Fungal NRPS-Dependent Siderophores: From Function to Prediction

  • Jens Laurids Sørensen
  • Michael Knudsen
  • Frederik Teilfeldt Hansen
  • Claus Olesen
  • Patricia Romans Fuertes
  • T. Verne Lee
  • Teis Esben Sondergaard
  • Christian Nørgaard Storm Pedersen
  • Ditlev Egeskov Brodersen
  • Henriette GieseEmail author
Part of the Fungal Biology book series (FUNGBIO)


Iron is an essential, yet often limiting element for the growth of many organisms. In response to iron limitation, fungi have developed siderophores that provide a high-affinity iron uptake system and safe intracellular storage and transport mechanisms to gain a competitive advantage. Here, we discuss the function of siderophores in relation to fungal iron uptake mechanisms and their importance for coexistence with host organisms. The chemical nature of the major groups of siderophores and their regulation is described along with the function and architecture of the large multi-domain enzymes responsible for siderophore synthesis, namely the non-ribosomal peptide synthetases (NRPSs). Finally, we present the most recent advances in our understanding of the structural biology of fungal NRPSs and discuss opportunities for the development of a fungal NRPS prediction server.


NRPS Gene Adenylation Domain Siderophore Biosynthesis Microbial Siderophores NRPS Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Halliwell B, Gutteridge JMC. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J. 1984;219:1–14.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Lindsay WL, Schwab AP. The chemistry of iron in soils and its availability to plants. J Plant Nutr. 1982;5:821–40.CrossRefGoogle Scholar
  3. 3.
    Miethke M. Molecular strategies of microbial iron assimilation: from high-affinity complexes to cofactor assembly systems. Metallomics. 2013;5:15–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Haas H, Eisendle M, Turgeon BG. Siderophores in fungal physiology and virulence. Annu Rev Phytopathol. 2008;46:149–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Grissa I, Bidard F, Grognet P, Grossetete S, Silar P. The Nox/Ferric reductase/Ferric reductase-like families of Eumycetes. Fungal Biol. 2010;114:766–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Blatzer M, Schrettl M, Sarg B, Lindner HH, Pfaller K, Haas H. SidL, an Aspergillus fumigatus transacetylase involved in biosynthesis of the siderophores ferricrocin and hydroxyferricrocin. Appl Environ Microbiol. 2011;77:4959–66.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kosman DJ. Redox cycling in iron uptake, efflux, and trafficking. J Biol Chem. 2010;285: 26729–35.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Kosman DJ. Iron metabolism in aerobes: managing ferric iron hydrolysis and ferrous iron autoxidation. Coord Chem Rev. 2013;257:210–7.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN, et al. Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigates virulence. J Exp Med. 2004;200:1213–9.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Eichhorn H, Lessing F, Winterberg B, Schirawski J, Kaemper J, Mueller P, Kahmann R. A ferroxidation/permeation iron uptake system is required for virulence in Ustilago maydis. Plant Cell. 2006;18:3332–45.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Park Y-S, Kim J-H, Cho J-H, Chang H-I, Kim S-W, Paik H-D, et al. Physical and functional interaction of FgFtr1-FgFet1 and FgFtr2-FgFet2 is required for iron uptake in Fusarium graminearum. Biochem J. 2007;408:97–104.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Jung WH, Hu G, Kuo W, Kronstad JW. Role of ferroxidases in iron uptake and virulence of Cryptococcus neoformans. Eukaryot Cell. 2009;8:1511–20.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Kobayashi T, Nishizawa NK. Iron uptake, translocation, and regulation in higher plants. Annu Rev Plant Biol. 2012;63:131–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Saha R, Saha N, Donofrio RS, Bestervelt LL. Microbial siderophores: a mini review. J Basic Microbiol. 2013;53:303–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Van Ho A, Ward DM, Kaplan J. Transition metal transport in yeast. Annu Rev Microbiol. 2002;56:237–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Canessa P, Larrondo LF. Environmental responses and the control of iron homeostasis in fungal systems. Appl Microbiol Biotechnol. 2013;97:939–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Wallner A, Blatzer M, Schrettl M, Sarg B, Lindner H, Haas H. Ferricrocin, a siderophore involved in intra- and transcellular iron distribution in Aspergillus fumigatus. Appl Environ Microbiol. 2009;75:4194–6.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Ardon O, Nudelman R, Caris C, Libman J, Shanzer A, Chen YN, Hadar Y. Iron uptake in Ustilago maydis: tracking the iron path. J Bacteriol. 1998;180:2021–6.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Kragl C, Schrettl M, Abt B, Sarg B, Lindner HH, Haas H. EstB-mediated hydrolysis of the siderophore triacetylfusarinine C optimizes iron uptake of Aspergillus fumigatus. Eukaryot Cell. 2007;6:1278–85.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Gsaller F, Eisendle M, Lechner BE, Schrettl M, Lindner H, Mueller D, et al. The interplay between vacuolar and siderophore-mediated iron storage in Aspergillus fumigatus. Metallomics. 2012;4:1262–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Eisendle M, Schrettl M, Kragl C, Mueller D, Illmer P, Haas H. The intracellular siderophore ferricrocin is involved in iron storage, oxidative-stress resistance, germination, and sexual development in Aspergillus nidulans. Eukaryot Cell. 2006;5:1596–603.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Oide S, Krasnoff SB, Gibson DM, Turgeon BG. Intracellular siderophores are essential for ascomycete sexual development in heterothallic Cochliobolus heterostrophus and homothallic Gibberella zeae. Eukaryot Cell. 2007;6:1339–53.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hof C, Eisfeld K, Antelo L, Foster AJ, Anke H. Siderophore synthesis in Magnaporthe grisea is essential for vegetative growth, conidiation and resistance to oxidative stress. Fungal Genet Biol. 2009;46:321–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, Eisendle M, et al. Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog. 2007;3:1195–207.PubMedCrossRefGoogle Scholar
  25. 25.
    Matzanke BF, Bill E, Trautwein AX, Winkelmann G. Role of siderophores in iron storage in spores of Neurospora crassa and Aspergillus ochraceus. J Bacteriol. 1987;169:5873–6.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Johnson LJ, Koulman A, Christensen M, Lane GA, Fraser K, Forester N, et al. An extracellular siderophore is required to maintain the mutualistic interaction of Epichloë festucae with Lolium perenne. PLoS Pathog. 2013;9:e1003332.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Kieu NP, Aznar A, Segond D, Rigault M, Simond-Cote E, Kunz C, et al. Iron deficiency affects plant defence responses and confers resistance to Dickeya dadantii and Botrytis cinerea. Mol Plant Pathol. 2012;13:816–27.PubMedCrossRefGoogle Scholar
  28. 28.
    Chen LH, Lin CH, Chung KR. A nonribosomal peptide synthetase mediates siderophore production and virulence in the citrus fungal pathogen Alternaria alternata. Mol Plant Pathol. 2013;14:497–505.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee BN, Kroken S, Chou DYT, Robbertse B, Yoder OC, Turgeon BG. Functional analysis of all nonribosomal peptide synthetases in Cochliobolus heterostrophus reveals a factor, NPS6, involved in virulence and resistance to oxidative stress. Eukaryot Cell. 2005;4:545–55.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Leong SA, Winkelmann G. Molecular biology of iron transport in fungi. Met Ions Biol Syst. 1998;35(35):147–86.PubMedGoogle Scholar
  31. 31.
    Schrettl M, Haas H. Iron homeostasis-Achilles’ heel of Aspergillus fumigatus? Curr Opin Microbiol. 2011;14:400–5.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Correnti C, Strong RK. Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J Biol Chem. 2012;287:13524–31.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Clifton MC, Corrent C, Strong RK. Siderocalins: siderophore-binding proteins of the innate immune system. Biometals. 2009;22:557–64.PubMedCrossRefGoogle Scholar
  34. 34.
    Bao G, Clifton M, Hoette TM, Mori K, Deng S-X, Qiu A, et al. Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol. 2010;6:602–9.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Correnti C, Richardson V, Sia AK, Bandaranayake AD, Ruiz M, Rahmanto YS, et al. Siderocalin/Lcn2/NGAL/24p3 does not drive apoptosis through gentisic acid mediated iron withdrawal in hematopoietic cell lines. PLoS One. 2012;7(8):e43696.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Cherayil BJ. The role of iron in the immune response to bacterial infection. Immunol Res. 2011;50:1–9.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Haas H. Iron—a key nexus in the virulence of Aspergillus fumigatus. Front Microbiol. 2012;3:28.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Linde J, Hortschansky P, Fazius E, Brakhage AA, Guthke R, Haas H. Regulatory interactions for iron homeostasis in Aspergillus fumigatus inferred by a systems biology approach. BMC Syst Biol. 2012;6:6.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Haas H, Angermayr K, Stoffler G. Molecular analysis of a Penicillium chrysogenum GATA factor encoding gene (sreP) exhibiting significant homology to the Ustilago maydis urbs1 gene. Gene. 1997;184:33–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Hortschansky P, Eisendle M, Al-Abdallah Q, Schmidt AD, Bergmann S, Thoen M, et al. Interaction of HapX with the CCAAT-binding complex—a novel mechanism of gene regulation by iron. EMBO J. 2007;26:3157–68.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Voisard C, Wang J, McEvoy JL, Xu PL, Leong SA. urbs1, a gene regulating siderophore biosynthesis in Ustilago maydis, encodes a protein similar to the erythroid transcription factor GATA-1. Mol Cell Biol. 1993;13:7091–100.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Haas H, Zadra I, Stoffler G, Angermayr K. The Aspergillus nidulans GATA factor SREA is involved in regulation of siderophore biosynthesis and control of iron uptake. J Biol Chem. 1999;274:4613–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Schrettl M, Kim HS, Eisendle M, Kragl C, Nierman WC, Heinekamp T, et al. SreA-mediated iron regulation in Aspergillus fumigatus. Mol Microbiol. 2008;70:27–43.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Zhou LW, Haas H, Marzluf GA. Isolation and characterization of a new gene, sre, which encodes a GATA-type regulatory protein that controls iron transport in Neurospora crassa. Mol Gen Genet. 1998;259:532–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Lan CY, Rodarte G, Murillo LA, Jones T, Davis RW, Dungan J, et al. Regulatory networks affected by iron availability in Candida albicans. Mol Microbiol. 2004;53:1451–69.PubMedCrossRefGoogle Scholar
  46. 46.
    Gauthier GM, Sullivan TD, Gallardo SS, Brandhorst TT, Vanden Wymelenberg AJ, Cuomo CA, et al. SREB, a GATA transcription factor that directs disparate fates in blastomyces dermatitidis including morphogenesis and siderophore biosynthesis. PLoS Pathog. 2010;6(4):e1000846.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Pelletier B, Beaudoin J, Mukai Y, Labbe S. Fep1, an iron sensor regulating iron transporter gene expression in Schizosaccharomyces pombe. J Biol Chem. 2002;277:22950–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Lopez-Berges MS, Capilla J, Turra D, Schafferer L, Matthijs S, Joechl C, et al. HapX-mediated iron homeostasis is essential for rhizosphere competence and virulence of the soilborne pathogen Fusarium oxysporum. Plant Cell. 2012;24:3805–22.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Tanaka A, Kato M, Nagase T, Kobayashi T, Tsukagoshi N. Isolation of genes encoding novel transcription factors which interact with the Hap complex from Aspergillus species. Biochim Biophys Acta. 2002;1576:176–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Forsburg SL, Guarente L. Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer. Genes Dev. 1989;3:1166–78.PubMedCrossRefGoogle Scholar
  51. 51.
    Knight SAB, Lesuisse E, Stearman R, Klausner RD, Dancis A. Reductive iron uptake by Candida albicans: role of copper, iron and the TUP1 regulator. Microbiology. 2002;148: 29–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Znaidi S, Pelletier B, Mukai Y, Labbe S. The Schizosaccharomyces pombe corepressor Tup11 interacts with the iron-responsive transcription factor Fep1. J Biol Chem. 2004;279:9462–74.PubMedCrossRefGoogle Scholar
  53. 53.
    Hsu PC, Yang CY, Lan CY. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell. 2011;10:207–25.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Liu H, Gravelat FN, Chiang LY, Chen D, Vanier G, Ejzykowicz DE, et al. Aspergillus fumigatus AcuM regulates both iron acquisition and gluconeogenesis. Mol Microbiol. 2010;78: 1038–54.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Boukhalfa H, Crumbliss AL. Chemical aspects of siderophore mediated iron transport. Biometals. 2002;15:325–39.PubMedCrossRefGoogle Scholar
  56. 56.
    Oves-Costales D, Kadi N, Challis GL. The long-overlooked enzymology of a nonribosomal peptide synthetase-independent pathway for virulence-conferring siderophore biosynthesis. Chem Commun (Camb). 2009;43:6530–41.CrossRefGoogle Scholar
  57. 57.
    Haas H. Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage. Appl Microbiol Biotechnol. 2003;62:316–30.PubMedCrossRefGoogle Scholar
  58. 58.
    Winkelmann G. Structures and functions of fungal siderophores containing hydroxamate and complex one type iron binding ligands. Mycol Res. 1992;96:529–34.CrossRefGoogle Scholar
  59. 59.
    Renshaw JC, Robson GD, Trinci APJ, Wiebe MG, Livens FR, Collison D, Taylor RJ. Fungal siderophores: structures, functions and applications. Mycol Res. 2002;106:1123–42.CrossRefGoogle Scholar
  60. 60.
    Engwilmot DL, Rahman A, Mendenhall JV, Grayson SL, Vanderhelm D. Molecular structure of ferric neurosporin, a minor siderophore-like compound containing J Am Chem Soc. 1984;106:1285–90.CrossRefGoogle Scholar
  61. 61.
    Neilands JB. A crystalline organo-iron pigment from a rust fungus (Ustilago sphaerogena). J Am Chem Soc. 1952;74:4846–7.CrossRefGoogle Scholar
  62. 62.
    Kim J-H, Kim H-W, Heo D-H, Chang M, Baek I-J, Yun C-W. FgEnd1 is a putative component of the endocytic machinery and mediates ferrichrome uptake in F. graminearum. Curr Genet. 2009;55:593–600.PubMedCrossRefGoogle Scholar
  63. 63.
    Bushley KE, Ripoll DR, Turgeon BG. Module evolution and substrate specificity of fungal nonribosomal peptide synthetases involved in siderophore biosynthesis. BMC Evol Biol. 2008;8:328.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Hansen FT, Sørensen JL, Giese H, Sondergaard TE, Frandsen RJ. Quick guide to polyketide synthase and nonribosomal synthetase genes in Fusarium. Int J Food Microbiol. 2012;155: 128–36.PubMedCrossRefGoogle Scholar
  65. 65.
    Lehner SM, Atanasova L, Neumann NKN, Krska R, Lemmens M, Druzhinina IS, Schuhmacher R. Isotope-assisted screening for iron-containing metabolites reveals a high degree of diversity among known and unknown siderophores produced by Trichoderma spp. Appl Environ Microbiol. 2013;79:18–31.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Diekmann H. Metabolic products of microorganisms. 81. Occurrence and structures of coprogen B and dimerum acid. Arch Mikrobiol. 1970;73:65–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Atkin CL, Neilands JB. Rhodotorulic acid, a diketopiperazine dihydroxamic acid with growth-factor activity. I. Isolation and characterization. Biochemistry. 1968;7:3734–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Antelo L, Hof C, Welzel K, Eisfeld K, Sterner O, Anke H. Siderophores produced by Magnaporthe grisea in the presence and absence of iron. Z Naturforsch C. 2006;61:461–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Jalal MA, Love SK, van der Helm D. N alpha-dimethylcoprogens. Three novel trihydroxamate siderophores from pathogenic fungi. Biol Met. 1988;1:4–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Winkelmann G, Zahner H. Metabolic products of microorganisms. 115. Uptake of iron by Neurospora crassa. 1. To the specificity of iron transport. Arch Mikrobiol. 1973;88:49–60.PubMedCrossRefGoogle Scholar
  71. 71.
    Ernst JF, Winkelmann G. Enzymatic release of iron from sideramines in fungi NADH:sideramine oxidoreductase in Neurospora crassa. Biochim Biophys Acta. 1977;500:27–41.PubMedCrossRefGoogle Scholar
  72. 72.
    Drechsel H, Metzger J, Freund S, Jung G, Boelaert JR, Winkelmann G. Rhizoferrin: a novel siderophore from the fungus Rhizopus microsporus var. rhizopodiformis. Biol Met. 1991;4:238–43.CrossRefGoogle Scholar
  73. 73.
    Thieken A, Winkelmann G. Rhizoferrin: a complex one type siderophore of the mocorales and entomophthorales (Zygomycetes). FEMS Microbiol Lett. 1992;94:37–42.CrossRefGoogle Scholar
  74. 74.
    Konetschnyrapp S, Jung G, Meiwes J, Zahner H. Staphyloferrin A: a structurally new siderophore from staphylococci. Eur J Biochem. 1990;191:65–74.CrossRefGoogle Scholar
  75. 75.
    Meiwes J, Fiedler HP, Haag H, Zahner H, Konetschnyrapp S, Jung G. Isolation and characterization of staphyloferrin A, a compound with siderophore activity from Staphylococcus hyicus DSM 20459. FEMS Microbiol Lett. 1990;67:201–5.CrossRefGoogle Scholar
  76. 76.
    Cotton JL, Tao J, Balibar CJ. Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry. 2009;48:1025–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Challis GL. A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases. Chembiochem. 2005;6:601–11.PubMedCrossRefGoogle Scholar
  78. 78.
    Yin W-B, Baccile JA, Bok JW, Chen Y, Keller NP, Schroeder FC. A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J Am Chem Soc. 2013;135:2064–7.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Arai K, Sato S, Shimizu S, Nitta K, Yamamoto Y. Metabolic products of Aspergillus terreus: 7. Astechrome, an iron-containing metabolite of the strain IFO 6123. Chem Pharm Bull. 1981;29:1510–7.CrossRefGoogle Scholar
  80. 80.
    van Berkel WJH, Kamerbeek NM, Fraaije MW. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J Biotechnol. 2006;124:670–89.PubMedCrossRefGoogle Scholar
  81. 81.
    Mei BG, Budde AD, Leong SA. sid1, a gene initiating siderophore biosynthesis in Ustilago maydis: molecular characterization, regulation by iron, and role in phytopathogenicity. Proc Natl Acad Sci U S A. 1993;90:903–7.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Eisendle M, Oberegger H, Zadra I, Haas H. The siderophore system is essential for viability of Aspergillus nidulans: functional analysis of two genes encoding L-ornithine N-5-monooxygenase (sidA) and a non-ribosomal peptide synthetase (sidC). Mol Microbiol. 2003;49:359–75.PubMedCrossRefGoogle Scholar
  83. 83.
    Yamada O, Nan SN, Akao T, Tominaga M, Watanabe H, Satoh T, et al. dffA gene from Aspergillus oryzae encodes L-ornithine N-5-oxygenase and is indispensable for deferriferrichrysin biosynthesis. J Biosci Bioeng. 2003;95:82–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Greenshields DL, Liu GS, Feng J, Selvaraj G, Wei YD. The siderophore biosynthetic gene SID1, but not the ferroxidase gene FET3, is required for full Fusarium graminearum virulence. Mol Plant Pathol. 2007;8:411–21.PubMedCrossRefGoogle Scholar
  85. 85.
    Turgeon BG, Oide S, Bushley K. Creating and screening Cochliobolus heterostrophus non-ribosomal peptide synthetase mutants. Mycol Res. 2008;112:200–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Winterberg B, Uhlmann S, Linne U, Lessing F, Marahiel MA, Eichhorn H, et al. Elucidation of the complete ferrichrome A biosynthetic pathway in Ustilago maydis. Mol Microbiol. 2010;75:1260–71.PubMedCrossRefGoogle Scholar
  87. 87.
    Welzel K, Eisfeld K, Antelo L, Anke T, Anke H. Characterization of the ferrichrome A biosynthetic gene cluster in the homobasidiomycete Omphalotus olearius. FEMS Microbiol Lett. 2005;249:157–63.PubMedCrossRefGoogle Scholar
  88. 88.
    Yasmin S, Alcazar-Fuoli L, Gruendlinger M, Puempel T, Cairns T, Blatzer M, et al. Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A. 2012;109:E497–504.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Munawar A, Marshall JW, Cox RJ, Bailey AM, Lazarus CM. Isolation and characterisation of a ferrirhodin synthetase gene from the sugarcane pathogen Fusarium sacchari. Chembiochem. 2013;14:388–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Heymann P, Gerads M, Schaller M, Dromer F, Winkelmann G, Ernst JF. The siderophore iron transporter of Candida albicans (Sit1p/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion. Infect Immun. 2002;70:5246–55.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Lesuisse E, Simon-Casteras M, Labbe P. Siderophore-mediated iron uptake in Saccharomyces cerevisiae: the SIT1 gene encodes a ferrioxamine B permease that belongs to the major facilitator superfamily. Microbiology. 1998;144:3455–62.PubMedCrossRefGoogle Scholar
  92. 92.
    Yun CW, Tiedeman JS, Moore RE, Philpott CC. Siderophore-iron uptake in Saccharomyces cerevisiae - Identification of ferrichrome and fusarinine transporters. J Biol Chem. 2000;275: 16354–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Raymond-Bouchard I, Carroll CS, Nesbitt JR, Henry KA, Pinto LJ, Moinzadeh M, et al. Structural requirements for the activity of the MirB Ferrisiderophore transporter of Aspergillus fumigatus. Eukaryot Cell. 2012;11:1333–44.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Tobiasen C, Aahman J, Ravnholt KS, Bjerrum MJ, Grell MN, Giese H. Nonribosomal peptide synthetase (NPS) genes in Fusarium graminearum, F. culmorum and F. pseudograminearium and identification of NPS2 as the producer of ferricrocin. Curr Genet. 2007;51:43–58.PubMedCrossRefGoogle Scholar
  95. 95.
    Anke H, Kinn J, Bergquist KE, Sterner O. Production of siderophores by strains of the genus Trichoderma. Isolation and characterization of the new lipophilic coprogen derivative, palmitoylcoprogen. Biol Met. 1991;4:176–80.CrossRefGoogle Scholar
  96. 96.
    Oide S, Moeder W, Krasnoff S, Gibson D, Haas H, Yoshioka K, Turgeon BG. NPS6, encoding a nonribosomal peptide synthetase involved in siderophore-mediated iron metabolism, is a conserved virulence determinant of plant pathogenic ascomycetes. Plant Cell. 2006;18:2836–53.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Reiber K, Reeves EP, Neville CM, Winkler R, Gebhardt P, Kavanagh K, Doyle S. The expression of selected non-ribosomal peptide synthetases in Aspergillus fumigatus is controlled by the availability of free iron. FEMS Microbiol Lett. 2005;248:83–91.PubMedCrossRefGoogle Scholar
  98. 98.
    Varga J, Kocsube S, Toth B, Mesterhazy A. Nonribosomal peptide synthetase genes in the genome of Fusarium graminearum, causative agent of wheat head blight. Acta Biol Hung. 2005;56:375–88.PubMedCrossRefGoogle Scholar
  99. 99.
    Strieker M, Tanovic A, Marahiel MA. Nonribosomal peptide synthetases: structures and dynamics. Curr Opin Struct Biol. 2010;20:234–40.PubMedCrossRefGoogle Scholar
  100. 100.
    Finking R, Marahiel MA. Biosynthesis of nonribosomal peptides. Annu Rev Microbiol. 2004;58:453–88.PubMedCrossRefGoogle Scholar
  101. 101.
    Schwecke T, Gottling K, Durek P, Duenas I, Kaufer NF, Zock-Emmenthal S, et al. Nonribosomal peptide synthesis in Schizosaccharomyces pombe and the architectures of ferrichrome-type siderophore synthetases in fungi. Chembiochem. 2006;7:612–22.PubMedCrossRefGoogle Scholar
  102. 102.
    Johnson L. Iron and siderophores in fungal-host interactions. Mycol Res. 2008;112:170–83.PubMedCrossRefGoogle Scholar
  103. 103.
    Bushley KE, Turgeon BG. Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships. BMC Evol Biol. 2010;10:26.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Franceschini S, Fedkenheuer M, Vogelaar NJ, Robinson HH, Sobrado P, Mattevi A. Structural insight into the mechanism of oxygen activation and substrate selectivity of flavin-dependent N-hydroxylating monooxygenases. Biochemistry. 2012;51:7043–5.PubMedCrossRefGoogle Scholar
  105. 105.
    Lee TV, Johnson LJ, Johnson RD, Koulman A, Lane GA, Lott JS, Arcus VL. Structure of a eukaryotic nonribosomal peptide synthetase adenylation domain that activates a large hydroxamate amino acid in siderophore biosynthesis. J Biol Chem. 2010;285:2415–27.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Olucha J, Meneely KM, Chilton AS, Lamb AL. Two structures of an N-hydroxylating flavoprotein monooxygenase: ornithine hydroxylase from Pseudomonas aeruginosa. J Biol Chem. 2011;286:31789–98.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Chocklett SW, Sobrado P. Aspergillus fumigatus SidA is a highly specific ornithine hydroxylase with bound flavin cofactor. Biochemistry. 2010;49:6777–83.PubMedCrossRefGoogle Scholar
  108. 108.
    Mayfield JA, Frederick RE, Streit BR, Wencewicz TA, Ballou DP, DuBois JL. Comprehensive spectroscopic, steady state, and transient kinetic studies of a representative siderophore-associated flavin monooxygenase. J Biol Chem. 2010;285:30375–88.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Romero E, Fedkenheuer M, Chocklett SW, Qi J, Oppenheimer M, Sobrado P. Dual role of NADP(H) in the reaction of a flavin dependent N-hydroxylating monooxygenase. Biochim Biophys Acta. 2012;1824:850–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Koulman A, Lee TV, Fraser K, Johnson L, Arcus V, Lott JS, et al. Identification of extracellular siderophores and a related peptide from the endophytic fungus Epichlöe festucae in culture and endophyte-infected Lolium perenne. Phytochemistry. 2012;75:128–39.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Conti E, Stachelhaus T, Marahiel MA, Brick P. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J. 1997;16:4174–83.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    May JJ, Kessler N, Marahiel MA, Stubbs MT. Crystal structure of DhbE, an archetype for aryl acid activating domains of modular nonribosomal peptide synthetases. Proc Natl Acad Sci U S A. 2002;99:12120–5.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Tanovic A, Samel SA, Essen LO, Marahiel MA. Crystal structure of the termination module of a nonribosomal peptide synthetase. Science. 2008;321:659–63.PubMedCrossRefGoogle Scholar
  114. 114.
    Gulick AM. Conformational dynamics in the acyl-CoA synthetases, adenylation domains of non-ribosomal peptide synthetases, and firefly luciferase. ACS Chem Biol. 2009;4:811–27.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Challis GL, Ravel J. Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett. 2000;187:111–4.PubMedCrossRefGoogle Scholar
  116. 116.
    Prieto C, Garcia-Estrada C, Lorenzana D, Martin JF. NRPSsp: non-ribosomal peptide synthase substrate predictor. Bioinformatics. 2012;28:426–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Rausch C, Weber T, Kohlbacher O, Wohlleben W, Huson DH. Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs). Nucleic Acids Res. 2005;33:5799–808.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Röttig M, Medema MH, Blin K, Weber T, Rausch C, Kohlbacher O. NRPSpredictor2-a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res. 2011;39: W362–7.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Stachelhaus T, Mootz HD, Marahiel MA. The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem Biol. 1999;6:493–505.PubMedCrossRefGoogle Scholar
  120. 120.
    Ansari MZ, Yadav G, Gokhale RS, Mohanty D. NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases. Nucleic Acids Res. 2004;32:W405–13.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.PubMedCrossRefGoogle Scholar
  122. 122.
    Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R, Takano E, Weber T. antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res. 2013;41:W204–12.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol. 2010;47:736–41.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Rabiner LR. A tutorial on hidden Markov models and selected applications in speech recognition. Proc IEEE. 1989;77:257–86.CrossRefGoogle Scholar
  125. 125.
    Cortes C, Vapnik V. Support-vector networks. Mach Learn. 1995;20:273–97.Google Scholar
  126. 126.
    Eddy SR. Profile hidden Markov models. Bioinformatics. 1998;14:755–63.PubMedCrossRefGoogle Scholar
  127. 127.
    Khayatt BI, Overmars L, Siezen RJ, Francke C. Classification of the adenylation and acyl-transferase activity of NRPS and PKS systems using ensembles of substrate specific hidden Markov models. PLoS One. 2013;8(4):e62136.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Mootz HD, Schwarzer D, Marahiel MA. Ways of assembling complex natural products on modular nonribosomal peptide synthetases. Chembiochem. 2002;3:490–504.PubMedCrossRefGoogle Scholar
  129. 129.
    Caboche S, Pupin M, Leclere V, Fontaine A, Jacques P, Kucherov G. NORINE: a database of nonribosomal peptides. Nucleic Acids Res. 2008;36:D326–31.PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Doekel S, Marahiel MA. Dipeptide formation on engineered hybrid peptide synthetases. Chem Biol. 2000;7:373–84.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jens Laurids Sørensen
    • 1
  • Michael Knudsen
    • 2
  • Frederik Teilfeldt Hansen
    • 3
  • Claus Olesen
    • 3
  • Patricia Romans Fuertes
    • 1
  • T. Verne Lee
    • 4
  • Teis Esben Sondergaard
    • 1
  • Christian Nørgaard Storm Pedersen
    • 2
  • Ditlev Egeskov Brodersen
    • 3
  • Henriette Giese
    • 1
    Email author
  1. 1.Department of Biotechnology, Chemistry and Environmental EngineeringAalborg UniversityAalborgDenmark
  2. 2.Bioinformatics Research CenterAarhus UniversityAarhusDenmark
  3. 3.Department of Molecular Biology and GeneticsAarhus UniversityAarhusDenmark
  4. 4.AgResearch Structural Biology LaboratorySchool of Biological Sciences, University of AucklandAucklandNew Zealand

Personalised recommendations