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Microbial production of riboflavin using riboflavin overproducers,Ashbya gossypii, Bacillus subtilis, andCandida famate: An overview

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Abstract

In this paper, the microbial production of riboflavin is reviewed and includes descriptions of riboflavin overproducers, and the biosynthesis and details of the key-enzyme genes related to riboflavin. Three kinds of riboflavin overproducers are known;Bacillus subtilis andCandida famate utilize glucose as a carbon source, but the fungusAshbya gossypii requires plant oil as its sole carbon source. The starting material in riboflavin biosynthesis is guanosine triphosphate (GTP), which is converted to riboflavin through six enzymatic reactions. ThoughBacillus subtilis, Candida famate, andAshbya gossypii operate via different pathways until GTP, they follow the same pathway from GTP to riboflavin. From the metabolic viewpoint, with respect to improved riboflavin production, the supplementation of GTP, a process-limiting precursor must be considered. The GTP fluxes originate from three sources, serine, threonine and glyoxylate cycles. The development of pathways to strengthen GTP supplementation using biotechnological techniques remains an issue for future research.

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References

  1. Demain, A. L. (1999) [Online] Stunning achievements of industrial microbiology. http://www.asmusa.org/memonly/asmnews/may99/feature7.html.

  2. Lago, B. D. and L. Kaplan (1981) Vitamin fermentations B2 and B12. pp. 241–242. In: M. Moo Young (eds.).Advance in Biotechnology: vol. 3, Pergamon, Toronto, Canada.

    Google Scholar 

  3. Vandamme, E. J. (1992) Production of vitamins, coenzymes and related biochemicals by biotechnological processe.J. Chem. Tech. Biotechnol. 53: 313–327.

    CAS  Google Scholar 

  4. Stamann, K.-P., J. L. Revuelta, and H. Seulberger (2000) Three biotechnical processes usingAshbya gossypii, Candida famate, or Bacillus subtilis compete with che-mical riboflavin production.Appl. Microbiol. Biotechnol. 53: 509–516.

    Google Scholar 

  5. Hickey, R. J. (1945) The inactivation of iron by 2,2′-bipyrimidine and its effect on riboflavin synthesis byClostridium acetobutylicum.Arch. Biochem. 8: 439–447.

    CAS  Google Scholar 

  6. Tanner, F. W. Jr., Ch. Vajnovich, and J. Van Lanen (1945) Riboflavin production byCandida species.Science 101: 180–181.

    CAS  Google Scholar 

  7. Goodwin, T. and D. McEvoy (1959) General factors controlling flavinogenesis in the yeastCandida flareri.Biochem. J. 71: 742–748.

    CAS  Google Scholar 

  8. Burkholder, P. R. (1943) Synthesis of riboflavin by yeast.Proc. Nat. Acad. Sci. USA 29: 166–172.

    CAS  Google Scholar 

  9. Burkholder, P. R. (1943) Influence of some environmental factors upon the production of riboflavin by yeast.Arch. Biochem. 3: 121–130.

    CAS  Google Scholar 

  10. Enari, T. M. (1955) Effect of cobalt and iron on riboflavin production byCandida guilliermondia.Acta Chem. Scand. 9: 1726–1727.

    CAS  Google Scholar 

  11. Takao, S. (1964) Riboflavin biosynthesis byCandida robusta. Part III. Effect of metal ion and necessity of CaCO3.Agr. Biol. Chem. 28: 765–769.

    CAS  Google Scholar 

  12. Ciri, K. V. and P. R. Krishnaswamy (1954) The synthesis of riboflavin by a mutant yeast,Saccharomyces cerevisiae.J. Bacteriol. 67: 309–332.

    Google Scholar 

  13. Levine, H., J. E. Oyaas, L. Wasserman, J. C. Hoogerheide, and F. M. Stern (1949) Riboflavin production byCandida yeasts.Ind. Eng. Chem. 41: 1665–1668.

    CAS  Google Scholar 

  14. Heefner, D., C. A. Weaver, M. J. Yarus, L. A. Burdzinski, D. C. Gyure, and E. W. Foster (1988) Riboflavin producing strains of microorganisms, method for selecting, and method for fermentation. Patent WO 88/09822.

  15. Guilliermond, A., M. Fontaine, and A. Raffy (1985) Sur l’Existence dans l’Eremothecium Ashbyii d’un pigment jaune se rapportant au groupe des flavines.C. R. Acad. Sci. 201: 1077–1080.

    Google Scholar 

  16. Mclaren, J. A. (1952) The effects of certain purines and pyrimidines upon the production of Riboflavin byEremothecium ashbyii.J. Bacteriol. 63: 233–241.

    Google Scholar 

  17. Yaw, K. E. (1952) Production of riboflavin byEremothecium ashbyii growth in a synthetic medium.Mycologia. 44: 307–317.

    CAS  Google Scholar 

  18. Hickey, R. J. (1953) Some nutritional requirements for biosynthesis of riboflavin byEremothecium ashbyii.J. Bacteriol. 66: 27–33.

    CAS  Google Scholar 

  19. Beesch, S. C. and B. N. Frazer (1953) Riboflavin by microbiology fermentation. To publiker Industries Inc. US patent 2.647,704.

  20. Stepanov, A. I., M. Yu. Beburov, and V. G. Zhdanov (1974) Mutants ofEremothecium ashbyii resistant to 8-azaguanine; Communication I. Isolation of mutants and study of the level of riboflavin biosynthesis.Sov. Genet. 8: 729–733.

    CAS  Google Scholar 

  21. Kalingan, A. E. and M. R. V. Krishnan (1997) Application of agro-industrial by-products for riboflavin production byEremothecium ashbyii NRRL 1363.Appl. Microbiol. Biotechnol. 47: 226–230.

    CAS  Google Scholar 

  22. Vaghy, T. (1971) Correlation between the morphological variability and riboflavin producing capacity ofEremothecium ashbyii.Acta Microbiol. Acad. Sci. Hung. 18: 75–80.

    CAS  Google Scholar 

  23. Stepanov, A. I., M. Yu. Beburov, and V. G. Zhdanov (1974) The use of mutagenic factors in the selection of the riboflavin producerEremothecium ashbyii.Sov. Genet. 8: 745–749.

    CAS  Google Scholar 

  24. Özbas, T. and T. Kutsal (1986) Riboflavin production byEremothecium ashbyii in a batch stirred tank fermentor.Biotechnol. Lett. 8: 441–444.

    Google Scholar 

  25. Özbas, T. and T. Kutsal (1986) Comparative study of riboflavin production by two organismsEremothecium ashbyii andAshbya gossypii.Enzyme Microb. Technol. 3: 593–596.

    Google Scholar 

  26. Kolonne, S., R. J. Seviour, and B. M. McDougall (1994) Effect of pH on exocellular riboflavin production byEremothecium ashbyii.Biotechnol. Lett. 16: 79–84.

    CAS  Google Scholar 

  27. Bigelis, R. (1989) Industrial products of biotechnology: application of gene technology, pp. 243. In: H. J. Rehm, and G. Reed (eds.).Biotechnology, vol. 7b, Weinheim: VCH.

    Google Scholar 

  28. Batra, L. R. (1973) Nematosporaceae (Hemiascomycetidae) taxonomy, pathogenicity distribution and vector relations.USDA Technical Bull. 1469. 8: 71–74.

    Google Scholar 

  29. Moore, H. N., G. de Becze, and E. Schraffenberger (1947) Studies onEremothecium ashbyii.J. Bacteriol. 53: 502.

    CAS  Google Scholar 

  30. Wickerham, L. J., M. H. Flickinger, and R. M. Johnston (1946) The production of riboflavin byAshbya gossypii.Arch. Biochem. 9: 95–98.

    CAS  Google Scholar 

  31. Demain, A. L. (1972) Riboflavin oversynthesis.Annu. Rev. Microbiol. 26: 369–388.

    CAS  Google Scholar 

  32. Coodman, J. J. and R. R. Ferrera (1954) Synthesis of riboflavin byAshbya gossypii grown in a synthetic medium.Mycologia 46: 556.

    Google Scholar 

  33. Smith, C. G., G. A. Smith, and Z. Papadoupoulou (1961) Effect of surface active agents on the biosynthesis of riboflavin byAshbya gossypii.Biochem. Biophys. Acta. 47: 344–349.

    CAS  Google Scholar 

  34. Kaplan, L. and A. L. Demain (1970) Nutritional studies on riboflavin overproduction byAshbya gossypii, pp. 137–159. In: D. G. Ahearn (eds.).Recent Trends in Yeast Research. Georgia State Univ., Atlanta, GA, USA.

    Google Scholar 

  35. Malzahn, R. C., R. F. Philips, and A. M. Hanson (1963) The production of riboflavin byAshbya gossypii. Bacteriol. Proc. 21.

  36. Hanson, A. M. (1967) Microbial production of pigments and vitamins. pp. 222–250. In: H. J. Peppler (eds.).Microbial Technology: Reinhold, USA.

  37. Szezesniak, T., L. Karabin, M. Szezepankowska, and K. Wituch (1971) Biosynthesis of Riboflavin byAshbya gossypii. Part I. The influence of fats of the animal origin on the riboflavin production.Acta Microbiologica Polonica Ser. B 3: 29–34.

    Google Scholar 

  38. Chiae, J., Y. Gwan, Y. Shen, W. Chen, C. Lang, and H. Wang (1960) Studies on the biosynthesis of riboflavin byAshbya gossypii I. Factors affecting the high yield of riboflavin.Acta Biol. Exp. Sinica 7: 161.

    Google Scholar 

  39. Szezesniak, T., L. Karabin, M. Szezepankowska, and K. Wituch (1971) Biosynthesis of Riboflavin byAshbya gossypii. Part II. The influence of animal proteins on the riboflavin production.Acta Microbiologica Polonica Ser. B 3: 91–95.

    Google Scholar 

  40. Plaut, G. W. E. (1961) Water-soluble vitamins, Part II. Folic acid, Riboflavin, Thiamine, Vitamin B12.Ann. Rev. Biochem. 30: 409–446.

    CAS  Google Scholar 

  41. Cerletti, P., R. Strom, M. G. Giordano, D. Barra, and S. Giovenco (1965) Flavin coenzymes, flavinogenesis and reproduction inAshbya gossypii.J. Biochem. 57: 773–786.

    CAS  Google Scholar 

  42. Mukerji, K. G. (1968) C. M. I. Descriptions of pathogenic fungi and bacteria No. 185.Commonwealth Agricultural Bureaux. The Eastern Press, London, UK.

    Google Scholar 

  43. Oberi, M., P. Peeifer, and M. Sernetz (1990) Microbial growth patterns described by fractal geometry.J. Bacteriol. 172: 1180–1185.

    Google Scholar 

  44. Stahmann, K.-P., C. Kupp, S. D. Feldmann, and H. Sahm (1994) Formation and degradation of lipid bodies found in the riboflavin-producing fungusAshbya gossypii.Appl. Microbiol. Biotechnol. 42: 121–127.

    CAS  Google Scholar 

  45. Weber, D. J. (1980) Lipid metabolism during fungal development. pp. 300–325. In: J. D. Weete (eds.).Lipid Bio-Chemistry of Fungi and Other Organisms, Plenum, NY, USA.

    Google Scholar 

  46. Schmidt, G., K.-P. Stahmann, and H. Sahm (1996) Inhibition of purified isocitrate lyase identified itaconate and oxalate as potential antimetabolites for the riboflavin overproducer.Ashbya gossypii Microbiology 142: 411–417.

    CAS  Google Scholar 

  47. Schmidt, G., K.-P. Stahmann, B. Kaesler, and H. Sahm (1996) Correlation of isocitrate lyase activity and riboflavin formation in the riboflavin overproducerAshbya gossypii.Microbiology 142: 419–426.

    CAS  Google Scholar 

  48. Stahmann, K.-P., T. Böddecker, and H. Sahm (1997) Regulation and properties of a fungal lipase showing interfacial inactivation by gas bubbles, or droplets of lipid or fatty acid.Eur. J. Biochem. 244: 220–225.

    CAS  Google Scholar 

  49. Föster, C., S. Marienfeld, V. F. Wendisch, and R. Krämer (1998) Adaptation of the filamentous fungusAshbya gossypii to hyperosmotic stress: different osmoresponse to NaCl and mannitol stress.Appl. Microbiol. Biotechnol. 50: 219–226.

    Google Scholar 

  50. Föster, C., S. Marienfeld, R. Wilhelm, and R. Krämer (1998) Organelle purification and selective permeabilisation of the plasma membrane: two different approaches to study vacuoles of the filamentous fungusAshbya gossypii.FEMS Microbiol. Lett. 167: 209–214.

    Article  Google Scholar 

  51. Bacher, A., M. Fisher, K. Kis, K. Kugelbrey, S. Mörtl, J. Scheuring, S. Weinkauf, S. Eberhardt, K. Schmidt-Bäse, R. Hurber, K. Ritsert, M. Cushman, and R. Ladenstein (1996) Biosynthesis of riboflavin: structure and mechanism of lumazine synthase.Biochem. Soc. Trans. 24: 89–94.

    CAS  Google Scholar 

  52. Sauer, U., V. Hatzimanikatis, H.-P. Hohmann, M. Manneberg, A. P. G. M. Loon, and J. E. Bailey (1996) Physiology and metabolic fluxes of wild-type and riboflavin-producingBacillus subtilis.Appl. Environ. Microbiol. 62: 3687–3696.

    CAS  Google Scholar 

  53. Perkins, J. B., J. G. Pero, and A. Sloma (1991) Riboflavin overproducing strains of bacteria. European patent application 0-405-370-A1.

  54. Contasti, V. and S. Bahar (1988) Riboflavin production byCandida guilliermondii from liquid brewery waste.Acta Cient. Venez. 39: 69–74.

    CAS  Google Scholar 

  55. Ghozlan, H. A. (1994) Utilization of beet molasses for riboflavin production byMycobacterium phIci.J. Basic Microbiol. 34: 157–162.

    CAS  Google Scholar 

  56. Sabry, S. A., A. H. El-Refai, and S. Y. Gamati (1989) Riboflavin formation by mould fungi cultivated on hydrocarbon-containing media.Microbios. 57: 33–40.

    CAS  Google Scholar 

  57. Omar, S. H. and Z. A. Olama (1985) Utilization of hydrocarbons by some fungi isolated from El-Alameen crude oil refineries.Commun. Sci. Devel. Res. 12: 1.

    Google Scholar 

  58. Sabry, S. A., K. M. Ghanem, and H. A. Ghozlan (1993) Riboflavin production byAspergillus terreus from beetmolasses.Microbiologia 9: 118–124.

    CAS  Google Scholar 

  59. Stryer, L. (1995) Biosynthesis of nucleotides: Biochemistry. 4th ed., pp. 739–740. W. H. Freeman and Co., NY, USA.

    Google Scholar 

  60. Ulane, R. and M. Ogur (1972) Genetic and physiological control of serine and glycine biosynthesis inSaccharomyces.J. Bacteriol. 109: 34–43.

    CAS  Google Scholar 

  61. McNeil, J. B., E. M. McIntosh, B. V. Taylor, F. Zhang, S. Tang, and A. L. Bognar (1994) Cloning and molecular characterization of three genes, including two genes encoding serine hydroxymethyltransferase, whose inactivation is required to render yeast auxotrophic for glycine.J. Biol. Chem. 269: 9155–9165.

    CAS  Google Scholar 

  62. Goodwin, T. W. and S. Pendlington (1954) Studies on the biosynthesis of riboflavin. Nitrogen metabolism and flavinogenesis inEremothecium ashbyii.Biochem. J. 57: 631–641.

    CAS  Google Scholar 

  63. Goodwin, T. W. and O. T. G. Jones (1956) Studies on the biosynthesis of riboflavin. 3. The utilization of14C-labelled serine for riboflavin biosynthesis byEremothecium ashbyii.Biochem. J. 64: 9–13.

    CAS  Google Scholar 

  64. Goodwin, T. W. and A. A. Horton (1960) Studies on flavinogenesis. 6. The role of threonine in riboflavin biosynthesis inEremothecium ashbyii.Biochem. J. 75: 53–57.

    CAS  Google Scholar 

  65. Bacher, A. and F. Lingens (1969) The structure of the purine precursor in riboflavin biosynthesis.Angew. Chem. Int. Ed. Engl. 8: 371–372.

    CAS  Google Scholar 

  66. Bacher, A. and B. Mailänder (1973) Biosynthesis of riboflavin. The structure of the purine precursor.J. Biol. Chem. 248: 6227–6231.

    CAS  Google Scholar 

  67. Shavlovskii, G. M., L. P. Strugovshchikova, and E. M. Logvinenko (1971) Flavinogenesis in guanine-dependent mutants ofCandida guilliermondii.Dokl. Akad. Nauk. SSSR 196: 701–704.

    CAS  Google Scholar 

  68. Baugh, C. M. and C. L. Krumdieck (1969) Biosynthesis of the purine precursor of riboflavin inCorynebacterium.J. Bacteriol. 98: 1114–1119.

    CAS  Google Scholar 

  69. Mailander, B. and A. Bacher (1976) Biosynthesis of riboflavin. Structure of the purine precursor and origin of the ribityl side chain.J. Biol. Chem. 251: 3623–3628.

    CAS  Google Scholar 

  70. Mitsuda, H. and K. Nakajima (1973) Effects of 8-azaguanine on riboflavin production and on the nucleotide pools in non-growing cells ofEremothecium ashbyii.J. Nutr. Sci. Vitaminol. 19: 215–227.

    CAS  Google Scholar 

  71. Mitsuda, H. and K. Nakajima (1975) Guanosine nucleotide precursor for flavinogenesis ofEremothecium ashbyii.J. Nutr. Sci. Vitaminol. 21: 331–345.

    CAS  Google Scholar 

  72. Mitsuda, H. and K. Nakajima (1975) The immediate nucleotide precursor, guanosine triphosphate, in the riboflavin biosynthetic pathway.J. Nutr. Sci. Vitaminol. 23: 23–24.

    Google Scholar 

  73. Bresler, S. E., G. F. Gorinchuk, T. P. Chernik, and D. A. Perumov (1978) Operon of riboflavin biosynthesis inBacillus subtilis. XV. A study of mutants related to the initial stages of biosynthesis. The origin of the ribityl chain of the riboflavin molecule.Genetika 14: 2082–2090.

    CAS  Google Scholar 

  74. Foor, F. and G. M. Brown (1975) Purification and properties of guanosine triphosphate cyclohydrolase II fromEscherichia coli.J. Biol. Chem. 250: 3545–3551.

    CAS  Google Scholar 

  75. Bresler, S. E. and D. A. Perumov (1979) Study of the operon for riboflavin biosynthesis inBacillus subtilis. Influence of genotype on regulating the synthesis of GTP-5-triphosphate cyclohydrolase.Genetika 15: 967–971.

    CAS  Google Scholar 

  76. Shavlovskii, G. M., E. M. Logvinenko, V. E. Kashchenko, L. V. Kolton, and A. E. Zakal’skii (1976) Determination of GTP-cyclohydrolase, the first enzyme of riboflavin biosynthesis from the yeastPichia guilliermondii.Dokl. Akad. Nauk. SSSR. 230: 1485–1487.

    CAS  Google Scholar 

  77. Shavlovskii, G. M., V. E. Kashchenko, L. V. Kolton, E. M. Logvinenko, and A. E. Zakal’skii (1977) Regulation of synthesis of GTP-cyclohydrolase participating in yeast falvinogenesis by iron.Mikrobiologiia 46: 578–580.

    CAS  Google Scholar 

  78. Hayes, D. H. and G. R. Greenberg (1969) Conversion of C-8 of guanine into a one carbon unit during riboflavin biosynthesis.Bull. Soc. Chim. Biol. 51: 1187–1198.

    CAS  Google Scholar 

  79. Bacher, A. and F. Lingens (1970) Formation of 2,5-diamino-6-hydroxy-4-(1′-D-ribitylamino) pyrimidine in a riboflavin auxotroph.J. Biol. Chem. 245: 4647–4652.

    CAS  Google Scholar 

  80. Mitsuda, H., K. Nakajima, and T. Nadamoto (1976) Nucleotide precursor in riboflavin biosynthesis.J. Nutr. Sci. Vitaminol. 22: 477–480.

    CAS  Google Scholar 

  81. Mitsuda, H., K. Nakajima, and Y. Yamada (1977) Studies on the intermediates in the biosynthetic pathway of riboflavin. I. Identification of a green fluorescent compound, Compound G1, accumulated in non-growing cells ofEremothecium ashbyii by the addition of dimeric diacetyl.J. Nutr. Sci. Vitaminol. 23: 305–318.

    CAS  Google Scholar 

  82. Miersch, J., E. M. Logvinenko, A. E. Zakalsky, G. M. Shavlovskii, and H. Reinbothe (1978) Origin of the ribityl side-chain of riboflavin from the ribose moiety of guanosine triphosphate inPichia guilliermondii yeast.Biochim. Biophys. Acta. 543: 305–312.

    CAS  Google Scholar 

  83. Logvinenko, E. M., G. M. Shavlovskii, and A. E. Zakalsky (1979) Product of second-stage riboflavin biosynthesis inPichia guilliermondii.Mikrobiologiia 48: 756–758.

    CAS  Google Scholar 

  84. Nielsen, P. and A. Bacher (1981) Biosynthesis of riboflavin. Characterization of the product of the deaminase.Biochim. Biophys. Acta 662: 312–317.

    CAS  Google Scholar 

  85. Bacher, A., U. Eggers, and F. Lingens (1973) Genetic control of riboflavin synthetase inBacillus subtilis.Arch. Mikrobiol. 89: 73–77.

    CAS  Google Scholar 

  86. Sadique, J., R. Shanmugasundaram, and E. R. B. Shanmugasundaram (1966) Isolation of 5-amino-4-ribityl-aminouracil from a riboflavinless mutant ofAspergillus nidulans.Biochem. J. 101: 2C.

    CAS  Google Scholar 

  87. Lingens, F., O. Oltmanns, and A. Bacher (1967) Über Zwischenproducte der Riboflavin-Biosynthese beiSaccharomyces cerevisiae.Z. naturforsch. 22B: 755–758.

    Google Scholar 

  88. Mitsuda, H. and K. Nakajima (1976) Isolation of 4-ribitylamino-5-amino-2,6-dihydroxypyrimidine from a high flavinogenic moldEremothecium ashbyii.J. Nutr. Sci. Vitaminol. 22: 307–312.

    CAS  Google Scholar 

  89. Mitsuda, H., K. Nakajima, and Y. Yamada (1978) Isolation of 4-(1′-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine from a riboflavin-adenine-deficient mutant ofBacillus subtilis.J. Biol. Chem. 253: 2238–2243.

    CAS  Google Scholar 

  90. Bacher, A. and F. Lingens (1970) Formation of 2,5-diamino-6-hydroxy-4-(1′-D-ribitylamino) pyrimidine in a riboflavin auxotroph.J. Biol. Chem. 245: 4647–4652.

    CAS  Google Scholar 

  91. Hollander, I. and G. M. Brown (1979) Biosynthesis of riboflavin: reductase and deaminase ofAshbya gossypii.Biochem Biophys. Res. Commun. 89: 759–763.

    Article  CAS  Google Scholar 

  92. Burrows, R. B. and G. M. Brown (1978) Presence inEscherichia coli of a deaminase and a reductase involved in biosynthesis of riboflavin.J. Bacteriol. 136: 657–667.

    CAS  Google Scholar 

  93. Bresler, S. E., E. A. Glazunov, D. A. Perumov, and T. P. Chernik (1977) Riboflavin biosynthesis operon ofBacillus subtilis. XIII. Genetic and biochemical study of mutants with regard to intermediate stages of biosynthesis.Genetika 13: 2006–2016.

    CAS  Google Scholar 

  94. Goodwin, T. W. and D. H. Treble (1958) The incorporation of (2-14C) acetylmethylcarbinol (acetone) into ring A of riboflavin byEremothecium ashbyii; a new route for the biosynthesis of an aromatic ring.Biochem. J. 70: 14–15.

    Google Scholar 

  95. Katagiri, H., I. Takeda, and K. Imai (1959) Synthesis of riboflavin by microorganisms. VII. The enzymic riboflavin synthesis from 4-(N-ribitylamino)-5-aminouracil.J. Vitaminol. 5: 287–297.

    CAS  Google Scholar 

  96. Goolwin, T. W. and A. A. Horton (1961) Biosynthesis of riboflavin in cell-free systems.Nature. 191: 772–774.

    Google Scholar 

  97. Jabasani, M. T. and U. A. S. Al-Khalidi (1975) Asymmetric labeling of the xylene ring in riboflavin.Int. J. Biochem. 6: 735–739.

    Google Scholar 

  98. Mitsuda, H., K. Nakajima, and Y. Ikeda (1978) Effects of various metabolites (sugars, carboxylic acids and alcohols) on riboflavin formation in non-growing cells ofAshbya gossypii.J. Nutr. Sci. Vitaminol. 24: 91–103.

    CAS  Google Scholar 

  99. Schlee, K. and H. Reinbothe (1970) Purinstoffwechsel und Riboflavin Bildung in Mikroorganismenn. VI. Der Einfluß von L-Valin auf die Flavinogenes vonCandida guilliermondii.Z. Allg. Mikrobiol. 10: 77–80.

    CAS  Google Scholar 

  100. Plaut, G. W. E. (1971) Metabolism of water-soluble vitamins. The biosynthesis of riboflavin. pp. 11–45. In: M. Florkin, and E. H. Stotz (eds.),Comprehensive Biochemistry, Vol. 21.

  101. Ali, S. N. and U. A. S. Al-Khalidi (1966) The precursors of the xylene ring in riboflavin.Biochem. J. 98: 182–188.

    CAS  Google Scholar 

  102. Alworth, W. C., H. N. Bacher, M. F. Winkler, A. M. Keenan, G. W. Gokel, and F. L. Wood (1970) Brosynthesis of the 4,5-dimehtyl-1,2-phenylene moiety of vitamin B12.Biochem. Biophys. Res. Commun 40: 1026–1031.

    CAS  Google Scholar 

  103. Keller, P. J., O. Le Van, A. Bacher, and H. G. Floss (1988) Biosynthesis of riboflavin.13C-NMR techniques for the analysis of multiply13C-labeled riboflavins.Tetrahedron 39: 3471–3481.

    Google Scholar 

  104. Floss, H. G., O. Le Van, P. J. Keller, and A. Bacher (1988) Biosynthesis of riboflavin. An unusual rearrangement in the Formation of 6,7-dimethyl-8-ribityllumazine.J. Am. Chem. Soc. 105: 2493–2494.

    Google Scholar 

  105. Nielsen, P., G. Neuberger, H. G. Floss, and A. Bacher (1984) Biosynthesis of riboflavin. Enzymatic formation of the xylene moiety from [14C]ribulose 5-phosphate.Biochem. Biophys. Res. Commun. 118, 814–822.

    CAS  Google Scholar 

  106. Le Van, O., P. J. Keller, D. H. Bown, H. G. Floss, and A. Bacher (1985) Biosynthesis of riboflavin inBacillus subtilis: origin of the four-carbon moiety.J. Bacteriol. 162. 1280–1284.

    Google Scholar 

  107. Voll, R. and A. Bacher (1990) Studies on the 4-carbon precirsor in the biosynthesis of ribofavin.J. Biol. Chem. 265: 19479–19485.

    Google Scholar 

  108. Katagiri, H., I. Takeda, and K. Imai (1958) Synthesis of riboflavin by microorganisms.J. Vitaminol. 4: 278–284.

    CAS  Google Scholar 

  109. Plauf, G. W. E. (1960) Studies on the stoichiometry of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin.J. Biol. Chem. 235: PC 41.

    Google Scholar 

  110. Beach, R. L. and G. W. E. Plaut (1970) Stereospecificity of the enzymatic synthesis of the o-xylene ring of riboflavin.J. Am. Chem. Soc. 92: 2913–2916.

    CAS  Google Scholar 

  111. Bacher, A., O. Le Van, P. J. Keller, and H. G. Floss (1983) Biosynthesis of riboflavin. Incorporation of13C-labelled precursors into the xylene ring.J. Biol. Chem. 258: 13431–13487.

    CAS  Google Scholar 

  112. Sedlmaier, H., F. Miller, P. J. Keller, and A. Bacher (1987) Enzymatic synthesis of riboflavin and FMN specifically labeled with13C in the xylene ring.Z. Naturforsch. 42c: 425–429.

    Google Scholar 

  113. Wacker, H., R. A. Harvey, C. H. Winestock, and G. W. E. Plaut (1964) 4-(1′-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine, the second product of the riboflavin synthetase reaction.J. Biol. Chem. 239: 3493–3497.

    CAS  Google Scholar 

  114. Mitsuda, H., T. Nadamoto, and K. Nakajima (1976) Reutilization of by-product for riboflavin formation in the riboflavin synthetase reaction.J. Nutr. Sci. Vitaminol. 22: 67–70.

    CAS  Google Scholar 

  115. Mironov, V. N., A. E. Kraev, B. K. Chernov, A. V. Ul’yanov, Y. B. Golva, G. E. Pozmogova, M. L. Simonova, V. K. Gordeev, A. I. stepanov, and K. G. Skryabin (1989) Riboflavin biosynthesis gene ofBacillus subtilis—complete primary structure and model of organization.Dokl. Akad. Nauk. SSSR. 305: 482–487.

    CAS  Google Scholar 

  116. Boretskii, Iu. R., Iu. S. Skoblov, O. M. Khodova, and P. M. Rabinivich (1992) Purification and properties of GTP-cyclohydrolase fromBacillus subtilis.Bickhimia 57: 1021–1030.

    CAS  Google Scholar 

  117. Richter, G., H. Ritz, G. Katzenmeier, R. Volk, A. Kohnle, F. Lottspeich, D. Allendorf, and A. Bacher (1993) Biosynthesis of riboflavin: cloning, sequencing, mapping and expression of the gene encoding for GTP cyclohydrolase II inEscherichia coli.J. Bacteriol. 175: 4045–4051.

    CAS  Google Scholar 

  118. Richter, G., R. Volk, C. Kriegger, H. W. Lahm, U. Rothlisberger, and A. Bacher (1992) Biosynthesis of riboflavin: cloning, sequencing, and expression of the gene encoding 3,4-dihydroxy-2-butanone 4-phosphate synthase ofEscherichia coli.J. Bacteriol. 174: 4050–4056.

    CAS  Google Scholar 

  119. Revuelta, J. L., M. A. Santos, and J. J. Garcia-ramirez (1990) Biosynthesis of vitamin B2 in yeast, pp. 117–122. In: Committee of Biotec-90 (eds.).From Genes to BioProducts. DM PPU, Murcia, Spain.

    Google Scholar 

  120. Buitrago, M.-J., G. A. Gonzalez, J. E. Saiz, and J. L. Revuelta (1993) Mapping of theRIB1 andRIB7 genes involved in the biosynthesis of riboflavin inSaccharomyces cerevisiaa.Yeast 9: 1099–1102.

    CAS  Google Scholar 

  121. Zakal’skii, A. E., M. L. Zlochevskii, I. Stasiv, E. M. Logvinenko, M. Beburov, and G. M. Shavlovskn (1990) Cloning of the gene coding for the enzyme of the first stage of flavinogenesis in the yeastPichia guilliermondii, GTP cyclohydrolase, inEscherichia coli cells.Genetika 26: 614–620.

    Google Scholar 

  122. Liauta-Teglivets, O., M. Hasslacher, Iu. R. Boretskii, S. D. Kohlwein, and G. M. Shavlovskii (1995) Molecular cloning of the GTP-cyclohydrolase structural geneRIB1 ofPichia guilliermondii involved in riboflavin biosynthesis.Yeast 11: 945–952.

    CAS  Google Scholar 

  123. Bacher, A. and F. Lingens (1971) Formation of 6-hydroxy-2,4,5-triaminopyrimidine inRIB7 mutants of Saccharomyces cerevisiae.J. Biol. Chem. 246: 7013–7022.

    Google Scholar 

  124. Bacher, A. (1991) Biosynthesis of flavins, pp. 215–259. In: F. Muller (eds.). Chemistry and biochemistry of flavins. vol. 1. Chemical Rubber Co., Boca Raton, Fla, USA.

    Google Scholar 

  125. Bandrin, S. V., P. M. Rabinovich, and A. I. Stepanov (1983) Three linkage groups of genes involved in riboflavin biosynthesis inEscherichia coil.Sov. Genet. 19: 1103–1109.

    Google Scholar 

  126. Perkins, J. B. and J. G. Pero (1993) Biosynthesis of riboflavin, biotin, folic acid, and cobalamin, pp. 319–334. In: A. Sonenshein (eds.).Bacillus subtilis and Other Grampositive Bacteria: Biochemistry, Physiology, and Mo-lecular Genetics. American Society for Microbiology, Washington, DC, USA.

    Google Scholar 

  127. Fischer, M., S. Eberhardt, G. Richter, C. Krieger, I. Gerstenschlager, and A. Bacher (1996) Biosynthesis of riboflavin. Bifunctional pyrimidine deaminase/reductase ofEscherichia coli andBacillus subtilis.Biochem. Soc. Trans. 24: 358.

    Google Scholar 

  128. Tetsuya, T., C. Ueguchi, K. Shiba, and K. Ito (1992) Insertional disruption of thenusB (ssyB) gene leads to cold-sensitive growth ofEscherichia coli and suppression of thesecY24 mutation.Mol. Gen. Genet. 234: 429–432.

    Google Scholar 

  129. Garcia-Ramirez, J. J., M. A. Santos, and J. L. Revuelta (1995) TheSaccharomyces cerevisiae RIB4 gene codes for 6,7-dimethyl-8-ribityllumazine synthase involved in riboflavin biosynthesis.J. Biol. Chem. 270: 23801–23807.

    CAS  Google Scholar 

  130. Bacher, A., R. Baur, U. Eggers, H.-D. Harders, M. K. Otto, and H. Schnepple (1980) Riboflavin synthases ofBacillus subtilis. Purification and properties.J. Biol. Chem. 255: 632–637.

    CAS  Google Scholar 

  131. Bacher, A., H. C. Ludwig, H. Schnepple, and Y. Ben-Shaul (1986) Heavy riboflavin synthase fromBacillus subtilis. Quaternary structure and reaggregation.J. Mol. Biol. 187: 75–86.

    CAS  Google Scholar 

  132. Ladenstein, R., B. Meyer, R. Huber, H. Labischinski, K. Bartels, H.-D. Bartunik, L. Bachmann, H. C. Ludwig, und A. Bacher (1986) Heavy riboflavin synthase fromBacidus subtilis. Particle dimensions, crystal packing and molecular symmetry.J. Mol. Biol. 187: 87–100.

    CAS  Google Scholar 

  133. Mirtl, S., M. Fischer, G. Richter, J. Tack, S. Weinkauf, and A. Bacher (1996) Biosynthesis of riboflavin. Lumazine synthase ofEscherichia coli.J. Biol. Chem. 271: 33201–33207.

    Google Scholar 

  134. Schott, K., J. Kellermann, F. Lottspeich, and A. Bacher (1990) Riboflavin synthases ofBacillus subtilis. Purification and amino acid sequence of the α subunit.J. Biol. Chem. 265: 4204–4209.

    CAS  Google Scholar 

  135. Harvey, R. A. and G. W. E. Plaut (1966) Riboflavin synthetase from yeast. Properties of complexes of the enzyme with lumazine derivatives and riboflavin.J. Biol. Chem. 241: 2120–2136.

    CAS  Google Scholar 

  136. Otto, M. K. and A. Bacher (1981) Ligand-binding studies on light riboflavin synthase fromBacillus subtilis.Eur. J. Biochem. 115: 511–517.

    Article  CAS  Google Scholar 

  137. Tibbelin, G., S. Eberhardt, G. Richter, and A. Bacher (1996) Structure investigation on recombinant riboflavin synthase fromE. coli.Biochem. Soc. Trans. 24: 348.

    Google Scholar 

  138. Santos, M. A., J. J. Garcia-Ramirez, and J. L. Revuelta (1995) Riboflavin biosynthesis inSaccharomyces cerevisiae. Cloning, characterization, and expression of theRIB5 gene encoding riboflavin synthase.J. Biol. Chem. 270: 437–444.

    CAS  Google Scholar 

  139. Volk, R. and A. Bacher (1991) Biosynthesis of riboflavin. Studies on the mechanism of L-3,4-dihydroxy-2-butanone 4-phosphate synthase.J. Biol. Chem. 266: 20610–20618.

    CAS  Google Scholar 

  140. Richter, G., C. Krieger, R. Volk, K. Kis, H. Ritz, E. Cotze, and A. Bacher (1997) Biosynthesis of riboflavin: 3,4-dihydroxy-2-butanone 4-phosphate synthase.Methods Enzymol. 280: 374–382.

    CAS  Google Scholar 

  141. Mehta, S. U., A. K. Matoo, and V. V. Modi (1972) Ribtol and flavinogenesis inEremothecium ashbyn.Biochem. J. 130: 159–166.

    CAS  Google Scholar 

  142. Moschau, N., K.-P. Stahmann, H. Sahm, J. B. McNeil, and A. L. Bognar (1997) Identification ofSaccharomyces cerevisiae GLY1 as a threonine aldolase: a key enzyme in glycine biosynthesis.FEMS Microbiol. Lett. 150: 55–60.

    Google Scholar 

  143. Monschau, N., H. Sahm, and K.-P. Stahmann (1998) Threonine aldolase overexpression plus threonine supplementation enhanced riboflavin production inAshbya gossypii.Appl. Environ. Microbiol. 64: 4283–4290.

    CAS  Google Scholar 

  144. Maeting, I., G. Schmidt, H. Sahm, J. L. Revuelta, Y.-D. Stierhof, and K.-P. Stahmann (1999) Isocitrate lyase ofAshbya gossypii—transcriptional regulation and peroxisomal location.FEBS Lett. 444: 15–21.

    CAS  Google Scholar 

  145. Taylor, K. M., C. P. Kaplan, X. Gao, and A. Baker (1996) Localization and targeting of isocitrate lyases inSaccharomyces cerevisiae.Biochem. J. 319, 255–262.

    CAS  Google Scholar 

  146. Chaves, R. S., P. Herrero, I. Ordiz, M. A. del Brio, and F. Moreno (1997) Isocitrate lyase localisation inSaccharomyces cerevisiae cells.Gene 198: 165–169.

    CAS  Google Scholar 

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  1. Laboratory of Biotechnology, Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, 836 Ohya, 422-8529, Shizuoka, Japan

    Seong Han Lim & Enoch Y. Park

  2. Laboratory of Fermentation, R&D Center, BASF Co. Ltd., 573-400, JeonBuk, Korea

    Jong Soo Choi

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Lim, S.H., Choi, J.S. & Park, E.Y. Microbial production of riboflavin using riboflavin overproducers,Ashbya gossypii, Bacillus subtilis, andCandida famate: An overview. Biotechnol. Bioprocess Eng. 6, 75–88 (2001). https://doi.org/10.1007/BF02931951

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