Advertisement

Applied Microbiology and Biotechnology

, Volume 71, Issue 3, pp 265–275 | Cite as

Riboflavin analogs and inhibitors of riboflavin biosynthesis

  • Matthias Mack
  • Simon Grill
Mini-Review

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.

Keywords

Riboflavin Flavin Flavin Adenine Dinucleotide Riboflavin Production Riboflavin Biosynthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Bacher A (1991) Riboflavin kinase and FAD synthetase. In: Muller F (ed) Chemistry and biochemistry of flavoenzymes. CRC, Boca Raton, FL, pp 349–370Google Scholar
  2. Bacher A et al (1997) Biosynthesis of riboflavin: lumazine synthase and riboflavin synthase. Methods Enzymol 280:389–399PubMedGoogle Scholar
  3. Bacher A et al (2001) Biosynthesis of riboflavin. Vitam Horm 61:1–49PubMedCrossRefGoogle Scholar
  4. Bandrin SV, Beburov M, Rabinovich PM, Stepanov AI (1979) Riboflavin auxotrophs of Escherichia coli. Genetika 15:2063–2065PubMedGoogle Scholar
  5. Bardos TJ (1974) Antimetabolites: molecular design and mode of action. Top Curr Chem 52:63–98PubMedGoogle Scholar
  6. Bereswill S, Hinkelmann S, Kist M, Sander A (1999) Molecular analysis of riboflavin synthesis genes in Bartonella henselae and use of the ribC gene for differentiation of Bartonella species by PCR. J Clin Microbiol 37:3159–3166PubMedGoogle Scholar
  7. Burgess C, O’Connell-Motherway M, Sybesma W, Hugenholtz J, van Sinderen D (2004) Riboflavin production in Lactococcus lactis: potential for in situ production of vitamin-enriched foods. Appl Environ Microbiol 70:5769–5777CrossRefPubMedGoogle Scholar
  8. Cecchini G, Kearney EB (1980) Uptake and binding of riboflavin by membrane vesicles of Bacillus subtilis. J Supramol Struct 13:93–100PubMedCrossRefGoogle Scholar
  9. Cecchini G, Perl M, Lipsick J, Singer TP, Kearney EB (1979) Transport and binding of riboflavin by Bacillus subtilis. J Biol Chem 254:7295–7301PubMedGoogle Scholar
  10. Chen J et al (2005) A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors. Anal Biochem 338:124–130PubMedCrossRefGoogle Scholar
  11. Choi KP, Kendrick N, Daniels L (2002) Demonstration that fbiC is required by Mycobacterium bovis BCG for coenzyme F(420) and FO biosynthesis. J Bacteriol 184:2420–2428PubMedCrossRefGoogle Scholar
  12. 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 20:312–314PubMedCrossRefGoogle Scholar
  13. 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) 42:472–474Google Scholar
  14. 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 9:39–42PubMedCrossRefGoogle Scholar
  15. 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 66:8320–8327PubMedCrossRefGoogle Scholar
  16. 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 67:5807–5816CrossRefPubMedGoogle Scholar
  17. 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 69:601–612CrossRefPubMedGoogle Scholar
  18. Dahl SG, Sylte I, Ravna AW (2004) Structures and models of transporter proteins. J Pharmacol Exp Ther 309:853–860CrossRefPubMedGoogle Scholar
  19. Daniels L, Bakhiet N, Harmon K (1985) Widespread distribution of a 5-deazaflavin cofactor in actinomycetes and related bacteria. Syst Appl Microbiol 6:12–17Google Scholar
  20. DiMarco AA, Bobik TA, Wolfe RS (1990) Unusual coenzymes of methanogenesis. Annu Rev Biochem 59:355–394CrossRefPubMedGoogle Scholar
  21. 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 Candida albicans. J Mol Biol 341:1085–1096CrossRefPubMedGoogle Scholar
  22. Edmondson D, Ghisla S (1999) Flavoenzyme structure and function. Approaches using flavin analogues. Methods Mol Biol 131:157–179PubMedGoogle Scholar
  23. Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593CrossRefPubMedGoogle Scholar
  24. Eirich LD, Vogels GD, Wolfe RS (1979) Distribution of coenzyme F420 and properties of its hydrolytic fragments. J Bacteriol 140:20–27PubMedGoogle Scholar
  25. Fischer M, Bacher A (2005) Biosynthesis of flavocoenzymes. Nat Prod Rep 22:324–350CrossRefPubMedGoogle Scholar
  26. Fuller TE, Mulks MH (1995) Characterization of Actinobacillus pleuropneumoniae riboflavin biosynthesis genes. J Bacteriol 177:7265–7270PubMedGoogle Scholar
  27. Fuller TE, Thacker BJ, Mulks MH (1996) A riboflavin auxotroph of Actinobacillus pleuropneumoniae is attenuated in swine. Infect Immun 64:4659–4664PubMedGoogle Scholar
  28. Gerhardt S et al (2002a) The structural basis of riboflavin binding to Schizosaccharomyces pombe6,7-dimethyl-8-ribityllumazine synthase. J Mol Biol 318:1317–1329CrossRefPubMedGoogle Scholar
  29. 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) 10:1371–1381CrossRefGoogle Scholar
  30. Ghisla S, Massey V (1986) New flavins for old: artificial flavins as active site probes of flavoproteins. Biochem J 239:1–12PubMedGoogle Scholar
  31. Ghisla S, Mayhew SG (1976) Identification and properties of 8-hydroxyflavin-adenine dinucleotide in electron-transferring flavoprotein from Peptostreptococcus elsdenii. Eur J Biochem 63:373–390CrossRefPubMedGoogle Scholar
  32. Graham DW, Brown JE, Ashton WT, Brown RD, Rogers EF (1977) Anticoccidial riboflavine antagonists. Experientia 33:1274–1276CrossRefPubMedGoogle Scholar
  33. Graupner M, White RH (2001) Biosynthesis of the phosphodiester bond in coenzyme F(420) in the methanoarchaea. Biochemistry 40:10859–10872CrossRefPubMedGoogle Scholar
  34. Green JM, Nichols BP, Matthews RG (1996) Folate biosynthesis, reduction, and polyglutamylation. In: Neidhardt FC (ed) Escherichia coli and Salmonella: cellular and molecular biology. ASM, Washington, DC, pp 665–673Google Scholar
  35. Gusarov II et al (1997) Riboflavin biosynthetic genes in Bacillus amyloliquefaciens: primary structure, organization and regulation of activity. Mol Biol (Mosk) 31:446–453Google Scholar
  36. 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) 101:705–711Google Scholar
  37. Kasai S et al (1978) Anti-riboflavin activity of 8N-alkyl analogues of roseoflavin in some Gram-positive bacteria. J Nutr Sci Vitaminol (Tokyo) 24:339–350Google Scholar
  38. 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) 25:289–298Google Scholar
  39. Kearney EB, Goldenberg J, Lipsick J, Perl M (1979) Flavokinase and FAD synthetase from Bacillus subtilis specific for reduced flavins. J Biol Chem 254:9551–9557PubMedGoogle Scholar
  40. Kisker C, Schindelin H, Rees DC (1997) Molybdenum-cofactor-containing enzymes: structure and mechanism. Annu Rev Biochem 66:233–267CrossRefPubMedGoogle Scholar
  41. 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 353:124–137CrossRefPubMedGoogle Scholar
  42. 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) 42:475–478Google Scholar
  43. Kurth R, Paust J, Hähnlein W (1996) Vitamins, chapter 7. In: Ullmann’s encyclopedia of industrial chemistry. VCH, Weinheim, pp 521–530Google Scholar
  44. Ladenstein R et al (1988) Heavy riboflavin synthase from Bacillus subtilis. Crystal structure analysis of the icosahedral beta 60 capsid at 3.3 A resolution. J Mol Biol 203:1045–1070CrossRefPubMedGoogle Scholar
  45. Lambooy JP (1951) Activity of 6,7-diethyl-9-(d-1′-ribityl)-isoalloxazine for Lactobacillus casei. J Biol Chem 188:459–462PubMedGoogle Scholar
  46. Lambooy JP (1975) Biological activities of analogs of riboflavin. Plenum, New York, NYGoogle Scholar
  47. Lambooy JP, Shaffner CS (1977) Utilization of analogues of riboflavin by the riboflavin-deficient chick embryo. J Nutr 107:245–250PubMedGoogle Scholar
  48. Lee CY, Szittner RB, Miyamoto CM, Meighen EA (1993) The gene convergent to luxG in Vibrio fischeri codes for a protein related in sequence to RibG and deoxycytidylate deaminase. Biochim Biophys Acta 1143:337–339PubMedCrossRefGoogle Scholar
  49. Lee CY, O’Kane DJ, Meighen EA (1994) Riboflavin synthesis genes are linked with the lux operon of Photobacterium phosphoreum. J Bacteriol 176:2100–2104PubMedGoogle Scholar
  50. 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) 9:11–18CrossRefGoogle Scholar
  51. Liao DI, Wawrzak Z, Calabrese JC, Viitanen PV, Jordan DB (2001b) Crystal structure of riboflavin synthase. Structure (Camb) 9:399–408CrossRefGoogle Scholar
  52. Lin JW, Chao YF, Weng SF (2001) Riboflavin synthesis genes ribE, ribB, ribH, ribA reside in the lux operon of Photobacterium leiognathi. Biochem Biophys Res Commun 284:587–595CrossRefPubMedGoogle Scholar
  53. Logvinenko EM, Shavlovskii GM, Koltun LV (1972) Preparation and properties of riboflavin-dependent mutants of Pichia guilliermondii Wickerham yeasts. Mikrobiologiia 41:1103–1104PubMedGoogle Scholar
  54. Manstein DJ, Pai EF (1986) Purification and characterization of FAD synthetase from Brevibacterium ammoniagenes. J Biol Chem 261:16169–16173PubMedGoogle Scholar
  55. 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 6:251–263CrossRefPubMedGoogle Scholar
  56. Matsui K, Juri N, Kubo Y, Kasai S (1979) Formation of roseoflavin from guanine through riboflavin. J Biochem (Tokyo) 86:167–175Google Scholar
  57. Matsui K et al (1982) Riboflavin production by roseoflavin-resistant strains of some bacteria. Agric Biol Chem 46:2003–2008Google Scholar
  58. Meining W, Mortl S, Fischer M, Cushman M, Bacher A, Ladenstein R (2000) The atomic structure of pentameric lumazine synthase from Saccharomyces cerevisiae at 1.85 A resolution reveals the binding mode of a phosphonate intermediate analogue. J Mol Biol 299:181–197CrossRefPubMedGoogle Scholar
  59. Miller SM (2004) A new role for an old cofactor. Nat Struct Mol Biol 11:497–498CrossRefPubMedGoogle Scholar
  60. Mironov AS et al (2002) Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111:747–756CrossRefPubMedGoogle Scholar
  61. Morgunova E et al (2005) Crystal structure of lumazine synthase from Mycobacterium tuberculosis as a target for rational drug design: binding mode of a new class of purinetrione inhibitors. Biochemistry 44:2746–2758CrossRefPubMedGoogle Scholar
  62. Mortl S, Fischer M, Richter G, Tack J, Weinkauf S, Bacher A (1996) Biosynthesis of riboflavin. Lumazine synthase of Escherichia coli. J Biol Chem 271:33201–33207CrossRefPubMedGoogle Scholar
  63. Muller F (1991) Chemistry and biochemistry of flavoproteins. CRC, Boca Raton, FLGoogle Scholar
  64. Murthy YV, Massey V (1997) Syntheses and applications of flavin analogs as active site probes for flavoproteins. Methods Enzymol 280:436–460PubMedGoogle Scholar
  65. Nakajima H (1993) Tuberculosis: a global emergency. World Health 46:3Google Scholar
  66. Nielsen P, Rauschenbach P, Bacher A (1986) Preparation, properties, and separation by high-performance liquid chromatography of riboflavin phosphates. Methods Enzymol 122:209–220PubMedGoogle Scholar
  67. Odur A (1994) Flavin derivatives as anti-viral agents. Patent application, Radopath, PCT/GB94/02292Google Scholar
  68. O’Farrell PA, Walsh MA, McCarthy AA, Higgins TM, Voordouw G, Mayhew SG (1998) Modulation of the redox potentials of FMN in Desulfovibrio vulgaris flavodoxin: thermodynamic properties and crystal structures of glycine-61 mutants. Biochemistry 37:8405–8416CrossRefPubMedGoogle Scholar
  69. Oltmanns O, Lingens F (1967) Isolation of riboflavin-deficient mutants of Saccharomyces cerevisiae. Z Naturforsch B 22:751–754PubMedGoogle Scholar
  70. Otani S, Takatsu M, Nakano M, Kasai S, Miura R (1974) Letter: roseoflavin, a new antimicrobial pigment from Streptomyces. J Antibiot (Tokyo) 27:86–87Google Scholar
  71. Otani S, Kasai S, Matsui K (1980) Isolation, chemical synthesis, and properties of roseoflavin. Methods Enzymol 66:235–241PubMedCrossRefGoogle Scholar
  72. 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, Washington, DC, pp 271–286Google Scholar
  73. 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 8:2355–2365PubMedCrossRefGoogle Scholar
  74. Platz M (2003) Flavin N-oxides: new anti-cancer agents and pathogen eradication agents. Patent application, Ohio State University, PCT/US2003/014673Google Scholar
  75. 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 146:129–134PubMedCrossRefGoogle Scholar
  76. Reuke B, Korn S, Eisenreich W, Bacher A (1992) Biosynthetic precursors of deazaflavins. J Bacteriol 174:4042–4049PubMedGoogle Scholar
  77. Ritsert K, Huber R, Turk D, Ladenstein R, Schmidt-Base K, Bacher A (1995) Studies on the lumazine synthase/riboflavin synthase complex of Bacillus subtilis: crystal structure analysis of reconstituted, icosahedral beta-subunit capsids with bound substrate analogue inhibitor at 2.4 A resolution. J Mol Biol 253:151–167CrossRefPubMedGoogle Scholar
  78. Schwogler A, Carell T (2000) Toward catalytically active oligonucleotides: synthesis of a flavin nucleotide and its incorporation into DNA. Org Lett 2:1415–1418CrossRefPubMedGoogle Scholar
  79. 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 14:119–133CrossRefGoogle Scholar
  80. Singer TP, Edmondson DE (1974) 8 alpha-substituted flavins of biological importance. FEBS Lett 42:1–14CrossRefPubMedGoogle Scholar
  81. Stahmann KP, Revuelta JL, Seulberger H (2000) Three biotechnical processes using Ashbya gossypii, Candida famata, or Bacillus subtilis compete with chemical riboflavin production. Appl Microbiol Biotechnol 53:509–516CrossRefPubMedGoogle Scholar
  82. Stover CK et al (2000) A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405:962–966CrossRefPubMedGoogle Scholar
  83. Stratton CW (2000) Mechanisms of bacterial resistance to antimicrobial agents. J Med Liban 48:186–198PubMedGoogle Scholar
  84. Sybesma W, Burgess C, Starrenburg M, van Sinderen D, Hugenholtz J (2004) Multivitamin production in Lactococcus lactis using metabolic engineering. Metab Eng 6:109–115CrossRefPubMedGoogle Scholar
  85. 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 30:3141–3151CrossRefPubMedGoogle Scholar
  86. 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 9:1084–1097CrossRefPubMedGoogle Scholar
  87. Vitreschak AG, Rodionov DA, Mironov AA, Gelfand MS (2004) Riboswitches: the oldest mechanism for the regulation of gene expression? Trends Genet 20:44–50CrossRefPubMedGoogle Scholar
  88. Walsh C et al (1978) Chemical and enzymatic properties of riboflavin analogues. Biochemistry 17:1942–1951CrossRefPubMedGoogle Scholar
  89. Zhang X, Meining W, Fischer M, Bacher A, Ladenstein R (2001) X-ray structure analysis and crystallographic refinement of lumazine synthase from the hyperthermophile Aquifex aeolicus at 1.6 A resolution: determinants of thermostability revealed from structural comparisons. J Mol Biol 306:1099–1114CrossRefPubMedGoogle Scholar
  90. Zhang X et al (2003) A structure-based model of the reaction catalyzed by lumazine synthase from Aquifex aeolicus. J Mol Biol 328:167–182CrossRefPubMedGoogle Scholar
  91. 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 279:8093–8101CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Institute for Technical MicrobiologyMannheim University of Applied SciencesMannheimGermany

Personalised recommendations