN but not AFMN as a substrate. Consequently, roseoflavin adenine dinucleotide (RoFAD) was synthesized by the latter enzyme but not 8-demethyl-8-amino-riboflavin adenine dinucleotide (AFAD). The cofactor analogs RoFMN, AFMN and RoFAD have different physicochemical properties as compared to FMN and FAD. Thus, the cofactor analogs have the potential to render flavoenzymes inactive, which may negatively affect human metabolism. RoF, but not AF, was found to inhibit human flavokinase. In summary, we suggest that AF has a lower toxic potential and may be better suited as a lead structure to develop antimicrobial compounds. © 2011 Elsevier Inc.

Pedrolli D.B.,Institute For Technische Mikrobiologie | Matern A.,Institute For Technische Mikrobiologie | Wang J.,Yale University | Ester M.,Institute For Technische Mikrobiologie | And 3 more authors.
Nucleic Acids Research | Year: 2012

Streptomyces davawensis is the only organism known to synthesize the antibiotic roseoflavin, a riboflavin (vitamin B2) 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. © 2012 The Author(s).

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