title: The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase.
abstract: 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 2.7.1.26) and FAD synthetase (EC 2.7.7.2) 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.
authors.affiliation: Institut für Technische Mikrobiologie, Hochschule Mannheim, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany.
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Pedrolli
authors.forename: Shinobu
authors.initials: S
authors.lastname: Nakanishi
authors.forename: Maria
authors.initials: M
authors.lastname: Barile
authors.forename: Madina
authors.initials: M
authors.lastname: Mansurova
authors.forename: Eleonora C
authors.initials: EC
authors.lastname: Carmona
authors.forename: Andreas
authors.initials: A
authors.lastname: Lux
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gärtner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D004227:Dithionite / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D012256:Riboflavin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013302:Streptomyces / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004227:Dithionite; C009191:roseoflavin; C023644:8-amino-8-demethylriboflavin; D017853:Phosphotransferases (Alcohol Group Acceptor); C022532:riboflavin kinase; D009713:Nucleotidyltransferases; C020143:FMN adenylyltransferase; D012256:Riboflavin