Recent Advances in Riboflavin Biosynthesis

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1146)

Abstract

Riboflavin is biosynthesized from GTP and ribulose 5-phosphate. Whereas the early reactions conducing to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5′-phosphate show significant taxonomic variation, the subsequent reaction steps are universal in all taxonomic kingdoms. With the exception of a hitherto elusive phosphatase, all enzymes of the pathway have been characterized in some detail at the structural and mechanistic level. Some of the pathway enzymes (GTP cycloyhdrolase II, 3,4-dihydroxy-2-butanone 4-phosphate synthase, riboflavin synthase) have exceptionally complex reaction mechanisms. The commercial production of the vitamin is now entirely based on highly productive fermentation processes. Due to their absence in animals, the pathway enzymes are potential targets for the development of novel anti-infective drugs.

Key words

Biosynthesis of flavocoenzymes Riboflavin synthase Lumazine synthase GTP cyclohydrolase II Riboflavin biosynthesis 

References

  1. 1.
    Chaves I, Pokorny R, Byrdin M, Hoang N, Ritz T, Brettel K, Essen LO, van der Horst GT, Batschauer A, Ahmad M (2011) The cryptochromes: blue light photoreceptors in plants and animals. Annu Rev Plant Biol 62:335–364PubMedGoogle Scholar
  2. 2.
    Christie JM (2007) Phototropin blue-light receptors. Annu Rev Plant Biol 58:21–45PubMedGoogle Scholar
  3. 3.
    Sancar A (2008) Structure and function of photolyase and in vivo enzymology: 50th anniversary. J Biol Chem 283:32153–32157PubMedCentralPubMedGoogle Scholar
  4. 4.
    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 53:509–516PubMedGoogle Scholar
  5. 5.
    Bacher A, Eberhardt S, Eisenreich W, Fischer M, Herz S, Illarionov B, Kis K, Richter G (2001) Biosynthesis of riboflavin. Vitam Horm 61:1–49PubMedGoogle Scholar
  6. 6.
    Bacher A, Eberhardt S, Fischer M, Kis K, Richter G (2000) Biosynthesis of vitamin B2 (riboflavin). Annu Rev Nutr 20:153–167PubMedGoogle Scholar
  7. 7.
    Fischer M, Bacher A (2005) Biosynthesis of flavocoenzymes. Nat Prod Rep 22:324–350PubMedGoogle Scholar
  8. 8.
    Fischer M, Bacher A (2006) Biosynthesis of vitamin B2 in plants. Physiol Plant 126:304–318Google Scholar
  9. 9.
    Fischer M, Bacher A (2011) Biosynthesis of vitamin B2 and flavocoenzymes in plants. Adv Bot Res 58:93–152Google Scholar
  10. 10.
    Fischer M, Bacher A (2011) Biosynthesis of vitamin B2: a unique way to assemble a xylene ring. Chembiochem 12:670–680PubMedGoogle Scholar
  11. 11.
    Foor F, Brown GM (1975) Purification and properties of guanosine triphosphate cyclohydrolase II from Escherichia coli. J Biol Chem 250:3545–3551PubMedGoogle Scholar
  12. 12.
    Foor F, Brown GM (1980) GTP cyclohydrolase II from Escherichia coli. Methods Enzymol 66:303–307PubMedGoogle Scholar
  13. 13.
    Ritz H, Schramek N, Bracher A, Herz S, Eisenreich W, Richter G, Bacher A (2001) Biosynthesis of riboflavin: studies on the mechanism of GTP cyclohydrolase II. J Biol Chem 276:22273–22277PubMedGoogle Scholar
  14. 14.
    Ren J, Kotaka M, Lockyer M, Lamb HK, Hawkins AR, Stammers DK (2005) GTP cyclohydrolase II structure and mechanism. J Biol Chem 280:36912–36919PubMedGoogle Scholar
  15. 15.
    Bracher A, Fischer M, Eisenreich W, Ritz H, Schramek N, Boyle P, Gentili P, Huber R, Nar H, Auerbach G, Bacher A (1999) Histidine 179 mutants of GTP cyclohydrolase I catalyze the formation of 2-amino-5-formylamino-6-ribofuranosylamino-4(3H)-pyrimidinone triphosphate. J Biol Chem 274:16727–16735PubMedGoogle Scholar
  16. 16.
    Lehmann M, Degen S, Hohmann HP, Wyss M, Bacher A, Schramek N (2009) Biosynthesis of riboflavin. Screening for an improved GTP cyclohydrolase II mutant. FEBS J 276:4119–4129PubMedGoogle Scholar
  17. 17.
    Graham DE, Xu H, White RH (2002) A member of a new class of GTP cyclohydrolases produces formylaminopyrimidine nucleotide monophosphates. Biochemistry 41:15074–15084PubMedGoogle Scholar
  18. 18.
    Morrison SD, Roberts SA, Zegeer AM, Montfort WR, Bandarian V (2008) A new use for a familiar fold: the X-ray crystal structure of GTP-bound GTP cyclohydrolase III from Methanocaldococcus jannaschii reveals a two metal ion catalytic mechanism. Biochemistry 47:230–242PubMedGoogle Scholar
  19. 19.
    Grochowski LL, Xu H, White RH (2009) An iron(II) dependent formamide hydrolase catalyzes the second step in the archaeal biosynthetic pathway to riboflavin and 7,8-didemethyl-8-hydroxy-5-deazariboflavin. Biochemistry 48:4181–4188PubMedGoogle Scholar
  20. 20.
    Kaiser J, Schramek N, Eberhardt S, Püttmer S, Schuster M, Bacher A (2002) Biosynthesis of vitamin B2. An essential zinc ion at the catalytic site of GTP cyclohydrolase II. Eur J Biochem 269:5264–5270PubMedGoogle Scholar
  21. 21.
    Chatwell L, Krojer T, Fidler A, Romisch W, Eisenreich W, Bacher A, Huber R, Fischer M (2006) Biosynthesis of riboflavin: structure and properties of 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5′-phosphate reductase of Methanocaldococcus jannaschii. J Mol Biol 359:1334–1351PubMedGoogle Scholar
  22. 22.
    Chen SC, Chang YC, Lin CH, Liaw SH (2006) Crystal structure of a bifunctional deaminase and reductase from Bacillus subtilis involved in riboflavin biosynthesis. J Biol Chem 281:7605–7613PubMedGoogle Scholar
  23. 23.
    Stenmark P, Moche M, Gurmu D, Nordlund P (2007) The crystal structure of the bifunctional deaminase/reductase RibD of the riboflavin biosynthetic pathway in Escherichia coli: implications for the reductive mechanism. J Mol Biol 373:48–64PubMedGoogle Scholar
  24. 24.
    Chen SC, Lin YH, Yu HC, Liaw SH (2009) Complex structure of Bacillus subtilis RibG: the reduction mechanism during riboflavin biosynthesis. J Biol Chem 284:1725–1731PubMedGoogle Scholar
  25. 25.
    Yuan D, Wang Q, Gao W, Sheng F, Zhang Z, Lu Q, Cang H, Bi R (2007) Cloning, expression, purification, characterization, crystallization and X-ray diffraction of bifunctional pyrimidine deaminase/reductase from Shigella flexneri 2a. Protein Pept Lett 14:925–927PubMedGoogle Scholar
  26. 26.
    Le Van Q, Keller PJ, Bown DH, Floss HG, Bacher A (1985) Biosynthesis of riboflavin in Bacillus subtilis: origin of the four-carbon moiety. J Bacteriol 162:1280–1284PubMedCentralPubMedGoogle Scholar
  27. 27.
    Volk R, Bacher A (1990) Studies on the 4-carbon precursor in the biosynthesis of riboflavin. Purification and properties of L-3,4-dihydroxy-2-butanone-4-phosphate synthase. J Biol Chem 265:19479–19485PubMedGoogle Scholar
  28. 28.
    Volk R, Bacher A (1991) Biosynthesis of riboflavin. Studies on the mechanism of L-3,4-dihydroxy-2-butanone 4-phosphate synthase. J Biol Chem 266:20610–20618PubMedGoogle Scholar
  29. 29.
    Richter G, Volk R, Krieger C, Lahm HW, Rothlisberger U, Bacher A (1992) Biosynthesis of riboflavin: cloning, sequencing, and expression of the gene coding for 3,4-dihydroxy-2-butanone 4-phosphate synthase of Escherichia coli. J Bacteriol 174:4050–4056PubMedCentralPubMedGoogle Scholar
  30. 30.
    Richter G, Krieger C, Volk R, Kis K, Ritz H, Gotze E, Bacher A (1997) Biosynthesis of riboflavin: 3,4-dihydroxy-2-butanone-4-phosphate synthase. Methods Enzymol 280:374–382PubMedGoogle Scholar
  31. 31.
    Goetze E, Kis K, Eisenreich W, Yamauchi N, Kakinuma K, Bacher A (1998) Biosynthesis of riboflavin. Stereochemistry of the 3,4-dihydroxy-2-butanone 4-phosphate synthase reaction. J Org Chem 63:6456–6457Google Scholar
  32. 32.
    Steinbacher S, Schiffmann S, Richter G, Huber R, Bacher A, Fischer M (2003) Structure of 3,4-dihydroxy-2-butanone 4-phosphate synthase from Methanococcus jannaschii in complex with divalent metal ions and the substrate ribulose 5-phosphate: implications for the catalytic mechanism. J Biol Chem 278:42256–42265PubMedGoogle Scholar
  33. 33.
    Kis K, Volk R, Bacher A (1995) Biosynthesis of riboflavin. Studies on the reaction mechanism of 6,7-dimethyl-8-ribityllumazine synthase. Biochemistry 34:2883–2892PubMedGoogle Scholar
  34. 34.
    Takahashi S, Kuzuyama T, Watanabe H, Seto H (1998) A 1-deoxy-D-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-D-erythritol 4-phosphate in an alternative nonmevalonate pathway for terpenoid biosynthesis. Proc Natl Acad Sci U S A 95:9879–9884PubMedCentralPubMedGoogle Scholar
  35. 35.
    Lauw S, Illarionova V, Bacher A, Rohdich F, Eisenreich W (2008) Biosynthesis of isoprenoids: studies on the mechanism of 2C-methyl-D-erythritol-4-phosphate synthase. FEBS J 275:4060–4073PubMedGoogle Scholar
  36. 36.
    Le Trong I, Stenkamp RE (2008) Alternative models for two crystal structures of Candida albicans 3,4-dihydroxy-2-butanone 4-phosphate synthase. Acta Crystallogr D Biol Crystallogr 64:219–220PubMedGoogle Scholar
  37. 37.
    Kumar P, Singh M, Gautam R, Karthikeyan S (2010) Potential anti-bacterial drug target: structural characterization of 3,4-dihydroxy-2-butanone-4-phosphate synthase from Salmonella typhimurium LT2. Proteins 78:3292–3303PubMedGoogle Scholar
  38. 38.
    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 341:1085–1096PubMedGoogle Scholar
  39. 39.
    Liao DI, Zheng YJ, Viitanen PV, Jordan DB (2002) Structural definition of the active site and catalytic mechanism of 3,4-dihydroxy-2-butanone-4-phosphate synthase. Biochemistry 41:1795–1806PubMedGoogle Scholar
  40. 40.
    Liao DI, Wawrzak Z, Calabrese JC, Viitanen PV, Jordan DB (2001) Crystal structure of riboflavin synthase. Structure 9:399–408PubMedGoogle Scholar
  41. 41.
    Steinbacher S, Schiffmann S, Bacher A, Fischer M (2004) Metal sites in 3,4-dihydroxy-2-butanone 4-phosphate synthase from Methanococcus jannaschii in complex with the substrate ribulose 5-phosphate. Acta Crystallogr D Biol Crystallogr 60:1338–1340PubMedGoogle Scholar
  42. 42.
    Kelly MJ, Ball LJ, Krieger C, Yu Y, Fischer M, Schiffmann S, Schmieder P, Kuhne R, Bermel W, Bacher A, Richter G, Oschkinat H (2001) The NMR structure of the 47-kDa dimeric enzyme 3,4-dihydroxy-2-butanone-4-phosphate synthase and ligand binding studies reveal the location of the active site. Proc Natl Acad Sci U S A 98:13025–13030PubMedCentralPubMedGoogle Scholar
  43. 43.
    Singh M, Kumar P, Karthikeyan S (2011) Structural basis for pH dependent monomer-dimer transition of 3,4-dihydroxy 2-butanone-4-phosphate synthase domain from Mycobacterium tuberculosis. J Struct Biol 174:374–384PubMedGoogle Scholar
  44. 44.
    Andersson I, Backlund A (2008) Structure and function of Rubisco. Plant Physiol Biochem 46:275–291PubMedGoogle Scholar
  45. 45.
    Kannappan B, Gready JE (2008) Redefinition of rubisco carboxylase reaction reveals origin of water for hydration and new roles for active-site residues. J Am Chem Soc 130:15063–15080PubMedGoogle Scholar
  46. 46.
    Tabita FR, Hanson TE, Li H, Satagopan S, Singh J, Chan S (2007) Function, structure, and evolution of the RubisCO-like proteins and their RubisCO homologs. Microbiol Mol Biol Rev 71:576–599PubMedCentralPubMedGoogle Scholar
  47. 47.
    Wildman SG (2005) Along the trail from fraction I protein to Rubisco (ribulose bisphosphate carboxylase-oxygenase). Photosynth Res 20:843–850Google Scholar
  48. 48.
    Braden BC, Velikovsky CA, Cauerhff AA, Polikarpov I, Goldbaum FA (2000) Divergence in macromolecular assembly: X-ray crystallographic structure analysis of lumazine synthase from Brucella abortus. J Mol Biol 297:1031–1036PubMedGoogle Scholar
  49. 49.
    Gerhardt S, Haase I, Steinbacher S, Kaiser JT, Cushman M, Bacher A, Huber R, Fischer M (2002) The structural basis of riboflavin binding to Schizosaccharomyces pombe 6,7-dimethyl-8-ribityllumazine synthase. J Mol Biol 318:1317–1329PubMedGoogle Scholar
  50. 50.
    Klinke S, Zylberman V, Bonomi HR, Haase I, Guimaraes BG, Braden BC, Bacher A, Fischer M, Goldbaum FA (2007) Structural and kinetic properties of lumazine synthase isoenzymes in the order Rhizobiales. J Mol Biol 373:664–680PubMedGoogle Scholar
  51. 51.
    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 353:124–137PubMedGoogle Scholar
  52. 52.
    Koch M, Breithaupt C, Gerhardt S, Haase I, Weber S, Cushman M, Huber R, Bacher A, Fischer M (2004) Structural basis of charge transfer complex formation by riboflavin bound to 6,7-dimethyl-8-ribityllumazine synthase. Eur J Biochem 271:3208–3214PubMedGoogle Scholar
  53. 53.
    Kumar P, Singh M, Karthikeyan S (2011) Crystal structure analysis of icosahedral lumazine synthase from Salmonella typhimurium, an antibacterial drug target. Acta Crystallogr D Biol Crystallogr 67:131–139PubMedGoogle Scholar
  54. 54.
    Meining W, Moertl 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 299:181–197PubMedGoogle Scholar
  55. 55.
    Morgunova E, Illarionov B, Saller S, Popov A, Sambaiah T, Bacher A, Cushman M, Fischer M, Ladenstein R (2010) Structural study and thermodynamic characterization of inhibitor binding to lumazine synthase from Bacillus anthracis. Acta Crystallogr D Biol Crystallogr 66:1001–1011PubMedCentralPubMedGoogle Scholar
  56. 56.
    Morgunova E, Illarionov B, Sambaiah T, Haase I, Bacher A, Cushman M, Fischer M, Ladenstein R (2006) Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis. FEBS J 273:4790–4804PubMedGoogle Scholar
  57. 57.
    Morgunova E, Meining W, Illarionov B, Haase I, Jin G, Bacher A, Cushman M, Fischer M, Ladenstein R (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 44:2746–2758PubMedGoogle Scholar
  58. 58.
    Morgunova E, Saller S, Haase I, Cushman M, Bacher A, Fischer M, Ladenstein R (2007) Lumazine synthase from Candida albicans as an anti-fungal target enzyme: structural and biochemical basis for drug design. J Biol Chem 282:17231–17241PubMedGoogle Scholar
  59. 59.
    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 8:2355–2365PubMedCentralPubMedGoogle Scholar
  60. 60.
    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 253:151–167PubMedGoogle Scholar
  61. 61.
    Zhang X, Meining W, Cushman M, Haase I, Fischer M, Bacher A, Ladenstein R (2003) A structure-based model of the reaction catalyzed by lumazine synthase from Aquifex aeolicus. J Mol Biol 328:167–182PubMedGoogle Scholar
  62. 62.
    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 306:1099–1114PubMedGoogle Scholar
  63. 63.
    Zhang Y, Illarionov B, Morgunova E, Jin G, Bacher A, Fischer M, Ladenstein R, Cushman M (2008) A new series of N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-5-yl]oxalamic acid derivatives as inhibitors of lumazine synthase and riboflavin synthase: design, synthesis, biochemical evaluation, crystallography, and mechanistic implications. J Org Chem 73:2715–2724PubMedGoogle Scholar
  64. 64.
    Ladenstein R, Ritsert K, Huber R, Richter G, Bacher A (1994) The lumazine synthase/riboflavin synthase complex of Bacillus subtilis. X-ray structure analysis of hollow reconstituted beta-subunit capsids. Eur J Biochem 223:1007–1017PubMedGoogle Scholar
  65. 65.
    Zhang X, Konarev PV, Petoukhov MV, Svergun DI, Xing L, Cheng RH, Haase I, Fischer M, Bacher A, Ladenstein R, Meining W (2006) Multiple assembly states of lumazine synthase: a model relating catalytic function and molecular assembly. J Mol Biol 362:753–770PubMedGoogle Scholar
  66. 66.
    Ladenstein R, Schneider M, Huber R, Bartunik HD, Wilson K, Schott K, Bacher A (1988) Heavy riboflavin synthase from Bacillus subtilis. Crystal structure analysis of the icosahedral beta 60 capsid at 3.3 A resolution. J Mol Biol 203:1045–1070PubMedGoogle Scholar
  67. 67.
    Schott K, Ladenstein R, Konig A, Bacher A (1990) The lumazine synthase-riboflavin synthase complex of Bacillus subtilis. Crystallization of reconstituted icosahedral beta-subunit capsids. J Biol Chem 265:12686–12689PubMedGoogle Scholar
  68. 68.
    Fischer M, Schott AK, Romisch W, Ramsperger A, Augustin M, Fidler A, Bacher A, Richter G, Huber R, Eisenreich W (2004) Evolution of vitamin B2 biosynthesis. A novel class of riboflavin synthase in Archaea. J Mol Biol 343:267–278PubMedGoogle Scholar
  69. 69.
    Milne JL, Shi D, Rosenthal PB, Sunshine JS, Domingo GJ, Wu X, Brooks BR, Perham RN, Henderson R, Subramaniam S (2002) Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: a multifunctional catalytic machine. EMBO J 21:5587–5598PubMedCentralPubMedGoogle Scholar
  70. 70.
    Beach RL, Plaut GW (1969) The formation of riboflavin from 6,7-dimethyl-8-ribityllumazine an acid media. Tetrahedron Lett 40:3489–3492PubMedGoogle Scholar
  71. 71.
    Rowan T, Wood HC (1963) The biosynthesis of riboflavin. Proc Chem Soc 21–22Google Scholar
  72. 72.
    Rowan T, Wood HC (1968) The biosynthesis of pteridines. V. The synthesis of riboflavin from pteridine precursors. J Chem Soc Perkin 1(4):452–458Google Scholar
  73. 73.
    Illarionov B, Eisenreich W, Bacher A (2001) A pentacyclic reaction intermediate of riboflavin synthase. Proc Natl Acad Sci U S A 98:7224–7229PubMedCentralPubMedGoogle Scholar
  74. 74.
    Illarionov B, Haase I, Fischer M, Bacher A, Schramek N (2005) Pre-steady-state kinetic analysis of riboflavin synthase using a pentacyclic reaction intermediate as substrate. Biol Chem 386:127–136PubMedGoogle Scholar
  75. 75.
    Ramsperger A, Augustin M, Schott AK, Gerhardt S, Krojer T, Eisenreich W, Illarionov B, Cushman M, Bacher A, Huber R, Fischer M (2006) Crystal structure of an archaeal pentameric riboflavin synthase in complex with a substrate analog inhibitor: stereochemical implications. J Biol Chem 281:1224–1232PubMedGoogle Scholar
  76. 76.
    Fischer M, Romisch W, Illarionov B, Eisenreich W, Bacher A (2005) Structures and reaction mechanisms of riboflavin synthases of eubacterial and archaeal origin. Biochem Soc Trans 33:780–784PubMedGoogle Scholar
  77. 77.
    Plaut GWE (1971) Metabolism of water-soluble vitamins: the biosynthesis of riboflavin. In: Florkin M, Stotz EH (eds) Comprehensive biochemistry, vol 21. Elsevier, Amsterdam, pp 11–45Google Scholar
  78. 78.
    Plaut GWE, Harvey RA (1971) The enzymatic synthesis of riboflavin. Methods Enzymol 18:515–538Google Scholar
  79. 79.
    Plaut GW, Smith CM, Alworth WL (1974) Biosynthesis of water-soluble vitamins. Annu Rev Biochem 43:899–922PubMedGoogle Scholar
  80. 80.
    Plaut GW (1960) Studies on the stoichiometry of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin. J Biol Chem 235:41–42Google Scholar
  81. 81.
    Plaut GW (1963) Studies on the nature of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin. J Biol Chem 238:2225–2243Google Scholar
  82. 82.
    Plaut GW, Beach RL (1976) Substrate specificity and stereospecific mode of action of riboflavin synthase. Flavins Flavoproteins. Proc Int Symp 5th 737–746.Google Scholar
  83. 83.
    Plaut GW, Beach RL, Aogaichi T (1970) Studies on the mechanism of elimination of protons from the methyl groups of 6,7-dimethyl-8-ribityllumazine by riboflavin synthetase. Biochemistry 9:771–785PubMedGoogle Scholar
  84. 84.
    Paterson T, Wood HC (1972) Studies of the mechanism of riboflavin biosynthesis. J Chem Soc Perkin 1(8):1051–1056Google Scholar
  85. 85.
    Paterson T, Wood HCS (1969) Deuterium exchange of C7-methyl protons in 6,7-dimethyl-8-D-ribityllumazine, and studies of the mechanism of riboflavin biosynthesis. J Chem Soc Commun 290–291Google Scholar
  86. 86.
    Kim RR, Illarionov B, Joshi M, Cushman M, Lee CY, Eisenreich W, Fischer M, Bacher A (2010) Mechanistic insights on riboflavin synthase inspired by selective binding of the 6,7-dimethyl-8-ribityllumazine exomethylene anion. J Am Chem Soc 132:2983–2990PubMedCentralPubMedGoogle Scholar
  87. 87.
    Truffault V, Coles M, Diercks T, Abelmann K, Eberhardt S, Luttgen H, Bacher A, Kessler H (2001) The solution structure of the N-terminal domain of riboflavin synthase. J Mol Biol 309:949–960PubMedGoogle Scholar
  88. 88.
    Gerhardt S, Schott AK, Kairies N, Cushman M, Illarionov B, Eisenreich W, Bacher A, Huber R, Steinbacher S, Fischer M (2002) Studies on the reaction mechanism of riboflavin synthase: X-ray crystal structure of a complex with 6-carboxyethyl-7-oxo-8-ribityllumazine. Structure 10:1371–1381PubMedGoogle Scholar
  89. 89.
    Meining W, Eberhardt S, Bacher A, Ladenstein R (2003) The structure of the N-terminal domain of riboflavin synthase in complex with riboflavin at 2.6.A resolution. J Mol Biol 331:1053–1063PubMedGoogle Scholar
  90. 90.
    Kis K, Bacher A (1995) Substrate channeling in the lumazine synthase/riboflavin synthase complex of Bacillus subtilis. J Biol Chem 270:16788–16795PubMedGoogle Scholar
  91. 91.
    Seebeck FP, Woycechowsky KJ, Zhuang W, Rabe JP, Hilvert D (2006) A simple tagging system for protein encapsulation. J Am Chem Soc 128:4516–4517PubMedGoogle Scholar
  92. 92.
    Woersdoerfer B, Woycechowsky KJ, Hilvert D (2011) Directed evolution of a protein container. Science 331:589–592Google Scholar
  93. 93.
    Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593PubMedGoogle Scholar
  94. 94.
    Eker APM, Hessels JKC, van de Velde J (1988) Photoreactivating enzyme from the green alga Scenedesmus acutus. Evidence for the presence of two different flavin chromophores. Biochemistry 27:1758–1765Google Scholar
  95. 95.
    Glas AF, Maul MJ, Cryle M, Barends TR, Schneider S, Kaya E, Schlichting I, Carell T (2009) The archaeal cofactor F0 is a light-harvesting antenna chromophore in eukaryotes. Proc Natl Acad Sci U S A 106:11540–11545PubMedCentralPubMedGoogle Scholar
  96. 96.
    Maul MJ, Barends TR, Glas AF, Cryle MJ, Domratcheva T, Schneider S, Schlichting I, Carell T (2008) Crystal structure and mechanism of a DNA (6-4) photolyase. Angew Chem Int Ed Engl 47:10076–10080PubMedGoogle Scholar
  97. 97.
    Mueller M, Carell T (2009) Structural biology of DNA photolyases and cryptochromes. Curr Opin Struct Biol 19:277–285Google Scholar
  98. 98.
    Petersen JL, Ronan PJ (2010) Critical role of 7,8-didemethyl-8-hydroxy-5-deazariboflavin for photoreactivation in Chlamydomonas reinhardtii. J Biol Chem 285:32467–33275PubMedCentralPubMedGoogle Scholar
  99. 99.
    Eisenreich W, Schwarzkopf B, Bacher A (1991) Biosynthesis of nucleotides, flavins, and deazaflavins in Methanobacterium thermoautotrophicum. J Biol Chem 266:9622–9631PubMedGoogle Scholar
  100. 100.
    Reuke B, Korn S, Eisenreich W, Bacher A (1992) Biosynthetic precursors of deazaflavins. J Bacteriol 174:4042–4049PubMedCentralPubMedGoogle Scholar
  101. 101.
    Graham DE, Xu H, White RH (2003) Identification of the 7,8-didemethyl-8-hydroxy-5-deazariboflavin synthase required for coenzyme F(420) biosynthesis. Arch Microbiol 180:455–564PubMedGoogle Scholar
  102. 102.
    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
  103. 103.
    Matsui K, Juri N, Kubo Y, Kasai S (1979) Formation of roseoflavin from guanine through riboflavin. J Biochem 86:167–175PubMedGoogle Scholar
  104. 104.
    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 286:38275–38285PubMedCentralPubMedGoogle Scholar
  105. 105.
    Chatwell L, Illarionova V, Illarionov B, Eisenreich W, Huber R, Skerra A, Bacher A, Fischer M (2008) Structure of lumazine protein, an optical transponder of luminescent bacteria. J Mol Biol 382:44–55PubMedGoogle Scholar
  106. 106.
    Lee J (1993) Lumazine protein and the excitation mechanism in bacterial bioluminescence. Biophys Chem 48:149–158PubMedGoogle Scholar
  107. 107.
    Illarionov B, Eisenreich W, Wirth M, Yong Lee C, Eun Woo Y, Bacher A, Fischer M (2007) Lumazine proteins from photobacteria: localization of the single ligand binding site to the N-terminal domain. Biol Chem 388:1313–1323PubMedGoogle Scholar
  108. 108.
    Illarionov B, Lee CY, Bacher A, Fischer M, Eisenreich W (2005) Random isotopolog libraries for protein perturbation studies. 13C NMR studies on lumazine protein of Photobacterium leiognathi. J Org Chem 70:9947–9954PubMedGoogle Scholar
  109. 109.
    Ainciart N, Zylberman V, Craig PO, Nygaard D, Bonomi HR, Cauerhff AA, Goldbaum FA (2010) Sensing the dissociation of a polymeric enzyme by means of an engineered intrinsic probe. Proteins 79:1079–1088Google Scholar
  110. 110.
    Lalli M, Facey SJ, Hauer B (2011) Protein containers—promising tools for the future. Chem Bio Chem 12:1519–1521PubMedGoogle Scholar
  111. 111.
    Sutter M, Boehringer D, Gutmann S, Gunther S, Prangishvili D, Loessner MJ, Stetter KO, Weber-Ban E, Ban N (2008) Structural basis of enzyme encapsulation into a bacterial nanocompartment. Nat Struct Mol Biol 15:939–947PubMedGoogle Scholar
  112. 112.
    Cushman M, Jin G, Sambaiah T, Illarionov B, Fischer M, Ladenstein R, Bacher A (2005) Design, synthesis, and biochemical evaluation of 1,5,6,7-tetrahydro-6,7-dioxo-9-D-ribitylaminolumazines bearing alkyl phosphate substituents as inhibitors of lumazine synthase and riboflavin synthase. J Org Chem 70:8162–8170PubMedCentralPubMedGoogle Scholar
  113. 113.
    Cushman M, Mavandadi F, Kugelbrey K, Bacher A (1998) Synthesis of 2,6-dioxo-(1H,3H)-9-N-ribitylpurine and 2,6-dioxo-(1H,3H)-8-aza-9-N-ribitylpurine as inhibitors of lumazine synthase and riboflavin synthase. Bioorg Med Chem 6:409–415PubMedGoogle Scholar
  114. 114.
    Cushman M, Mavandadi F, Yang D, Kugelbrey K, Kis K, Bacher A (1999) Synthesis and biochemical evaluation of bis(6,7-dimethyl-8-D-ribityllumazines) as potential bisubstrate analogue inhibitors of riboflavin synthase. J Org Chem 64:4635–4642PubMedGoogle Scholar
  115. 115.
    Cushman M, Yang D, Gerhardt S, Huber R, Fischer M, Kis K, Bacher A (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 67:5807–5816PubMedGoogle Scholar
  116. 116.
    Cushman M, Yang D, Mihalic JT, Chen J, Gerhardt S, Huber R, Fischer M, Kis K, Bacher A (2002) Incorporation of an amide into 5-phosphonoalkyl-6-D-ribitylaminopyrimidinedione lumazine synthase inhibitors results in an unexpected reversal of selectivity for riboflavin synthase vs lumazine synthase. J Org Chem 67:6871–6877PubMedGoogle Scholar
  117. 117.
    Chen J, Sambaiah T, Illarionov B, Fischer M, Bacher A, Cushman M (2004) Design, synthesis, and evaluation of acyclic C-nucleoside and N-methylated derivatives of the ribitylaminopyrimidine substrate of lumazine synthase as potential enzyme inhibitors and mechanistic probes. J Org Chem 69:6996–7003PubMedGoogle Scholar
  118. 118.
    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 69:601–612PubMedGoogle Scholar
  119. 119.
    Chen J, Illarionov B, Bacher A, Fischer M, Haase I, Georg G, Ye QZ, Ma Z, Cushman M (2005) A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors. Anal Biochem 338:124–130PubMedGoogle Scholar
  120. 120.
    Talukdar A, Illarionov B, Bacher A, Fischer M, Cushman M (2007) Synthesis and enzyme inhibitory activity of the s-nucleoside analogue of the ribitylaminopyrimidine substrate of lumazine synthase and product of riboflavin synthase. J Org Chem 72:7167–7175PubMedGoogle Scholar
  121. 121.
    Zhang Y, Jin G, Illarionov B, Bacher A, Fischer M, Cushman M (2007) A new series of 3-alkyl phosphate derivatives of 4,5,6,7-tetrahydro-1-D-ribityl-1H-pyrazolo[3,4-d]pyrimidinedione as inhibitors of lumazine synthase: design, synthesis, and evaluation. J Org Chem 72:7176–7184PubMedGoogle Scholar
  122. 122.
    Talukdar A, Breen M, Bacher A, Illarionov B, Fischer M, Georg G, Ye QZ, Cushman M (2009) Discovery and development of a small molecule library with lumazine synthase inhibitory activity. J Org Chem 74:5123–5134PubMedCentralPubMedGoogle Scholar
  123. 123.
    Zhao Y, Bacher A, Illarionov B, Fischer M, Georg G, Ye QZ, Fanwick PE, Franzblau SG, Wan B, Cushman M (2009) Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis. J Org Chem 74:5297–5303PubMedGoogle Scholar
  124. 124.
    Talukdar A, Morgunova E, Duan J, Meining W, Foloppe N, Nilsson L, Bacher A, Illarionov B, Fischer M, Ladenstein R, Cushman M (2010) Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase. Bioorg Med Chem 18:3518–3534PubMedCentralPubMedGoogle Scholar
  125. 125.
    Zhang Y, Illarionov B, Bacher A, Fischer M, Georg GI, Ye QZ, Vander Velde D, Fanwick PE, Song Y, Cushman M (2007) A novel lumazine synthase inhibitor derived from oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine to a tetraazaperylenehexaone derivative. J Org Chem 72:2769–2776PubMedCentralPubMedGoogle Scholar
  126. 126.
    Park EY, Zhang JH, Tajima S, Dwiarti L (2007) Isolation of Ashbya gossypii mutant for an improved riboflavin production targeting for biorefinery technology. J Appl Microbiol 103:468–476PubMedGoogle Scholar
  127. 127.
    Yang Y, Wang L, Yin J, Wang X, Cheng S, Lang X, Qu H, Sun C, Wang J, Zhang R (2011) Immunoproteomic analysis of Brucella melitensis and identification of a new immunogenic candidate protein for the development of brucellosis subunit vaccine. Mol Immunol 49:175–184PubMedGoogle Scholar
  128. 128.
    Bellido D, Craig PO, Mozgovoj MV, Gonzalez DD, Wigdorovitz A, Goldbaum FA, Dus Santos MJ (2009) Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system. Vaccine 27:136–145PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Hamburg School of Food Science, Institute of Food Chemistry, University of HamburgHamburgGermany
  2. 2.Department of Chemistry, Organic Chemistry & BiochemistryTechnische Universität MünchenMunichGermany

Personalised recommendations