Abstract
Riboflavin analogs have a good potential to serve as basic structures for the development of novel anti-infectives. Riboflavin analogs have multiple cellular targets, since riboflavin (as a precursor to flavin cofactors) is active at more than one site in the cell. As a result, the frequency of developing resistance to antimicrobials based on riboflavin analogs is expected to be significantly lower. The only known natural riboflavin analog with antibiotic function is roseoflavin from the bacterium Streptomyces davawensis. This antibiotic negatively affects flavoenzymes and FMN riboswitches. Another roseoflavin producer, Streptomyces cinnabarinus, was recently identified. Possibly, flavin analogs with antibiotic activity are more widespread than anticipated. The same could be true for flavin analogs yet to be discovered, which could constitute tools for cellular chemistry, thus allowing a further extension of the catalytic spectrum of flavoenzymes.
Key words
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Kurth R, Paust J, Hähnlein W (1996) Vitamins, Chapter 7. In: Ullmann’s Encyclopedia of industrial chemistry. Wiley-VCH, Weinheim, pp 521–530
Bacher A (1991) Riboflavin kinase and FAD synthetase. In: Müller F (ed) Chemistry and biochemistry of flavoenzymes. CRC press, Boca Raton, FL, pp 349–370
Ghisla S, Massey V (1986) New flavins for old: artificial flavins as active site probes of flavoproteins. Biochem J 239:1–12
Massey V, Hemmerich P (1980) Active-site probes of flavoproteins. Biochem Soc Trans 8:246–257
Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593
Eirich LD, Vogels GD, Wolfe RS (1979) Distribution of coenzyme F420 and properties of its hydrolytic fragments. J Bacteriol 140:20–27
Bardos TJ (1974) Antimetabolites: molecular design and mode of action. Top Curr Chem 52:63–98
Mack M, Grill S (2006) Riboflavin analogs and inhibitors of riboflavin biosynthesis. Appl Microbiol Biotechnol 71:265–275
French GL (2010) The continuing crisis in antibiotic resistance. Int J Antimicrob Agents 36(Suppl 3):S3–S7
Fischer M, Bacher A (2005) Biosynthesis of flavocoenzymes. Nat Prod Rep 22:324–350
Perkins J, Pero J (2002) Biosynthesis of riboflavin, biotin, folic acid, and cobalamin. In: Sonenshein A, Hoch J, Losick R (eds) Bacillus subtilis and its closest relatives: from genes to cells. ASM Press, Washington DC, pp 271–286
Perkins JB, Pero JG, Sloma A (1990) Riboflavin overproducing strains of Bacillus subtilis. European Patent Application 0 405 730 A1
Nudler E, Mironov AS (2004) The riboswitch control of bacterial metabolism. Trends Biochem Sci 29:11–17
Winkler WC, Breaker RR (2005) Regulation of bacterial gene expression by riboswitches. Annu Rev Microbiol 59:487–517
Abbas CA, Sibirny AA (2011) Genetic control of biosynthesis and transport of riboflavin and flavin nucleotides and construction of robust biotechnological producers. Microbiol Mol Biol Rev 75:321–360
García Angulo VA, Bonomi HR, Posadas DM, Serer MI, Torres AG, Zorreguieta Á, Goldbaum FA(2013) Identification and characterization of RibN, a novel family of riboflavin transporters from Rhizobium leguminosarum and other proteobacteria. J Bacteriol 195(20):4611–4619
Vogl C, Grill S, Schilling O, Stulke J, Mack M, Stolz J (2007) Characterization of riboflavin (vitamin B2) transport proteins from Bacillus subtilis and Corynebacterium glutamicum. J Bacteriol 189:7367–7375
Burgess CM, Slotboom DJ, Geertsma ER, Duurkens RH, Poolman B, van Sinderen D (2006) The riboflavin transporter RibU in Lactococcus lactis: molecular characterization of gene expression and the transport mechanism. J Bacteriol 188:2752–2760
Duurkens RH, Tol MB, Geertsma ER, Permentier HP, Slotboom DJ (2007) Flavin binding to the high affinity riboflavin transporter RibU. J Biol Chem 282:10380–10386
Vitreschak AG, Rodionov DA, Mironov AA, Gelfand MS (2002) Regulation of riboflavin biosynthesis and transport genes in bacteria by transcriptional and translational attenuation. Nucleic Acids Res 30:3141–3151
Eitinger T, Rodionov DA, Grote M, Schneider E (2011) Canonical and ECF-type ATP-binding cassette importers in prokaryotes: diversity in modular organization and cellular functions. FEMS Microbiol Rev 35:3–67
ter Beek J, Duurkens RH, Erkens GB, Slotboom DJ (2011) Quaternary structure and functional unit of energy coupling factor (ECF)-type transporters. J Biol Chem 286:5471–5475
Hemberger S, Pedrolli DB, Stolz J, Vogl C, Lehmann M, Mack M (2011) RibM from Streptomyces davawensis is a riboflavin/roseoflavin transporter and may be useful for the optimization of riboflavin production strains. BMC Biotechnol 11:119–129
Reihl P, Stolz J (2005) The monocarboxylate transporter homolog Mch5p catalyzes riboflavin (vitamin B2) uptake in Saccharomyces cerevisiae. J Biol Chem 280:39809–39817
Yao Y, Yonezawa A, Yoshimatsu H, Masuda S, Katsura T, Inui K (2010) Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain. J Nutr 140:1220–1226
Yonezawa A, Masuda S, Katsura T, Inui K (2008) Identification and functional characterization of a novel human and rat riboflavin transporter, RFT1. Am J Physiol Cell Physiol 295:C632–C641
Macheroux P, Kappes B, Ealick SE (2011) Flavogenomics—a genomic and structural view of flavin-dependent proteins. FEBS J 278:2625–2634
Langer S, Hashimoto M, Hobl B, Mathes T, Mack M (2013) Flavoproteins are potential targets for the antibiotic roseoflavin in Escherichia coli. J Bacteriol 195(18):4037–4045
Kitagawa M, Ara T, Arifuzzaman M, Ioka-Nakamichi T, Inamoto E, Toyonaga H, Mori H (2005) Complete set of ORF clones of Escherichia coli ASKA library (a complete set of E. coli K-12 ORF archive): unique resources for biological research. DNA Res 12:291–299
Mathes T, Vogl C, Stolz J, Hegemann P (2009) In vivo generation of flavoproteins with modified cofactors. J Mol Biol 385:1511–1518
Cowden WB, Butcher GA, Hunt NH, Clark IA, Yoneda F (1987) Antimalarial activity of a riboflavin analog against Plasmodium vinckei in vivo and Plasmodium falciparum in vitro. Am J Trop Med Hyg 37:495–500
Becker K, Christopherson RI, Cowden WB, Hunt NH, Schirmer RH (1990) Flavin analogs with antimalarial activity as glutathione reductase inhibitors. Biochem Pharmacol 39:59–65
DiMarco AA, Bobik TA, Wolfe RS (1990) Unusual coenzymes of methanogenesis. Annu Rev Biochem 59:355–394
White RH (2001) Biosynthesis of the methanogenic cofactors. Vitam Horm 61:299–337
Kuo MS, Yurek DA, Coats JH, Li GP (1989) Isolation and identification of 7,8-didemethyl-8-hydroxy-5-deazariboflavin, an unusual cosynthetic factor in streptomycetes, from Streptomyces lincolnensis. J Antibiot (Tokyo) 42:475–478
Coats JH, Li GP, Kuo MS, Yurek DA (1989) Discovery, production, and biological assay of an unusual flavenoid cofactor involved in lincomycin biosynthesis. J Antibiot (Tokyo) 42:472–474
Mao Y, Varoglu M, Sherman DH (1999) Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564. Chem Biol 6:251–263
Daniels L, Bakhiet N, Harmon K (1985) Widespread distribution of a 5-deazaflavin cofactor in actinomycetes and related bacteria. Syst Appl Microbiol 6:12–17
Purwantini E, Gillis TP, Daniels L (1997) Presence of F420-dependent glucose-6-phosphate dehydrogenase in Mycobacterium and Nocardia species, but absence from Streptomyces and Corynebacterium species and methanogenic archaea. FEMS Microbiol Lett 146:129–134
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR (2000) A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405:962–966
Tachibana S, Murakami T (1975) The isolation and some properties of new flavins (“schizoflavin”) formed by Schizophyllum commune. J Nutr Sci Vitaminol (Tokyo) 21:61–63
Kisker C, Schindelin H, Rees DC (1997) Molybdenum-cofactor-containing enzymes: structure and mechanism. Annu Rev Biochem 66:233–267
Leimkuhler S, Wuebbens MM, Rajagopalan KV (2011) The history of the discovery of the molybdenum cofactor and novel aspects of its biosynthesis in bacteria. Coord Chem Rev 255:1129–1144
Mayhew SG, Whitfield CD, Ghisla S, Jorns MS (1974) Identification and properties of new flavins in electron-transferring flavoprotein from Peptostreptococcus elsdenii and pig-liver glycolate oxidase. Eur J Biochem 44:579–591
Ghisla S, Mayhew SG (1973) Identification and structure of a novel flavin prosthetic group associated with reduced nicotinamide adenine dinucleotide dehydrogenase from Peptostreptococcus elsdenii. J Biol Chem 248:6568–6570
Ghisla S, Mayhew SG (1976) Identification and properties of 8-hydroxyflavin–adenine dinucleotide in electron-transferring flavoprotein from Peptostreptococcus elsdenii. Eur J Biochem 63:373–390
Matsui K (1965) Nekoflavin, a new flavin compound, in the choroid of cat’s eye. J Biochem 57:201–206
Matsui K, Kasai S (1996) Identification of nekoflavin as 7 alpha-hydroxyriboflavin. J Biochem 119:441–447
Ohkawa H, Ohishi N, Yagi K (1983) New metabolites of riboflavin appear in human urine. J Biol Chem 258:5623–5628
Ohkawa H, Ohishi N, Yagi K (1983) New metabolites of riboflavin appeared in rat urine. Biochem Int 6:239–247
West DW, Owen EC (1969) The urinary excretion of metabolites of riboflavine by man. Br J Nutr 23:889–898
Susin S, Abian J, Sanchez-Baeza F, Peleato ML, Abadia A, Gelpi E, Abadia J (1993) Riboflavin 3′- and 5′-sulfate, two novel flavins accumulating in the roots of iron-deficient sugar beet (Beta vulgaris). J Biol Chem 268:20958–20965
Otani S, Takatsu M, Nakano M, Kasai S, Miura R (1974) Letter: roseoflavin, a new antimicrobial pigment from Streptomyces. J Antibiot (Tokyo) 27:88–89
Grill S, Yamaguchi H, Wagner H, Zwahlen L, Kusch U, Mack M (2007) Identification and characterization of two Streptomyces davawensis riboflavin biosynthesis gene clusters. Arch Microbiol 188:377–387
Mansjo M, Johansson J (2011) The riboflavin analog roseoflavin targets an FMN-riboswitch and blocks Listeria monocytogenes growth, but also stimulates virulence gene-expression and infection. RNA Biol 8:674–680
Jankowitsch F, Kuhm C, Kellner R, Kalinowski J, Pelzer S, Macheroux P, Mack M (2011) A novel N, N-8-amino-8-demethyl-D-riboflavin dimethyltransferase (RosA) catalyzing the two terminal steps of roseoflavin biosynthesis in Streptomyces davawensis. J Biol Chem 286:38275–38285
Jankowitsch F, Schwarz J, Ruckert C, Gust B, Szczepanowski R, Blom J, Pelzer S, Kalinowski J, Mack M (2012) Genome sequence of the bacterium Streptomyces davawensis JCM 4913 and heterologous production of the unique antibiotic roseoflavin. J Bacteriol 194:6818–6827
Otani S, Matsui K, Kasai S (1997) Chemistry and biochemistry of 8-aminoflavins. Osaka City Med J 43:107–137
Kasai S, Kubo Y, Yamanaka S, Hirota T, Sato H, Tsuzukida Y, Matusi K (1978) Anti-riboflavin activity of 8N-alkyl analogues of roseoflavin in some Gram-positive bacteria. J Nutr Sci Vitaminol (Tokyo) 24:339–350
Matsui K, Kasai S (1976) Photolysis products of roseoflavin. In: Singer T (ed) Flavins and flavoproteins. Proc. Int. Symp. 5th, 1975. Elsevier, Amsterdam, pp 328–333
Kasai S, Yamanaka S, Wang SC, Matsui K (1979) Anti-riboflavin activity of 8-O-alkyl derivatives of riboflavin in some Gram-positive bacteria. J Nutr Sci Vitaminol (Tokyo) 25:289–298
Juri N, Kubo Y, Kasai S, Otani S, Kusunose M, Matsui K (1987) Formation of roseoflavin from 8-amino- and 8-methylamino-8-demethyl-D-riboflavin. J Biochem (Tokyo) 101:705–711
Matsui K, Juri N, Kubo Y, Kasai S (1979) Formation of roseoflavin from guanine through riboflavin. J Biochem (Tokyo) 86:167–175
Chen H, Yamase H, Murakami K, Chang CW, Zhao L, Zhao Z, Liu HW (2002) Expression, purification, and characterization of two N, N-dimethyltransferases, tylM1 and desVI, involved in the biosynthesis of mycaminose and desosamine. Biochemistry 41:9165–9183
Cooke G, Legrand YM, Rotello VM (2004) Model systems for flavoenzyme activity: an electrochemically tuneable model of roseoflavin. Chem Commun 1088–1089
Hasford J, Rizzo C (1998) Linear free energy substituent effect on flavin redox chemistry. J Am Chem Soc 120:2251–2255
Pedrolli DB, Nakanishi S, Barile M, Mansurova M, Carmona EC, Lux A, Gärtner W, Mack M (2011) The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase. Biochem Pharmacol 82:1853–1859
Grill S, Busenbender S, Pfeiffer M, Kohler U, Mack M (2008) The bifunctional flavokinase/flavin adenine dinucleotide synthetase from Streptomyces davawensis produces inactive flavin cofactors and is not involved in resistance to the antibiotic roseoflavin. J Bacteriol 190:1546–1553
Yorita K, Misaki H, Palfey BA, Massey V (2000) On the interpretation of quantitative structure-function activity relationship data for lactate oxidase. Proc Natl Acad Sci U S A 97:2480–2485
Walsh C, Fisher J, Spencer R, Graham DW, Ashton WT, Brown JE, Brown RD, Rogers EF (1978) Chemical and enzymatic properties of riboflavin analogues. Biochemistry 17:1942–1951
Shinkai S, Kameoka K, Honda N, Ueda K, Manabe O, Lindsey J (1986) Spectral and reactivity studies of roseoflavin analogs: correlation between reactivity and spectral parameters. Bioorg Chem 14:119–133
Otani S, Kasai S, Matsui K (1980) Isolation, chemical synthesis, and properties of roseoflavin. Methods Enzymol 66:235–241
Nakanishi M, Yatome C, Ishida N, Kitade Y (2001) Putative ACP phosphodiesterase gene (acpD) encodes an azoreductase. J Biol Chem 276:46394–46399
Langer S, Nakanishi S, Mathes T, Knaus T, Binter A, Macheroux P, Mase T, Miyakawa T, Tanokura M, Mack M (2013) The flavoenzyme azobenzene reductase AzoR from Escherichia coli binds roseoflavin mononucleotide (RoFMN) with high affinity and is less active in its RoFMN form. Biochemistry 52:4288–4295
Ito K, Nakanishi M, Lee WC, Sasaki H, Zenno S, Saigo K, Kitade Y, Tanokura M (2006) Three-dimensional structure of AzoR from Escherichia coli. An oxidereductase conserved in microorganisms. J Biol Chem 281:20567–20576
Caldwell ST, Farrugia LJ, Hewage SG, Kryvokhyzha N, Rotello VM, Cooke G (2009) Model systems for flavoenzyme activity: an investigation of the role functionality attached to the C(7) position of the flavin unit has on redox and molecular recognition properties. Chem Commun 1350–1352
Reddick JJ, Saha S, Lee J, Melnick JS, Perkins J, Begley TP (2001) The mechanism of action of bacimethrin, a naturally occurring thiamin antimetabolite. Bioorg Med Chem Lett 11:2245–2248
Fiehe K, Arenz A, Drewke C, Hemscheidt T, Williamson RT, Leistner E (2000) Biosynthesis of 4′-O-methylpyridoxine (Ginkgotoxin) from primary precursors. J Nat Prod 63:185–189
Blount KF, Breaker RR (2006) Riboswitches as antibacterial drug targets. Nat Biotechnol 24:1558–1564
Ott E, Stolz J, Lehmann M, Mack M (2009) The RFN riboswitch of Bacillus subtilis is a target for the antibiotic roseoflavin produced by Streptomyces davawensis. RNA Biol 6:276–280
Lee ER, Blount KF, Breaker RR (2009) Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression. RNA Biol 6:187–194
Pedrolli DB, Matern A, Wang J, Ester M, Siedler K, Breaker R, Mack M (2012) A highly specialized flavin mononucleotide riboswitch responds differently to similar ligands and confers roseoflavin resistance to Streptomyces davawensis. Nucleic Acids Res 40:8662–8673
Schwarz G, Mendel RR, Ribbe MW (2009) Molybdenum cofactors, enzymes and pathways. Nature 460:839–847
Acknowledgments
This work was funded by the German “Federal Ministry of Education and Research” (BMBF) (FKZ 17PNT006) (“Qualifizierungs-/Profilierungsgruppe neue Technologien“) and the research training group NANOKAT (FKZ 0316052A) of the BMBF.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Pedrolli, D.B., Jankowitsch, F., Schwarz, J., Langer, S., Nakanishi, S., Mack, M. (2014). Natural Riboflavin Analogs. In: Weber, S., Schleicher, E. (eds) Flavins and Flavoproteins. Methods in Molecular Biology, vol 1146. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0452-5_3
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0452-5_3
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0451-8
Online ISBN: 978-1-4939-0452-5
eBook Packages: Springer Protocols