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.
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References
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 62:335–364
Christie JM (2007) Phototropin blue-light receptors. Annu Rev Plant Biol 58:21–45
Sancar A (2008) Structure and function of photolyase and in vivo enzymology: 50th anniversary. J Biol Chem 283:32153–32157
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 53:509–516
Bacher A, Eberhardt S, Eisenreich W, Fischer M, Herz S, Illarionov B, Kis K, Richter G (2001) Biosynthesis of riboflavin. Vitam Horm 61:1–49
Bacher A, Eberhardt S, Fischer M, Kis K, Richter G (2000) Biosynthesis of vitamin B2 (riboflavin). Annu Rev Nutr 20:153–167
Fischer M, Bacher A (2005) Biosynthesis of flavocoenzymes. Nat Prod Rep 22:324–350
Fischer M, Bacher A (2006) Biosynthesis of vitamin B2 in plants. Physiol Plant 126:304–318
Fischer M, Bacher A (2011) Biosynthesis of vitamin B2 and flavocoenzymes in plants. Adv Bot Res 58:93–152
Fischer M, Bacher A (2011) Biosynthesis of vitamin B2: a unique way to assemble a xylene ring. Chembiochem 12:670–680
Foor F, Brown GM (1975) Purification and properties of guanosine triphosphate cyclohydrolase II from Escherichia coli. J Biol Chem 250:3545–3551
Foor F, Brown GM (1980) GTP cyclohydrolase II from Escherichia coli. Methods Enzymol 66:303–307
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 276:22273–22277
Ren J, Kotaka M, Lockyer M, Lamb HK, Hawkins AR, Stammers DK (2005) GTP cyclohydrolase II structure and mechanism. J Biol Chem 280:36912–36919
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 274:16727–16735
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 276:4119–4129
Graham DE, Xu H, White RH (2002) A member of a new class of GTP cyclohydrolases produces formylaminopyrimidine nucleotide monophosphates. Biochemistry 41:15074–15084
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 47:230–242
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 48:4181–4188
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 269:5264–5270
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 359:1334–1351
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 281:7605–7613
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 373:48–64
Chen SC, Lin YH, Yu HC, Liaw SH (2009) Complex structure of Bacillus subtilis RibG: the reduction mechanism during riboflavin biosynthesis. J Biol Chem 284:1725–1731
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 14:925–927
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 162:1280–1284
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 265:19479–19485
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 266:20610–20618
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 174:4050–4056
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 280:374–382
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 63:6456–6457
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 278:42256–42265
Kis K, Volk R, Bacher A (1995) Biosynthesis of riboflavin. Studies on the reaction mechanism of 6,7-dimethyl-8-ribityllumazine synthase. Biochemistry 34:2883–2892
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 95:9879–9884
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 275:4060–4073
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 64:219–220
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 78:3292–3303
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 341:1085–1096
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 41:1795–1806
Liao DI, Wawrzak Z, Calabrese JC, Viitanen PV, Jordan DB (2001) Crystal structure of riboflavin synthase. Structure 9:399–408
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 60:1338–1340
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 98:13025–13030
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 174:374–384
Andersson I, Backlund A (2008) Structure and function of Rubisco. Plant Physiol Biochem 46:275–291
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 130:15063–15080
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 71:576–599
Wildman SG (2005) Along the trail from fraction I protein to Rubisco (ribulose bisphosphate carboxylase-oxygenase). Photosynth Res 20:843–850
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 297:1031–1036
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 318:1317–1329
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 373:664–680
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
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 271:3208–3214
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 67:131–139
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 299:181–197
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 66:1001–1011
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 273:4790–4804
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 44:2746–2758
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 282:17231–17241
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
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 253:151–167
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 328:167–182
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 306:1099–1114
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 73:2715–2724
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 223:1007–1017
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 362:753–770
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 203:1045–1070
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 265:12686–12689
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 343:267–278
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 21:5587–5598
Beach RL, Plaut GW (1969) The formation of riboflavin from 6,7-dimethyl-8-ribityllumazine an acid media. Tetrahedron Lett 40:3489–3492
Rowan T, Wood HC (1963) The biosynthesis of riboflavin. Proc Chem Soc 21–22
Rowan T, Wood HC (1968) The biosynthesis of pteridines. V. The synthesis of riboflavin from pteridine precursors. J Chem Soc Perkin 1(4):452–458
Illarionov B, Eisenreich W, Bacher A (2001) A pentacyclic reaction intermediate of riboflavin synthase. Proc Natl Acad Sci U S A 98:7224–7229
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 386:127–136
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 281:1224–1232
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 33:780–784
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 11–45
Plaut GWE, Harvey RA (1971) The enzymatic synthesis of riboflavin. Methods Enzymol 18:515–538
Plaut GW, Smith CM, Alworth WL (1974) Biosynthesis of water-soluble vitamins. Annu Rev Biochem 43:899–922
Plaut GW (1960) Studies on the stoichiometry of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin. J Biol Chem 235:41–42
Plaut GW (1963) Studies on the nature of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin. J Biol Chem 238:2225–2243
Plaut GW, Beach RL (1976) Substrate specificity and stereospecific mode of action of riboflavin synthase. Flavins Flavoproteins. Proc Int Symp 5th 737–746.
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 9:771–785
Paterson T, Wood HC (1972) Studies of the mechanism of riboflavin biosynthesis. J Chem Soc Perkin 1(8):1051–1056
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 290–291
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 132:2983–2990
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 309:949–960
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 10:1371–1381
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 331:1053–1063
Kis K, Bacher A (1995) Substrate channeling in the lumazine synthase/riboflavin synthase complex of Bacillus subtilis. J Biol Chem 270:16788–16795
Seebeck FP, Woycechowsky KJ, Zhuang W, Rabe JP, Hilvert D (2006) A simple tagging system for protein encapsulation. J Am Chem Soc 128:4516–4517
Woersdoerfer B, Woycechowsky KJ, Hilvert D (2011) Directed evolution of a protein container. Science 331:589–592
Eirich LD, Vogels GD, Wolfe RS (1978) Proposed structure for coenzyme F420 from Methanobacterium. Biochemistry 17:4583–4593
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 27:1758–1765
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 106:11540–11545
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 47:10076–10080
Mueller M, Carell T (2009) Structural biology of DNA photolyases and cryptochromes. Curr Opin Struct Biol 19:277–285
Petersen JL, Ronan PJ (2010) Critical role of 7,8-didemethyl-8-hydroxy-5-deazariboflavin for photoreactivation in Chlamydomonas reinhardtii. J Biol Chem 285:32467–33275
Eisenreich W, Schwarzkopf B, Bacher A (1991) Biosynthesis of nucleotides, flavins, and deazaflavins in Methanobacterium thermoautotrophicum. J Biol Chem 266:9622–9631
Reuke B, Korn S, Eisenreich W, Bacher A (1992) Biosynthetic precursors of deazaflavins. J Bacteriol 174:4042–4049
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 180:455–564
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
Matsui K, Juri N, Kubo Y, Kasai S (1979) Formation of roseoflavin from guanine through riboflavin. J Biochem 86:167–175
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
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 382:44–55
Lee J (1993) Lumazine protein and the excitation mechanism in bacterial bioluminescence. Biophys Chem 48:149–158
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 388:1313–1323
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 70:9947–9954
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 79:1079–1088
Lalli M, Facey SJ, Hauer B (2011) Protein containers—promising tools for the future. Chem Bio Chem 12:1519–1521
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 15:939–947
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 70:8162–8170
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 6:409–415
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 64:4635–4642
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 67:5807–5816
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 67:6871–6877
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 69:6996–7003
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
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 338:124–130
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 72:7167–7175
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 72:7176–7184
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 74:5123–5134
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 74:5297–5303
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 18:3518–3534
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 72:2769–2776
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 103:468–476
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 49:175–184
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 27:136–145
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Haase, I., Gräwert, T., Illarionov, B., Bacher, A., Fischer, M. (2014). Recent Advances in Riboflavin Biosynthesis. 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_2
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DOI: https://doi.org/10.1007/978-1-4939-0452-5_2
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