Analytical and Bioanalytical Chemistry

, Volume 395, Issue 5, pp 1225–1242 | Cite as

Review of secondary metabolites and mycotoxins from the Aspergillus niger group

  • Kristian Fog Nielsen
  • Jesper Mølgaard Mogensen
  • Maria Johansen
  • Thomas O. Larsen
  • Jens Christian Frisvad


Filamentous fungi in the Aspergillus section Nigri (the black aspergilli) represent some of the most widespread food and feed contaminants known but they are also some of the most important workhorses used by the biotechnological industry. The Nigri section consists of six commonly found species (excluding A. aculeatus and its close relatives) from which currently 145 different secondary metabolites have been isolated and/or detected. From a human and animal safety point of view, the mycotoxins ochratoxin A (from A. carbonarius and less frequently A. niger) and fumonisin B2 (from A. niger) are currently the most problematic compounds. Especially in foods and feeds such as coffee, nuts, dried fruits, and grape-based products where fumonisin-producing fusaria are not a problem, fumonisins pose a risk. Moreover, compounds such as malformins, naptho-γ-pyrones, and bicoumarins (kotanins) call for monitoring in food, feed, and biotechnology products as well as for a better toxicological evaluation, since they are often produced in large amounts by the black aspergilli. For chemical differentiation/identification of the less toxic species the diketopiperazine asperazine can be used as a positive marker since it is consistently produced by A. tubingensis (177 of 177 strains tested) and A. acidus (47 of 47 strains tested) but never by A. niger (140 strains tested). Naptho-γ-pyrones are the compounds produced in the highest quantities and are produced by all six common species in the group (A. niger 134 of 140; A. tubingensis 169 of 177; A. acidus 44 of 47; A. carbonarius 40 of 40, A. brasiliensis 18 of 18; and A. ibericus three of three).


Image of Aspergillus niger growing on YES agar, and the resulting extract analysed by LCDAD-TOFMS


Metabolomics Fumonisin Ochratoxin Liquid chromatography–mass spectrometry Polyketide synthase Polyketide 



K.F.N. and J.M.M. were funded by the Danish Food Industry Agency (grant 3304-FVEP-07-730-01). Dr. Techn. A.N. Neergaards & Hustrus Fond is acknowledged for its support of the LC-MS/MS instrument. The remaining authors are grateful for support from the Danish Research Council for Technology and Production Sciences (grants no. 26-03-0147 and 274-08-0021).


  1. 1.
    Pitt JI, Hocking AD (1997) Fungi and food spoilage II. Blackie, LondonGoogle Scholar
  2. 2.
    Perrone G et al (2007) Stud Mycol 59:53–66Google Scholar
  3. 3.
    Frisvad JC et al (2007) Stud Mycol 59:31–37Google Scholar
  4. 4.
    Frisvad JC, Smedsgaard J, Larsen TO, Samson RA (2004) Stud Mycol 49:201–241CrossRefGoogle Scholar
  5. 5.
    Samson RA, Noonim P, Meijer M, Houbraken J, Frisvad JC, Varga J (2007) Stud Mycol 59:129–145CrossRefGoogle Scholar
  6. 6.
    Abarca ML, Accensi F, Cano J, Cabanes FJ (2004) Antonie Van Leeuwenhoek 86:33–49CrossRefGoogle Scholar
  7. 7.
    Abarca ML, Bragulat MR, Castella G, Cabanes FJ (1994) Appl Environ Microbiol 60:2650–2652Google Scholar
  8. 8.
    Samson RA, Houbraken JAMP, Kuijpers AFA, Frank JM, Frisvad JC (2004) Stud Mycol 50:45–61Google Scholar
  9. 9.
    Esteban A, Abarca ML, Bragulat MR, Cabanes FJ (2006) Food Microbiol 23:634–640CrossRefGoogle Scholar
  10. 10.
    Frisvad JC, Smedsgaard J, Samson RA, Larsen TO, Thrane U (2007) J Agric Food Chem 55:9727–9732CrossRefGoogle Scholar
  11. 11.
    Noonim P, Mahakarnchanakul W, Nielsen KF, Frisvad JC, Samson RA (2009) Food Addit Contam 26:94–100CrossRefGoogle Scholar
  12. 12.
    Schuster E, Dunn-Coleman N, Frisvad JC, Van Dijck PW (2002) Appl Microbiol Biotechnol 59:426–435CrossRefGoogle Scholar
  13. 13.
    Pel HJ et al (2007) Nat Biotechnol 25:221–231CrossRefGoogle Scholar
  14. 14.
    Blumenthal CZ (2004) Regul Toxicol Pharmacol 39:214–228CrossRefGoogle Scholar
  15. 15.
    Varga J et al (2007) Int J Syst Evol Microbiol 57:1925–1932CrossRefGoogle Scholar
  16. 16.
    Frisvad JC, Thrane U (1987) J Chromatogr 404:195–214CrossRefGoogle Scholar
  17. 17.
    Smedsgaard J (1997) J Chromatogr A 760:264–270CrossRefGoogle Scholar
  18. 18.
    Jennessen J, Nielsen KF, Houbraken J, Schnürer J, Lyhne EK, Frisvad JC, Samson RA (2005) J Agric Food Chem 53:1833–1840CrossRefGoogle Scholar
  19. 19.
    Nielsen KF, Smedsgaard J (2003) J Chromatogr A 1002:111–136CrossRefGoogle Scholar
  20. 20.
    Nielsen KF, Graefenhan T, Zafari D, Thrane U (2005) J Agric Food Chem 53:8190–8196CrossRefGoogle Scholar
  21. 21.
    Noonim P, Mahakarnchanakul W, Nielsen KF, Frisvad JC, Samson RA (2008) Int J Food Microbiol 128:197–202CrossRefGoogle Scholar
  22. 22.
    Johansen M (2007) MSc thesis. Technical University of Denmark, LyngbyGoogle Scholar
  23. 23.
    Medina A, Mateo R, Lopez-Ocana L, Valle-Algarra FM, Jimenez M (2005) Appl Environ Microbiol 71:4696–4702CrossRefGoogle Scholar
  24. 24.
    Perrone G, Mule G, Susca A, Battilani P, Pietri A, Logrieco A (2006) Appl Environ Microbiol 72:680–685CrossRefGoogle Scholar
  25. 25.
    Gomez C, Bragulat MR, Abarca ML, Minguez S, Cabanes FJ (2006) Food Microbiol 23:541–545CrossRefGoogle Scholar
  26. 26.
    Bayman P, Baker JL (2006) Mycopathologia 162:215–223CrossRefGoogle Scholar
  27. 27.
    Creppy EE (2002) Toxicol Lett 127:19–28CrossRefGoogle Scholar
  28. 28.
    Stoev SD, Vitanov S, Anguelov G, Petkova-Bocharova T, Creppy EE (2001) Vet Res Commun 25:205–223CrossRefGoogle Scholar
  29. 29.
    Krska R, Schubert-Ullrich P, Molinelli A, Sulyok M, MacDonald S, Crews C (2008) Food Addit Contam 25:152–163CrossRefGoogle Scholar
  30. 30.
    Songsermsakul P, Razzazi-Fazeli E (2008) J Liq Chromatogr Relat Technol 31:1641–1686CrossRefGoogle Scholar
  31. 31.
    Mateo R, Medina A, Mateo EM, Mateo F, Jimenez M (2007) Int J Food Microbiol 1:79–83CrossRefGoogle Scholar
  32. 32.
    Dall'Asta C, Galaverna G, Dossena A, Marchelli R (2004) J Chromatogr A 1024:275–279CrossRefGoogle Scholar
  33. 33.
    Saez JM, Medina A, Gimeno-Adelantado JV, Mateo R, Jimenez M (2004) J Chromatogr A 1029:125–133CrossRefGoogle Scholar
  34. 34.
    Krska R, Molinelli A (2007) Anal Bioanal Chem 387:145–148CrossRefGoogle Scholar
  35. 35.
    Zheng MZ, Richard JL, Binder J (2006) Mycopathologia 161:261–273CrossRefGoogle Scholar
  36. 36.
    Gelderblom WCA, Jaskiewicz K, Marasas WFO, Thiel PG, Horak RM, Vleggaar R, Kriek NPJ (1988) Appl Environ Microbiol 54:1806–1811Google Scholar
  37. 37.
    Bartok T, Szecsi A, Szekeres A, Mesterhazy A, Bartok M (2006) Rapid Commun Mass Spectrom 20:2447–2462CrossRefGoogle Scholar
  38. 38.
    Shepard GS (1998) J Chromatogr A 815:31–39CrossRefGoogle Scholar
  39. 39.
    Sulyok M, Krska R, Schuhmacher R (2007) Anal Bioanal Chem 389:1505–1523CrossRefGoogle Scholar
  40. 40.
    Sulyok M, Krska R, Schuhmacher R (2007) Food Addit Contam 24:1184–1195CrossRefGoogle Scholar
  41. 41.
    Senyuva HZ, Gilbert J (2008) J Food Prot 71:1500–1504Google Scholar
  42. 42.
    Song YC, Li H, Ye YH, Shan CY, Yang YM, Tan RX (2004) FEMS Microbiol Lett 241:67–72CrossRefGoogle Scholar
  43. 43.
    Koyama K, Ominato K, Natori S, Tashiro T, Tsuruo T (1988) J Pharmacobio-dyn 11:630–635Google Scholar
  44. 44.
    Ghosal S, Biswas K, Chakrabarti DK (1979) J Agric Food Chem 27:1347–1351CrossRefGoogle Scholar
  45. 45.
    Palmgren MS, Lee LS (1986) Environ Health Perspect 66:105–108CrossRefGoogle Scholar
  46. 46.
    Mogensen JM, Varga J, Thrane U, Frisvad JC (2009) Int J Food Microbiol 132:141–144CrossRefGoogle Scholar
  47. 47.
    Bouras N, Mathieu F, Coppel Y, Strelkov SE, Lebrihi A (2007) J Agric Food Chem 55:8920–8927CrossRefGoogle Scholar
  48. 48.
    Bouras N, Mathieu F, Coppel Y, Lebrihi A (2005) Nat Prod Res 19:653–659CrossRefGoogle Scholar
  49. 49.
    Zhang YP, Ling S, Fang YC, Zhu TJ, Gu QQ, Zhu WM (2008) Chem Biodivers 5:93–100CrossRefGoogle Scholar
  50. 50.
    Kanaujia PK, Pardasani D, Gupta AK, Kumar R, Srivastava RK, Dubey DK (2007) J Chromatogr A 1161:98–104CrossRefGoogle Scholar
  51. 51.
    Shiomi K, Uchida R, Inokoshi J, Tanaka H, Iwai Y, Omura S (1996) Tetrahedron Lett 37:11265–1268CrossRefGoogle Scholar
  52. 52.
    Shu Y-Z, Cutrone JQ, Klohr SE, Huang S (1995) J Antibiot 48:1060–1065Google Scholar
  53. 53.
    Nielsen KF, Gravesen S, Nielsen PA, Andersen B, Thrane U, Frisvad JC (1999) Mycopathologia 145:43–56CrossRefGoogle Scholar
  54. 54.
    Ray AC, Eakin RE (1975) Appl Microbiol 30:909–915Google Scholar
  55. 55.
    Inokoshi J, Shiomi K, Masuma R, Tanaka H, Yamada H, Omura S (1999) J Antibiot. 52:1095–1100Google Scholar
  56. 56.
    Cutler HG, Crumley FG, Cox RH, Hernandez O, Cole PJ, Dorner JW (1979) J Agric Food Chem 27:592–595CrossRefGoogle Scholar
  57. 57.
    Hiort J et al (2004) J Nat Prod 67:1543CrossRefGoogle Scholar
  58. 58.
    Hiort J, Maksimenka K, Reichert M, Perovic-Ottstadt S, Lin WH, Wray V, Steube K, Schaumann K, Weber H, Proksch P, Ebel R, Muller WEG, Bringmann G (2005) J Nat Prod 68:1821 (Erratum to previous reference)Google Scholar
  59. 59.
    Buchi G, Klaubert DH, Shank RC, Weinreb SM, Wogan GN (1971) J Org Chem 36:1143CrossRefGoogle Scholar
  60. 60.
    Takahashi N, Curtis RW (1961) Plant Physiol 36:30–36CrossRefGoogle Scholar
  61. 61.
    Kobbe B, Cushman M, Wogan GN, Demain AL (1977) Appl Environ Microbiol 33:996–997Google Scholar
  62. 62.
    Herbert JM, Savi P, Lale A, Laplace MC, Baudry N, Pereillo JM, Emondsalt X (1994) Biochem Pharmacol 48:1211–1217CrossRefGoogle Scholar
  63. 63.
    Yoshizawa T, Tsuchiya Y, Morooka N, Sawada Y (1975) Agric Biol Chem 39:1325–1326Google Scholar
  64. 64.
    Varoglu M, Corbett TH, Valeriote FA, Crews P (1997) J Org Chem 62:7078–7079CrossRefGoogle Scholar
  65. 65.
    Varoglu M, Crews P (2000) J Nat Prod 63:41–43CrossRefGoogle Scholar
  66. 66.
    Senyuva HZ, Gilbert J, Ozturkoglu S (2008) Anal Chim Acta 617:97–106CrossRefGoogle Scholar
  67. 67.
    Kim K-W, Sugawara F, Yoshida S, Murofushi N, Takahashi N, Curtis RW (1993) Biosci Biotechnol Biochem 57:787–791CrossRefGoogle Scholar
  68. 68.
    Ovenden SP et al (2004) J Nat Prod 67:2093–2095CrossRefGoogle Scholar
  69. 69.
    Govek SP, Overman LE (2007) Tetrahedron 63:8499–8513CrossRefGoogle Scholar
  70. 70.
    de Vries EGE, Frisvad JC, van de Vondervoort PJI, Burgers K, Kuijpers AFF, Samson RA, Visser J (2005) Antonie Van Leeuwenhoek 87:195–203CrossRefGoogle Scholar
  71. 71.
    Iwamoto T, Shima S, Hirota A, Isogai A, Sakai H (1983) Agric Biol Chem 47:739–743Google Scholar
  72. 72.
    Bringmann G, Maksimenka K, Gulder T, Schaumann K, Perovic-Ottstadt S, Mueller WEG, Hiort J, Ebel R, Proksch P (2004) Patent DE102004002884-A1Google Scholar
  73. 73.
    Shen L, Ye Y-H, Wang X-T, Zhu H-L, Xu C (2006) Chem Eur J 4395–4396Google Scholar
  74. 74.
    Cole RJ, Cox RH (1981) Handbook of toxic fungal metabolites. Academic, LondonGoogle Scholar
  75. 75.
    Schlingmann G et al (2007) J Nat Prod 70:1180–1187CrossRefGoogle Scholar
  76. 76.
    Henrikson JC, Hoover AR, Joyner PM, Cichewicz RH (2009) Org Biomol Chem 7:435–438CrossRefGoogle Scholar
  77. 77.
    Bugni TS, Abbanat D, Bernan VS, Maisese WM, Greenstein M, Van Wagoner RM, Ireland CM (2000) J Org Chem 65:7195–7200CrossRefGoogle Scholar
  78. 78.
    Ates S, Ozenir S, Gokdere M (2006) Appl Biochem Microbiol 42:500–501CrossRefGoogle Scholar
  79. 79.
    Rao KCS, Divakar S, Babu KN, Rao AGA (2003) J Antibiot 55:789–793Google Scholar
  80. 80.
    Sørensen JL, Phipps RK, Nielsen KF, Schroers HJ, Frank J, Thrane U (2009) J Agric Food Chem 57:1632–1639CrossRefGoogle Scholar
  81. 81.
    O'Brien M, Nielsen KF, O'Kiely P, Forristal PD, Fuller H, Frisvad JC (2006) J Agric Food Chem 54:9268–9276CrossRefGoogle Scholar
  82. 82.
    Herebian D, Zuhlke S, Lamshoft M, Spiteller M (2009) J Sep Sci 32:939–948CrossRefGoogle Scholar
  83. 83.
    Zhang YP, Zhu TJ, Fang YC, Liu HB, Gu QQ, Zhu WM (2007) J Antibiot 60:153–157CrossRefGoogle Scholar
  84. 84.
    Lang G et al (2008) J Nat Prod 71:1595–1599CrossRefGoogle Scholar
  85. 85.
    Burton IW, Quilliam MA, Walter JA (2005) Anal Chem 77:3123–3131CrossRefGoogle Scholar
  86. 86.
    Kersters K, Deley J (1963) Biochim Biophys Acta 71:311CrossRefGoogle Scholar
  87. 87.
    Challenger F, Subramaniam V, Walker TK (1927) J Chem Soc 200–208Google Scholar
  88. 88.
    Turner WB, Aldridge DC (1983) Fungal metabolites II. Academic, LondonGoogle Scholar
  89. 89.
    Rosenberj AJ, Nisman B (1949) Biochim Biophys Acta 3:348–357CrossRefGoogle Scholar
  90. 90.
    Wehmer C (1918) Ber Dtsch Chem Ges 51:1663–1668CrossRefGoogle Scholar
  91. 91.
    Nair MG, Burke BA (1988) Phytochemistry 27:3169–3173CrossRefGoogle Scholar
  92. 92.
    Yu J, Tamura G, Takahash N, Arima K (1967) Agric Biol Chem 31:831–836Google Scholar
  93. 93.
    Alvi KA, Nair BG, Rabenstein J, Davis G, Baker DD (2000) J Antibiot 53:110–113Google Scholar
  94. 94.
    Caesar F, Jansson K, Mutschle E (1969) Pharm Acta Helv 44:676–680Google Scholar
  95. 95.
    Curie JN (1917) J Biol Chem 31:15–37Google Scholar
  96. 96.
    Ye YH, Zhu HL, Song YC, Liu JY, Tan RX (2005) J Nat Prod 68:1106–1108CrossRefGoogle Scholar
  97. 97.
    Kimura Y, Baba K, Hata K (1983) Planta Med 48:164–168CrossRefGoogle Scholar
  98. 98.
    Almassi F, Ghisalberti EL, Rowland CY (1994) J Nat Prod 57:833–836CrossRefGoogle Scholar
  99. 99.
    Isogai A, Washizu M, Kondo K, Murakoshi S, Suzuki A (1984) Agric Biol Chem 48:2607–2609Google Scholar
  100. 100.
    Fukuda T, Hasegawa Y, Hagimori K, Yamaguchi Y, Masuma R, Tomoda H, Omura S (2006) J Antibiot 59:480–485CrossRefGoogle Scholar
  101. 101.
    Weidenmueller H-L, Cavagna F, Fehlhaber H-W, Praeve P (1972) Tetrahedron Lett 33:3519–3522CrossRefGoogle Scholar
  102. 102.
    Hasegawa Y, Fukuda T, Hagimori K, Tomoda H, Omura S (2007) Chem Pharm Bull 55:1338–1341CrossRefGoogle Scholar
  103. 103.
    Fukami H (1991) Patent JP3118376-AGoogle Scholar
  104. 104.
    Fujimoto Y, Miyagawa H, Tsurushima T, Irie H, Okamura K, Ueno T (1993) Biosci Biotechnol Biochem 57:1222–1224CrossRefGoogle Scholar
  105. 105.
    Sakurai M, Kohno J, Yamamoto K, Okuda T, Nishio M, Kawano K, Ohnuki T (2002) J Antibiot 55:685–692Google Scholar
  106. 106.
    Gorst-Allman CP, Steyn PS, Rabie CJ (1980) J Chem Soc Perkin Trans I 2474-2479Google Scholar
  107. 107.
    Rabache M, Neumann J, Lavollay J (1974) Phytochemistry 1974:637–642CrossRefGoogle Scholar
  108. 108.
    Tanaka H, Wang P-L, Yamada O, Tamura H (1966) Agric Biol Chem 30:107–113Google Scholar
  109. 109.
    Wang PL, Tanaka H (1966) Agric Biol Chem 30:683–687Google Scholar
  110. 110.
    Galmarini OL, Stodola FH (1965) J Org Chem 30:112–115CrossRefGoogle Scholar
  111. 111.
    Zhang Y, Li XM, Wang BG (2007) J Antibiot 60:204–210CrossRefGoogle Scholar
  112. 112.
    Ehrlich KC, DeLucca AJ, Ciegler A (1984) Appl Environ Microbiol 48:1–4Google Scholar
  113. 113.
    Guang-yi L, Lenz J, Franck B (1989) Heterocycles 28:899–904CrossRefGoogle Scholar
  114. 114.
    Alfatafta AA, Dowd PF, Gloer JB, Wicklow DT (1996) US Patent 5(519):052Google Scholar
  115. 115.
    Ui H et al (2001) J Antibiot 54:234–238Google Scholar
  116. 116.
    Tepaske MR, Gloer JB, Wicklow DT, Dowd PF (1989) J Org Chem 54:4743–4746CrossRefGoogle Scholar
  117. 117.
    Tepaske MR, Gloer JB, Wicklow DT, Dowd PF (1989) Tetrahedron Lett 30:5965–5968CrossRefGoogle Scholar
  118. 118.
    Varga J, Kevei F, Hamari Z, Toth B, Teren J, Croft JH, Kozakiewicz Z (2000) In: Samson R, Pitt JI (eds) Integration of modern taxonomic methods from Penicillium and Aspergillus classification. Harwood, Amsterdam, pp 397–411Google Scholar
  119. 119.
    Sings HL, Harris GH, Dombrowski AW (2001) J Nat Prod 64:836–838CrossRefGoogle Scholar
  120. 120.
    Tepaske MR, Gloer JB, Wicklow DT, Dowd PF (1989) Tetrahedron 45:4961–4968CrossRefGoogle Scholar
  121. 121.
    Kodukula K, Arcuri M, Cutrone JQ, Hugill RM, Lowe SE, Pirnik DM, Shu Y-Z (1995) J Antibiot 48:1055–1059Google Scholar
  122. 122.
    Tepaske MR, Gloer JB, Wicklow DT, Dowd PF (1991) Tetrahedron Lett 32:5687–5690CrossRefGoogle Scholar
  123. 123.
    Kobbe B, Cushman M, Wogan GN, Demain AL (1977) Appl Environ Microbiol 33:996–997Google Scholar
  124. 124.
    Akiyama K, Teraguchi S, Hamasaki Y, Mori M, Tatsumi K, Ohnishi K, Hayashi H (2003) J Nat Prod 66:136–139CrossRefGoogle Scholar
  125. 125.
    Ikeda S, Sugita M, Yoshimura A, Sumizawa T, Douzono H, Nagata Y, Akiyama S (1990) Int J Cancer 45:508–513CrossRefGoogle Scholar
  126. 126.
    Priestap HA (1984) Tetrahedron 40:3617–3624CrossRefGoogle Scholar
  127. 127.
    Umezawa H, Tobe H, Shibamoto N, Nakamura F, Nakamura K, Matsuzaki M, Takeuchi T (1975) J Antibiot 28:947–952Google Scholar
  128. 128.
    Tobe H, Naganawa H, Takita T, Takeuchi T, Umezawa H (1976) J Antibiot 29:623–625Google Scholar
  129. 129.
    Savard ME, Miller JD, Blais LA, Seifert KA, Samson RA (1994) Mycopathologia 127:19–27CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Kristian Fog Nielsen
    • 1
  • Jesper Mølgaard Mogensen
    • 1
  • Maria Johansen
    • 1
  • Thomas O. Larsen
    • 1
  • Jens Christian Frisvad
    • 1
  1. 1.Center for Microbial Biotechnology, Department of Systems BiologyTechnical University of DenmarkLyngbyDenmark

Personalised recommendations