Skip to main content
Log in

Riboflavin analogs and inhibitors of riboflavin biosynthesis

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Flavins are active components of many enzymes. In most cases, riboflavin (vitamin B2) as a coenzyme represents the catalytic part of the holoenzyme. Riboflavin is an amphiphatic molecule and allows a large variety of different interactions with the enzyme itself and also with the substrate. A great number of active riboflavin analogs can readily be synthesized by chemical methods and, thus, a large number of possible inhibitors for many different enzyme targets is conceivable. As mammalian and especially human biochemistry depends on flavins as well, the target of the inhibiting flavin analog has to be carefully selected to avoid unwanted effects. In addition to flavoproteins, enzymes, which are involved in the biosynthesis of flavins, are possible targets for anti-infectives. Only a few flavin analogs or inhibitors of flavin biosynthesis have been subjected to detailed studies to evaluate their biological activity. Nevertheless, flavin analogs certainly have the potential to serve as basic structures for the development of novel anti-infectives and it is possible that, in the future, the urgent need for new molecules to fight multiresistant microorganisms will be met.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bacher A (1991) Riboflavin kinase and FAD synthetase. In: Muller F (ed) Chemistry and biochemistry of flavoenzymes. CRC, Boca Raton, FL, pp 349–370

    Google Scholar 

  • Bacher A et al (1997) Biosynthesis of riboflavin: lumazine synthase and riboflavin synthase. Methods Enzymol 280:389–399

    CAS  PubMed  Google Scholar 

  • Bacher A et al (2001) Biosynthesis of riboflavin. Vitam Horm 61:1–49

    CAS  PubMed  Google Scholar 

  • Bandrin SV, Beburov M, Rabinovich PM, Stepanov AI (1979) Riboflavin auxotrophs of Escherichiacoli. Genetika 15:2063–2065

    CAS  PubMed  Google Scholar 

  • Bardos TJ (1974) Antimetabolites: molecular design and mode of action. Top Curr Chem 52:63–98

    CAS  PubMed  Google Scholar 

  • Bereswill S, Hinkelmann S, Kist M, Sander A (1999) Molecular analysis of riboflavin synthesis genes in Bartonellahenselae and use of the ribC gene for differentiation of Bartonella species by PCR. J Clin Microbiol 37:3159–3166

    CAS  PubMed  PubMed Central  Google Scholar 

  • Burgess C, O’Connell-Motherway M, Sybesma W, Hugenholtz J, van Sinderen D (2004) Riboflavin production in Lactococcuslactis: potential for in situ production of vitamin-enriched foods. Appl Environ Microbiol 70:5769–5777

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cecchini G, Kearney EB (1980) Uptake and binding of riboflavin by membrane vesicles of Bacillussubtilis. J Supramol Struct 13:93–100

    CAS  PubMed  Google Scholar 

  • Cecchini G, Perl M, Lipsick J, Singer TP, Kearney EB (1979) Transport and binding of riboflavin by Bacillussubtilis. J Biol Chem 254:7295–7301

    CAS  PubMed  Google Scholar 

  • Chen J et al (2005) A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors. Anal Biochem 338:124–130

    CAS  PubMed  Google Scholar 

  • Choi KP, Kendrick N, Daniels L (2002) Demonstration that fbiC is required by Mycobacteriumbovis BCG for coenzyme F(420) and FO biosynthesis. J Bacteriol 184:2420–2428

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chu CK, Bardos TJ (1977) Synthesis and inhibition analysis of 2(4)-imino-4(2)-amino-2,4-dideoxyriboflavin, a dual antagonist of riboflavin and folinic acid. J Med Chem 20:312–314

    CAS  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Cushman M, Mihalic JT, Kis K, Bacher A (1999) Design and synthesis of 6-(6-d-ribitylamino-2,4-dihydroxypyrimidin-5-yl)-1-hexyl phosphonic acid, a potent inhibitor of lumazine synthase. Bioorg Med Chem Lett 9:39–42

    CAS  PubMed  Google Scholar 

  • Cushman M, Yang D, Kis K, Bacher A (2001) Design, synthesis, and evaluation of 9-d-ribityl-1,3,7-trihydro-2,6,8-purinetrione, a potent inhibitor of riboflavin synthase and lumazine synthase. J Org Chem 66:8320–8327

    CAS  PubMed  Google Scholar 

  • Cushman M et al (2002) Design, synthesis, and evaluation of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase. J Org Chem 67:5807–5816

    CAS  PubMed  Google Scholar 

  • Cushman M, Sambaiah T, Jin G, Illarionov B, Fischer M, Bacher A (2004) Design, synthesis, and evaluation of 9-d-ribitylamino-1,3,7,9-tetrahydro-2,6,8-purinetriones bearing alkyl phosphate and alpha,alpha-difluorophosphonate substituents as inhibitors of tiboflavin synthase and lumazine synthase. J Org Chem 69:601–612

    CAS  PubMed  Google Scholar 

  • Dahl SG, Sylte I, Ravna AW (2004) Structures and models of transporter proteins. J Pharmacol Exp Ther 309:853–860

    CAS  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • DiMarco AA, Bobik TA, Wolfe RS (1990) Unusual coenzymes of methanogenesis. Annu Rev Biochem 59:355–394

    CAS  PubMed  Google Scholar 

  • Echt S, Bauer S, Steinbacher S, Huber R, Bacher A, Fischer M (2004) Potential anti-infective targets in pathogenic yeasts: structure and properties of 3,4-dihydroxy-2-butanone 4-phosphate synthase of Candidaalbicans. J Mol Biol 341:1085–1096

    CAS  PubMed  Google Scholar 

  • Edmondson D, Ghisla S (1999) Flavoenzyme structure and function. Approaches using flavin analogues. Methods Mol Biol 131:157–179

    CAS  PubMed  Google Scholar 

  • Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593

    CAS  PubMed  Google Scholar 

  • Eirich LD, Vogels GD, Wolfe RS (1979) Distribution of coenzyme F420 and properties of its hydrolytic fragments. J Bacteriol 140:20–27

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer M, Bacher A (2005) Biosynthesis of flavocoenzymes. Nat Prod Rep 22:324–350

    CAS  PubMed  Google Scholar 

  • Fuller TE, Mulks MH (1995) Characterization of Actinobacilluspleuropneumoniae riboflavin biosynthesis genes. J Bacteriol 177:7265–7270

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fuller TE, Thacker BJ, Mulks MH (1996) A riboflavin auxotroph of Actinobacilluspleuropneumoniae is attenuated in swine. Infect Immun 64:4659–4664

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gerhardt S et al (2002a) The structural basis of riboflavin binding to Schizosaccharomycespombe6,7-dimethyl-8-ribityllumazine synthase. J Mol Biol 318:1317–1329

    CAS  PubMed  Google Scholar 

  • Gerhardt S et al (2002b) Studies on the reaction mechanism of riboflavin synthase: X-ray crystal structure of a complex with 6-carboxyethyl-7-oxo-8-ribityllumazine. Structure (Camb) 10:1371–1381

    CAS  Google Scholar 

  • Ghisla S, Massey V (1986) New flavins for old: artificial flavins as active site probes of flavoproteins. Biochem J 239:1–12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghisla S, Mayhew SG (1976) Identification and properties of 8-hydroxyflavin-adenine dinucleotide in electron-transferring flavoprotein from Peptostreptococcuselsdenii. Eur J Biochem 63:373–390

    CAS  PubMed  Google Scholar 

  • Graham DW, Brown JE, Ashton WT, Brown RD, Rogers EF (1977) Anticoccidial riboflavine antagonists. Experientia 33:1274–1276

    CAS  PubMed  Google Scholar 

  • Graupner M, White RH (2001) Biosynthesis of the phosphodiester bond in coenzyme F(420) in the methanoarchaea. Biochemistry 40:10859–10872

    CAS  PubMed  Google Scholar 

  • Green JM, Nichols BP, Matthews RG (1996) Folate biosynthesis, reduction, and polyglutamylation. In: Neidhardt FC (ed) Escherichiacoli and Salmonella: cellular and molecular biology. ASM, Washington, DC, pp 665–673

    Google Scholar 

  • Gusarov II et al (1997) Riboflavin biosynthetic genes in Bacillus amyloliquefaciens: primary structure, organization and regulation of activity. Mol Biol (Mosk) 31:446–453

    CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Kasai S et al (1978) Anti-riboflavin activity of 8N-alkyl analogues of roseoflavin in some Gram-positive bacteria. J Nutr Sci Vitaminol (Tokyo) 24:339–350

    CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Kearney EB, Goldenberg J, Lipsick J, Perl M (1979) Flavokinase and FAD synthetase from Bacillussubtilis specific for reduced flavins. J Biol Chem 254:9551–9557

    CAS  PubMed  Google Scholar 

  • Kisker C, Schindelin H, Rees DC (1997) Molybdenum-cofactor-containing enzymes: structure and mechanism. Annu Rev Biochem 66:233–267

    CAS  PubMed  Google Scholar 

  • Klinke S, Zylberman V, Vega DR, Guimaraes BG, Braden BC, Goldbaum FA (2005) Crystallographic studies on decameric Brucella spp. lumazine synthase: a novel quaternary arrangement evolved for a new function? J Mol Biol 353:124–137

    CAS  PubMed  Google Scholar 

  • 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 Streptomyceslincolnensis. J Antibiot (Tokyo) 42:475–478

    CAS  Google Scholar 

  • Kurth R, Paust J, Hähnlein W (1996) Vitamins, chapter 7. In: Ullmann’s encyclopedia of industrial chemistry. VCH, Weinheim, pp 521–530

  • Ladenstein R et al (1988) Heavy riboflavin synthase from Bacillussubtilis. Crystal structure analysis of the icosahedral beta 60 capsid at 3.3 A resolution. J Mol Biol 203:1045–1070

    CAS  PubMed  Google Scholar 

  • Lambooy JP (1951) Activity of 6,7-diethyl-9-(d-1′-ribityl)-isoalloxazine for Lactobacilluscasei. J Biol Chem 188:459–462

    CAS  PubMed  Google Scholar 

  • Lambooy JP (1975) Biological activities of analogs of riboflavin. Plenum, New York, NY

    Google Scholar 

  • Lambooy JP, Shaffner CS (1977) Utilization of analogues of riboflavin by the riboflavin-deficient chick embryo. J Nutr 107:245–250

    CAS  PubMed  Google Scholar 

  • Lee CY, Szittner RB, Miyamoto CM, Meighen EA (1993) The gene convergent to luxG in Vibriofischeri codes for a protein related in sequence to RibG and deoxycytidylate deaminase. Biochim Biophys Acta 1143:337–339

    CAS  PubMed  Google Scholar 

  • Lee CY, O’Kane DJ, Meighen EA (1994) Riboflavin synthesis genes are linked with the lux operon of Photobacteriumphosphoreum. J Bacteriol 176:2100–2104

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liao DI, Calabrese JC, Wawrzak Z, Viitanen PV, Jordan DB (2001a) Crystal structure of 3,4-dihydroxy-2-butanone 4-phosphate synthase of riboflavin biosynthesis. Structure (Camb) 9:11–18

    CAS  Google Scholar 

  • Liao DI, Wawrzak Z, Calabrese JC, Viitanen PV, Jordan DB (2001b) Crystal structure of riboflavin synthase. Structure (Camb) 9:399–408

    CAS  Google Scholar 

  • Lin JW, Chao YF, Weng SF (2001) Riboflavin synthesis genes ribE, ribB, ribH, ribA reside in the lux operon of Photobacteriumleiognathi. Biochem Biophys Res Commun 284:587–595

    CAS  PubMed  Google Scholar 

  • Logvinenko EM, Shavlovskii GM, Koltun LV (1972) Preparation and properties of riboflavin-dependent mutants of Pichiaguilliermondii Wickerham yeasts. Mikrobiologiia 41:1103–1104

    CAS  PubMed  Google Scholar 

  • Manstein DJ, Pai EF (1986) Purification and characterization of FAD synthetase from Brevibacteriumammoniagenes. J Biol Chem 261:16169–16173

    CAS  PubMed  Google Scholar 

  • Mao Y, Varoglu M, Sherman DH (1999) Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyceslavendulae NRRL 2564. Chem Biol 6:251–263

    CAS  PubMed  Google Scholar 

  • Matsui K, Juri N, Kubo Y, Kasai S (1979) Formation of roseoflavin from guanine through riboflavin. J Biochem (Tokyo) 86:167–175

    CAS  Google Scholar 

  • Matsui K et al (1982) Riboflavin production by roseoflavin-resistant strains of some bacteria. Agric Biol Chem 46:2003–2008

    CAS  Google Scholar 

  • Meining W, Mortl S, Fischer M, Cushman M, Bacher A, Ladenstein R (2000) The atomic structure of pentameric lumazine synthase from Saccharomycescerevisiae at 1.85 A resolution reveals the binding mode of a phosphonate intermediate analogue. J Mol Biol 299:181–197

    CAS  PubMed  Google Scholar 

  • Miller SM (2004) A new role for an old cofactor. Nat Struct Mol Biol 11:497–498

    CAS  PubMed  Google Scholar 

  • Mironov AS et al (2002) Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111:747–756

    CAS  PubMed  Google Scholar 

  • Morgunova E et al (2005) Crystal structure of lumazine synthase from Mycobacteriumtuberculosis as a target for rational drug design: binding mode of a new class of purinetrione inhibitors. Biochemistry 44:2746–2758

    CAS  PubMed  Google Scholar 

  • Mortl S, Fischer M, Richter G, Tack J, Weinkauf S, Bacher A (1996) Biosynthesis of riboflavin. Lumazine synthase of Escherichiacoli. J Biol Chem 271:33201–33207

    CAS  PubMed  Google Scholar 

  • Muller F (1991) Chemistry and biochemistry of flavoproteins. CRC, Boca Raton, FL

    Google Scholar 

  • Murthy YV, Massey V (1997) Syntheses and applications of flavin analogs as active site probes for flavoproteins. Methods Enzymol 280:436–460

    CAS  PubMed  Google Scholar 

  • Nakajima H (1993) Tuberculosis: a global emergency. World Health 46:3

    Google Scholar 

  • Nielsen P, Rauschenbach P, Bacher A (1986) Preparation, properties, and separation by high-performance liquid chromatography of riboflavin phosphates. Methods Enzymol 122:209–220

    CAS  PubMed  Google Scholar 

  • Odur A (1994) Flavin derivatives as anti-viral agents. Patent application, Radopath, PCT/GB94/02292

  • O’Farrell PA, Walsh MA, McCarthy AA, Higgins TM, Voordouw G, Mayhew SG (1998) Modulation of the redox potentials of FMN in Desulfovibriovulgarisflavodoxin: thermodynamic properties and crystal structures of glycine-61 mutants. Biochemistry 37:8405–8416

    PubMed  Google Scholar 

  • Oltmanns O, Lingens F (1967) Isolation of riboflavin-deficient mutants of Saccharomycescerevisiae. Z Naturforsch B 22:751–754

    CAS  PubMed  Google Scholar 

  • Otani S, Takatsu M, Nakano M, Kasai S, Miura R (1974) Letter: roseoflavin, a new antimicrobial pigment from Streptomyces. J Antibiot (Tokyo) 27:86–87

    CAS  Google Scholar 

  • Otani S, Kasai S, Matsui K (1980) Isolation, chemical synthesis, and properties of roseoflavin. Methods Enzymol 66:235–241

    CAS  PubMed  Google Scholar 

  • Perkins J, Pero J (2002) Biosynthesis of riboflavin, biotin, folic acid, and cobalamin. In: Sonenshein A, Hoch J, Losick R (eds) Bacillussubtilis and its closest relatives: from genes to cells. ASM, Washington, DC, pp 271–286

    Google Scholar 

  • Persson K, Schneider G, Jordan DB, Viitanen PV, Sandalova T (1999) Crystal structure analysis of a pentameric fungal and an icosahedral plant lumazine synthase reveals the structural basis for differences in assembly. Protein Sci 8:2355–2365

    CAS  PubMed  PubMed Central  Google Scholar 

  • Platz M (2003) Flavin N-oxides: new anti-cancer agents and pathogen eradication agents. Patent application, Ohio State University, PCT/US2003/014673

  • 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

    CAS  PubMed  Google Scholar 

  • Reuke B, Korn S, Eisenreich W, Bacher A (1992) Biosynthetic precursors of deazaflavins. J Bacteriol 174:4042–4049

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ritsert K, Huber R, Turk D, Ladenstein R, Schmidt-Base K, Bacher A (1995) Studies on the lumazine synthase/riboflavin synthase complex of Bacillussubtilis: crystal structure analysis of reconstituted, icosahedral beta-subunit capsids with bound substrate analogue inhibitor at 2.4 A resolution. J Mol Biol 253:151–167

    CAS  PubMed  Google Scholar 

  • Schwogler A, Carell T (2000) Toward catalytically active oligonucleotides: synthesis of a flavin nucleotide and its incorporation into DNA. Org Lett 2:1415–1418

    CAS  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Singer TP, Edmondson DE (1974) 8 alpha-substituted flavins of biological importance. FEBS Lett 42:1–14

    CAS  PubMed  Google Scholar 

  • Stahmann KP, Revuelta JL, Seulberger H (2000) Three biotechnical processes using Ashbyagossypii, Candidafamata, or Bacillussubtilis compete with chemical riboflavin production. Appl Microbiol Biotechnol 53:509–516

    CAS  PubMed  Google Scholar 

  • Stover CK et al (2000) A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405:962–966

    CAS  PubMed  Google Scholar 

  • Stratton CW (2000) Mechanisms of bacterial resistance to antimicrobial agents. J Med Liban 48:186–198

    CAS  PubMed  Google Scholar 

  • Sybesma W, Burgess C, Starrenburg M, van Sinderen D, Hugenholtz J (2004) Multivitamin production in Lactococcuslactis using metabolic engineering. Metab Eng 6:109–115

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vitreschak AG, Rodionov DA, Mironov AA, Gelfand MS (2003) Regulation of the vitamin B12 metabolism and transport in bacteria by a conserved RNA structural element. RNA 9:1084–1097

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vitreschak AG, Rodionov DA, Mironov AA, Gelfand MS (2004) Riboswitches: the oldest mechanism for the regulation of gene expression? Trends Genet 20:44–50

    CAS  PubMed  Google Scholar 

  • Walsh C et al (1978) Chemical and enzymatic properties of riboflavin analogues. Biochemistry 17:1942–1951

    CAS  PubMed  Google Scholar 

  • Zhang X, Meining W, Fischer M, Bacher A, Ladenstein R (2001) X-ray structure analysis and crystallographic refinement of lumazine synthase from the hyperthermophile Aquifexaeolicus at 1.6 A resolution: determinants of thermostability revealed from structural comparisons. J Mol Biol 306:1099–1114

    CAS  PubMed  Google Scholar 

  • Zhang X et al (2003) A structure-based model of the reaction catalyzed by lumazine synthase from Aquifexaeolicus. J Mol Biol 328:167–182

    CAS  PubMed  Google Scholar 

  • Zylberman V, Craig PO, Klinke S, Braden BC, Cauerhff A, Goldbaum FA (2004) High order quaternary arrangement confers increased structural stability to Brucella sp. lumazine synthase. J Biol Chem 279:8093–8101

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthias Mack.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mack, M., Grill, S. Riboflavin analogs and inhibitors of riboflavin biosynthesis. Appl Microbiol Biotechnol 71, 265–275 (2006). https://doi.org/10.1007/s00253-006-0421-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-006-0421-7

Keywords

Navigation