Molecular Genetics of Iron Uptake and Homeostasis in Fungi

Part of the The Mycota book series (MYCOTA, volume 3)


Most prokaryotes and all eukaryotes require iron for their growth. This transition metal has two readily available ionization states, ferrous and ferric iron, and thus is involved in a great variety of enzymatic processes including electron transfer in respiration, redox reactions carried out by numerous oxygenases and hydrogenases, and DNA-synthesis. While iron is one of the most abundant metals on earth, in aerobic environments it is present mostly in very insoluble compounds such as oxyhydroxide polymers. Consequently, the concentration of ferric iron in solution at neutral pH is probably not greater than 10-18M (Neilands 1995). On the other hand, an excess of iron within cells can be deleterious, because of the potential to catalyze the generation of cell damaging reactive oxygen species. Therefore, microbes have developed various highly regulated systems for iron uptake and storage.


Iron Uptake Iron Transport Multicopper Oxidase Ferric Reductase Iron Starvation 
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.


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  1. Abbas A, Labbe-Bois R (1993) Structure-function studies of yeast ferrochelatase. Identification and functional analysis of amino acid substitutions that increase Vmax and the KM for both substrates. J Biol Chem 268:8541–8546PubMedGoogle Scholar
  2. Adjimani JP, Emery T (1987) Iron uptake in Mycelia sterilia EP-76. J Bacteriol 169:3664–3668PubMedGoogle Scholar
  3. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM (1999) Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8:743–749PubMedCrossRefGoogle Scholar
  4. Amulet JM, Galiazzo F, Labbe-Bois R (1996) Effect of heme and vacuole deficiency on FREI gene expression and ferrireductase activity in Saccharomyces cerevisiae. FEMS Microbiol Lett 137:25–29CrossRefGoogle Scholar
  5. An Z, Mei B, Yuan WM, Leong SA (1997a) The distal GATA sequences of the sidl promoter of Ustilago maydis mediate iron repression of siderophore production and interact directly with Urbs1, a GATA family transcription factor. EMBO J 16:1742–1750PubMedCrossRefGoogle Scholar
  6. An Z, Zhao Q, McEvoy J, Yuan WM, Markley JL, Leong SA (1997b) The second finger of Urbsl is required for iron-mediated repression of sidl in Ustilago maydis. Proc Natl Acad Sci USA 94:5882–5887PubMedCrossRefGoogle Scholar
  7. Anderson GJ, Dancis A, Roman DG, Klausner RD (1994) Ferric iron reduction and iron uptake in eucaryotes: studies with the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. Adv Exp Med Biol 356: 81–89PubMedCrossRefGoogle Scholar
  8. Ardon O, Nudelman R, Caris C, Libman J, Shanzer A, Chen Y, Hadar Y (1998) Iron uptake in Ustilago maydis: tracking the iron path. J Bacteriol 180:2021–2026PubMedGoogle Scholar
  9. Ardon O, Bussey H, Philpott C, Ward DM, Davis-Kaplan S, Verroneau S, Jiang B, Kaplan J (2001) Identification of a Candida albicans ferrichrome transporter and its characterization by expression in Saccharomyces cerevisiae. J Biol Chem 276:43049–43055PubMedCrossRefGoogle Scholar
  10. Askwith C, Kaplan J (1997) An oxidase-permease-based iron transport system in Schizosaccharomyces pombe and its expression in Saccharomyces cerevisiae. J Biol Chem 272:401–405PubMedCrossRefGoogle Scholar
  11. Askwith C, Kaplan J (1998) Iron and copper transport in yeast and its relevance to human disease. Trends Biochem Sci 23:135–138PubMedCrossRefGoogle Scholar
  12. Askwith C, Eide D, van Ho A, Bernard PS, Li L, Davis-Kaplan S, Sipe DM, Kaplan J (1994) The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76:403–410PubMedCrossRefGoogle Scholar
  13. Askwith CC, de Silva D, Kaplan J (1996) Molecular biology of iron acquisition in Saccharomyces cerevisiae. Mol Microbiol 20:27–34PubMedCrossRefGoogle Scholar
  14. Blaiseau PL, Lesuisse E, Camadro JM (2001) Aft2p, a novel iron-regulated transcription activator that modulates, with Aft1p, intracellular iron use and resistance to oxidative stress in yeast. J Biol Chem 276:34221–34226PubMedCrossRefGoogle Scholar
  15. Bode HP, Dumschat M, Garotti S, Fuhrmann GF (1995) Iron sequestration by the yeast vacuole. A study with vacuolar mutants of Saccharomyces cerevisiae. Eur J Biochem 228:337–342PubMedCrossRefGoogle Scholar
  16. Braun BR, Head WS, Wang MX, Johnson AD (2000) Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 156:31–44PubMedGoogle Scholar
  17. Brickman TJ, McIntosh MA (1992) Overexpression and purification of ferric enterobactin esterase from Escherichia coli. Demonstration of enzymatic hydrolysis of enterobactin and its iron complex. J Biol Chem 267:12350–12355PubMedGoogle Scholar
  18. Burt WR (1982) Identification of coprogen B and its breakdown products from Histoplasma capsulatum. Infect Immun 35:990–996PubMedGoogle Scholar
  19. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A et al. (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427PubMedCrossRefGoogle Scholar
  20. Carrano CJ, Raymond KN (1978) Coordination chemistry of microbial iron transport compounds: rhodotorulic acid and iron uptake in Rhodotorula pilimanae. J Bacteriol 136:69–74PubMedGoogle Scholar
  21. Casas C, Aldea M, Espinet C, Gallego C, Gil R, Herrero E (1997) The AFT1 transcriptional factor is differentially required for expression of high-affinity iron uptake genes in Saccharomyces cerevisiae. Yeast 13: 621–637PubMedCrossRefGoogle Scholar
  22. Cellier M, Prive G, Belouchi A, Kwan T, Rodrigues V, Chia W, Gros P (1995) Nramp defines a family of membrane proteins. Proc Natl Acad Sci USA 92:10089–10093PubMedCrossRefGoogle Scholar
  23. Charlang G, Ng B, Horowitz NH, Horowitz RM (1981) Cellular and extracellular siderophores of Aspergillus nidulans and Penicillium chrysogenum. Mol Cell Biol 1:94–100PubMedGoogle Scholar
  24. Chen OS, Hemenway S, Kaplan J (2002) Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis. Proc Natl Acad Sci USA 99:12321–12326PubMedCrossRefGoogle Scholar
  25. Chen XZ, Peng JB, Cohen A, Nelson H, Nelson N, Hediger MA (1999) Yeast SMF1 mediates H(+)-coupled iron uptake with concomitant uncoupled cation currents. J Biol Chem 274:35089–35094PubMedCrossRefGoogle Scholar
  26. Clarke TE, Tari LW, Vogel HJ (2001) Structural biology of bacterial iron uptake systems. Curr Top Med Chem 1:7–30PubMedCrossRefGoogle Scholar
  27. Connolly EL, Fett JP, Guerinot ML (2002) Expression of the IRT1 metal transporter is controlled by metals at the levels of transcript and protein accumulation. Plant Cell 14:1347–1357PubMedCrossRefGoogle Scholar
  28. Corson LB, Folmer J, Strain JJ, Culotta VC, Cleveland DW (1999) Oxidative stress and iron are implicated in fragmenting vacuoles of Saccharomyces cerevisiae lacking Cu, Zn-superoxide dismutase. J Biol Chem 274:27590–27596PubMedCrossRefGoogle Scholar
  29. Crosa JH, Walsh CT (2002) Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol Mol Biol Rev 66:223–249PubMedCrossRefGoogle Scholar
  30. Curie C, Alonso JM, Le Jean M, Ecker JR, Briat JF (2000) Involvement of NRAMP1 from Arabidopsis thaliana in iron transport. Biochem J 347(Pt 3):749–755PubMedCrossRefGoogle Scholar
  31. Dancis A (1998) Genetic analysis of iron uptake in the yeast Saccharomyces cerevisiae. J Pediatr 132:S24–S29PubMedCrossRefGoogle Scholar
  32. Dancis A, Klausner RD, Hinnebusch AG, Barriocanal JG (1990) Genetic evidence that ferric reductase is required for iron uptake in Saccharomyces cerevisiae. Mol Cell Biol 10:2294–2301PubMedGoogle Scholar
  33. Dancis A, Roman DG, Anderson GJ, Hinnebusch AG, Klausner RD (1992) Ferric reductase of Saccharomyces cerevisiae: molecular characterization, role in iron uptake, and transcriptional control by iron. Proc Natl Acad Sci USA 89:3869–3873PubMedCrossRefGoogle Scholar
  34. Dancis A, Yuan DS, Haile D, Askwith C, Eide D, Moehle C, Kaplan J, Klausner RD (1994) Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76:393–402PubMedCrossRefGoogle Scholar
  35. Davis RH (1986) Compartmental and regulatory mechanisms in the arginine pathways of Neurospora crassa and Saccharomyces cerevisiae. Microbiol Rev 50:280–313PubMedGoogle Scholar
  36. De Luca NG, Wood PM (2000) Iron uptake by fungi: contrasted mechanisms with internal or external reduction. Adv Microb Physiol 43:39–74PubMedCrossRefGoogle Scholar
  37. De Silva DM, Askwith CC, Eide D, Kaplan J (1995) The FET3 gene product required for high affinity iron transport in yeast is a cell surface ferroxidase. J Biol Chem 270: 1098–1101PubMedCrossRefGoogle Scholar
  38. De Silva D, Davis-Kaplan S, Fergestad J, Kaplan J (1997) Purification and characterization of Fet3 protein, a yeast homologue of ceruloplasmin. J Biol Chem 272: 14208–14213PubMedCrossRefGoogle Scholar
  39. Dix D, Bridgham J, Broderius M, Eide D (1997) Characterization of the FET4 protein of yeast. Evidence for a direct role in the transport of iron. J Biol Chem 272: 11770–11777PubMedCrossRefGoogle Scholar
  40. Dix DR, Bridgham JT, Broderius MA, Byersdorfer CA, Eide DJ (1994) The FET4 gene encodes the low affinity Fe(II) transport protein of Saccharomyces cerevisiae. J Biol Chem 269:26092–26099PubMedGoogle Scholar
  41. Eck R, Hundt S, Hartl A, Roemer E, Kunkel W (1999) A multicopper oxidase gene from Candida albicans: cloning, characterization and disruption. Microbiology 145:2415–2422PubMedGoogle Scholar
  42. Ecker DJ, Emery T (1983) Iron uptake from ferrichrome A and iron citrate in Ustilago sphaerogena. J Bacteriol 155:616–622PubMedGoogle Scholar
  43. Eide D (1997) Molecular biology of iron and zinc uptake in eukaryotes. Curr Opin Cell Biol 9:573–577PubMedCrossRefGoogle Scholar
  44. Eide D, Davis-Kaplan S, Jordan I, Sipe D, Kaplan J (1992) Regulation of iron uptake in Saccharomyces cerevisiae. The ferrireductase and Fe(II) transporter are regulated independently. J Biol Chem 267:20774–20781PubMedGoogle Scholar
  45. Eide D, Broderius M, Fett J, Guerinot ML (1996) A novel iron-regulated metal transporter from plants identified by functional expression in yeast. Proc Natl Acad Sci USA 93:5624–5628PubMedCrossRefGoogle Scholar
  46. Eide DJ (2000) Metal ion transport in eukaryotic microorganisms: insights from Saccharomyces cerevisiae. Adv Microb Physiol 43:1–38PubMedCrossRefGoogle Scholar
  47. Eide DJ, Bridgham JT, Zhao Z, Mattoon JR (1993) The vacuolar H(+)-ATPase of Saccharomyces cerevisiae is required for efficient copper detoxification, mitochondrial function, and iron metabolism. Mol Gen Genet 241:447–456PubMedCrossRefGoogle Scholar
  48. Eisenstein RS, Blemings KP (1998) Iron regulatory proteins, iron responsive elements and iron homeostasis. J Nutr 128:2295–2298PubMedGoogle Scholar
  49. Emery T (1971) Role of ferrichrome as a ferric ionophore in Ustilago sphaerogena. Biochemistry 10:1483–1488PubMedCrossRefGoogle Scholar
  50. Emery T (1976) Fungal ornithine esterases: relationship to iron transport. Biochemistry 15:2723–2728PubMedCrossRefGoogle Scholar
  51. Ernst JF, Winkelmann G (1977) Enzymatic release of iron from sideramines in fungi. NADH:sideramine oxi-doreductase in Neurospora crassa. Biochim Biophys Acta 500:27–41PubMedCrossRefGoogle Scholar
  52. Fang HM, Wang Y (2002) Characterization of iron binding motifs in Candida albicans high-affinity iron permease CaFtrlp by site-directed mutagenesis. Biochem J 368:641–647PubMedCrossRefGoogle Scholar
  53. Fedorovich D, Protchenko O, Lesuisse E (1999) Iron uptake by the yeast Pichia guilliermondii. Flavinogenesis and reductive iron assimilation are co-regulated processes. Biometals 12:295–300PubMedCrossRefGoogle Scholar
  54. Fiedler HP, Krastel P, Muller J, Gebhardt K, Zeeck A (2001) Enterobactin: the characteristic catecholate siderophore of Enterobacteriaceae is produced by Streptomyces species. FEMS Microbiol Lett 196:147–151PubMedGoogle Scholar
  55. Finegold AA, Shatwell KP, Segal AW, Klausner RD, Dancis A (1996) Intramembrane bis-heme motif for transmembrane electron transport conserved in a yeast iron reductase and the human NADPH oxidase. J Biol Chem 271:31021–31024PubMedCrossRefGoogle Scholar
  56. Forbes JR, Gros P (2001) Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol 9:397–403PubMedCrossRefGoogle Scholar
  57. Foster LA (2002) Utilization and cell-surface binding of hemin by Histoplasma capsulatum. Can J Microbiol 48:437–442PubMedCrossRefGoogle Scholar
  58. Foury F, Talibi D (2001) Mitochondrial control of iron homeostasis. A genome wide analysis of gene expression in a yeast frataxin-deficient strain. J Biol Chem 276:7762–7768PubMedCrossRefGoogle Scholar
  59. Foury F, Roganti T (2002) Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem 277:24475–24483PubMedCrossRefGoogle Scholar
  60. Fridovich I (1978) The biology of oxygen radicals. Science 201:875–880PubMedCrossRefGoogle Scholar
  61. Garcia MG, O’Connor JE, Garcia LL, Martinez SI, Herrero E, del Castillo Agudo L (2001) Isolation of a Candida albicans gene, tightly linked to URA3, coding for a putative transcription factor that suppresses a Saccharomyces cerevisiae aft1 mutation. Yeast 18:301–311PubMedCrossRefGoogle Scholar
  62. Gardner PR, Fridovich I (1992) Inactivation-reactivation of aconitase in Escherichia coli. A sensitive measure of superoxide radical. J Biol Chem 267:8757–8763PubMedGoogle Scholar
  63. Garland SA, Hoff K, Vickery LE, Culotta VC (1999) Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family for iron-sulfur cluster assembly. J Mol Biol 294:897–907PubMedCrossRefGoogle Scholar
  64. Georgatsou E, Alexandraki D (1994) Two distinctly regulated genes are required for ferric reduction, the first step of iron uptake in Saccharomyces cerevisiae. Mol Cell Biol 14:3065–3073PubMedGoogle Scholar
  65. Georgatsou E, Alexandraki D (1999) Regulated expression of the Saccharomyces cerevisiae Frelp/Fre2p Fe/Cu reductase related genes. Yeast 15:573–584PubMedCrossRefGoogle Scholar
  66. Georgatsou E, Mavrogiannis LA, Fragiadakis GS, Alexandraki D (1997) The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. J Biol Chem 272:13786–13792PubMedCrossRefGoogle Scholar
  67. Guerinot ML (2000) The ZIP family of metal transporters. Biochim Biophys Acta 1465:190–198PubMedCrossRefGoogle Scholar
  68. Haas H, Angermayr K, Stoffler G (1997) Molecular analysis of a Penicillium chrysogenum GATA factor encoding gene (sreP) exhibiting significant homology to the Ustilago maydis urhs1 gene. Gene 184:33–37PubMedCrossRefGoogle Scholar
  69. Haas H, Zadra I, Stoffler G, Angermayr K (1999) The Aspergillus nidulans GATA factor SREA is involved in regulation of siderophore biosynthesis and control of iron uptake. J Biol Chem 274:4613–4619PubMedCrossRefGoogle Scholar
  70. Haas H, Schoeser M, Lesuisse E, Ernst JF, Parson W, Abt B, Winkelmann G, Oberegger H (2003) Characterisation of the Aspergillus nidulans transporters for the siderophores enterobactin and triacetylfusarinine C. Biochem J 371:505–513PubMedCrossRefGoogle Scholar
  71. Halliwell B, Gutteridge JM (1984) Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 219: 1–14PubMedGoogle Scholar
  72. Hammacott JE, Williams PH, Cashmore AM (2000) Candida albicans CFL1 encodes a functional ferric reductase activity that can rescue a Saccharomyces cerevisiae fre1 mutant. Microbiology 146:869–876PubMedGoogle Scholar
  73. Haselwandter K (1995) Mycorrhizal fungi: siderophore production. Crit Rev Biotechnol 15:287–291CrossRefGoogle Scholar
  74. Haselwandter K, Winkelmann G (2002) Ferricrocin — an ectomycorrhizal siderophore of Cenococcum geophilum. Biometals 15:73–77PubMedCrossRefGoogle Scholar
  75. Hassett R, Kosman DJ (1995) Evidence for Cu(II) reduction as a component of copper uptake by Saccharomyces cerevisiae. J Biol Chem 270:128–134PubMedCrossRefGoogle Scholar
  76. Hassett RF, Romeo AM, Kosman DJ (1998) Regulation of high affinity iron uptake in the yeast Saccharomyces cerevisiae. Role of dioxygen and Fe. J Biol Chem 273:7628–7636PubMedCrossRefGoogle Scholar
  77. Hassett R, Dix DR, Eide DJ, Kosman DJ (2000) The Fe(II) permease Fet4p functions as a low affinity copper transporter and supports normal copper trafficking in Saccharomyces cerevisiae. Biochem J 351(Pt 2): 477–484PubMedCrossRefGoogle Scholar
  78. Heymann P, Ernst JF, Winkelmann G (1999) Identification of a fungal triacetylfusarinine C siderophore transport gene (TAF1) in Saccharomyces cerevisiae as a member of the major facilitator superfamily. Biometals 12:301–306PubMedCrossRefGoogle Scholar
  79. Heymann P, Ernst JF, Winkelmann G (2000a) A gene of the major facilitator superfamily encodes a transporter for enterobactin (Enb1p) in Saccharomyces cerevisiae. Biometals 13:65–72PubMedCrossRefGoogle Scholar
  80. Heymann P, Ernst JF, Winkelmann G (2000b) Identification and substrate specificity of a ferrichrome-type siderophore transporter (Arn1p) in Saccharomyces cerevisiae. FEMS Microbiol Lett 186:221–227PubMedCrossRefGoogle Scholar
  81. Heymann P, Gerads M, Schaller M, Dromer F, Winkelmann G, Ernst JF (2002) The siderophore iron transporter of Candida albicans (Sit1p/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion. Infect Immun 70:5246–5255PubMedCrossRefGoogle Scholar
  82. Hider RC (1984) Siderophore mediated absorption of iron. Struct Bond 58:25–87CrossRefGoogle Scholar
  83. Higgins CF (1995) The ABC of channel regulation. Cell 82:693–696PubMedCrossRefGoogle Scholar
  84. Hoe KL, Won MS, Yoo OJ, Yoo HS (1996) Molecular cloning of GAF2, a Schizosaccharomyces pombe GATA factor, which has two zinc-finger sequences. Biochem Mol Biol Int 39:127–135PubMedGoogle Scholar
  85. Holzberg M, Artis WM (1983) Hydroxamate siderophore production by opportunistic and systemic fungal pathogens. Infect Immun 40:1134–1139PubMedGoogle Scholar
  86. Hordt W, Romheld V, Winkelmann G (2000) Fusarinines and dimerum acid, mono- and dihydroxamate siderophores from Penicillium chrysogenum, improve iron utilization by strategy I and strategy II plants. Biometals 13:37–46PubMedCrossRefGoogle Scholar
  87. Horowitz NH, Charlang G, Horn G, Williams NP (1976) Isolation and identification of the conidial germination factor of Neurospora crassa. J Bacteriol 127:135–140PubMedGoogle Scholar
  88. Howard DH (1999) Acquisition, transport, and storage of iron by pathogenic fungi. Clin Microbiol Rev 12:394–404PubMedGoogle Scholar
  89. Hu CJ, Bai C, Zheng XD, Wang YM, Wang Y (2002) Characterization and functional analysis of the siderophore-Fe transporter CaArn1p in Candida albicans. J Biol Chem 11:11Google Scholar
  90. Ismail A, Bedell GW, Lupan DM (1985) Siderophore production by the pathogenic yeast, Candida albicans. Biochem Biophys Res Commun 130:885–891PubMedCrossRefGoogle Scholar
  91. Jensen LT, Culotta VC (2002) Regulation of Saccharomyces cerevisiae FET4 by oxygen and iron. J Mol Biol 318: 251–260PubMedCrossRefGoogle Scholar
  92. Joyner DC, Lindow SE (2000) Heterogeneity of iron bioavailability on plants assessed with a whole-cell GFP-based bacterial biosensor. Microbiology 146: 2435–2445PubMedGoogle Scholar
  93. Kawai S, Suzuki S, Mori S, Murata K (2001) Molecular cloning and identification of UTR1 of a yeast Saccharomyces cerevisiae as a gene encoding an NAD kinase. FEMS Microbiol Lett 200:181–184PubMedCrossRefGoogle Scholar
  94. Kim Y, Yun CW, Philpott CC (2002) Ferrichrome induces endosome to plasma membrane cycling of the ferrichrome transporter, Arnlp, in Saccharomyces cerevisiae. EMBO J 21:3632–3642Google Scholar
  95. Kispal G, Csere P, Prohl C, Lill R (1999) The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J 18:3981–3989PubMedCrossRefGoogle Scholar
  96. Kitamoto K, Yoshizawa K, Ohsumi Y, Anraku Y (1988) Mutants of Saccharomyces cerevisiae with defective vacuolar function. J Bacteriol 170:2687–2691PubMedGoogle Scholar
  97. Knight SA, Lesuisse E, Stearman R, Klausner RD, Dancis A (2002) Reductive iron uptake by Candida albicans: role of copper, iron and the TUP1 regulator. Microbiology 148:29–40PubMedGoogle Scholar
  98. Lamb TM, Xu W, Diamond A, Mitchell AP (2001) Alkaline response genes of Saccharomyces cerevisiae and their relationship to the RIM101 pathway. J Biol Chem 276:1850–1856PubMedCrossRefGoogle Scholar
  99. Lange H, Kispal G, Lill R (1999) Mechanism of iron transport to the site of heme synthesis inside yeast mitochondria. J Biol Chem 274:18989–18996PubMedCrossRefGoogle Scholar
  100. Lapinskas PJ, Lin SJ, Culotta VC (1996) The role of the Saccharomyces cerevisiae CCC1 gene in the homeostasis of manganese ions. Mol Microbiol 21:519–528PubMedCrossRefGoogle Scholar
  101. Leong SA, Winkelmann G (1998) Molecular biology of iron transport in fungi. Met Ions Biol Syst 35:147–186PubMedGoogle Scholar
  102. Lesuisse E, Labbe P (1989) Reductive and non-reductive mechanisms of iron assimilation by the yeast Saccharomyces cerevisiae. J Gen Microbiol 135:257–263PubMedGoogle Scholar
  103. Lesuisse E, Crichton RR, Labbe P (1990) Iron-reductases in the yeast Saccharomyces cerevisiae. Biochim Biophys Acta 1038:253–259PubMedCrossRefGoogle Scholar
  104. Lesuisse E, Simon M, Klein R, Labbe P (1992) Excretion of anthranilate and 3-hydroxyanthranilate by Saccharomyces cerevisiae: relationship to iron metabolism. J Gen Microbiol 138:85–89PubMedGoogle Scholar
  105. Lesuisse E, Casteras-Simon M, Labbe P (1995) Ferrireductase activity in Saccharomyces cerevisiae and other fungi: colorimetric assays on agar plates. Anal Biochem 226:375–377PubMedCrossRefGoogle Scholar
  106. Lesuisse E, Casteras-Simon M, Labbe P (1996) Evidence for the Saccharomyces cerevisiae ferrireductase system being a multicomponent electron transport chain. J Biol Chem 271:13578–13583PubMedCrossRefGoogle Scholar
  107. Lesuisse E, Simon-Casteras M, Labbe P (1998) Siderophore-mediated iron uptake in Saccharomyces cerevisiae: the SIT1 gene encodes a ferrioxamine B permease that belongs to the major facilitator super-family. Microbiology 144:3455–3462PubMedCrossRefGoogle Scholar
  108. Lesuisse E, Blaiseau PL, Dancis A, Camadro JM (2001) Siderophore uptake and use by the yeast Saccharomyces cerevisiae. Microbiology 147:289–298PubMedGoogle Scholar
  109. Lesuisse E, Knight SA, Camadro JM, Dancis A (2002) Siderophore uptake by Candida albicans: effect of serum treatment and comparison with Saccharomyces cerevisiae. Yeast 19:329–340PubMedCrossRefGoogle Scholar
  110. Li L, Kaplan J (1998) Defects in the yeast high affinity iron transport system result in increased metal sensitivity because of the increased expression of transporters with a broad transition metal specificity. J Biol Chem 273:22181–22187PubMedCrossRefGoogle Scholar
  111. Li L, Chen OS, McVey Ward D, Kaplan J (2001) CCC1 is a transporter that mediates vacuolar iron storage in yeast. J Biol Chem 276:29515–29519PubMedCrossRefGoogle Scholar
  112. Lill R, Kispal G (2000) Maturation of cellular Fe-S proteins: an essential function of mitochondria. Trends Biochem Sci 25:352–356PubMedCrossRefGoogle Scholar
  113. Lin SJ, Pufahl RA, Dancis A, O’Halloran TV, Culotta VC (1997) A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 272:9215–9220PubMedCrossRefGoogle Scholar
  114. Liu Q, Dunlap JC (1996) Isolation and analysis of the arg-13 gene of Neurospora crassa. Genetics 143:1163–1174PubMedGoogle Scholar
  115. Liu XF, Culotta VC (1999) Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene. J Biol Chem 274:4863–4868PubMedCrossRefGoogle Scholar
  116. Liu XF, Supek F, Nelson N, Culotta VC (1997) Negative control of heavy metal uptake by the Saccharomyces cerevisiae BSD2 gene. J Biol Chem 272:11763–11769PubMedCrossRefGoogle Scholar
  117. Luk EE, Culotta VC (2001) Manganese superoxide dis-mutase in Saccharomyces cerevisiae acquires its metal co-factor through a pathway involving the Nramp metal transporter, Smf2p. J Biol Chem 276:47556–47562PubMedCrossRefGoogle Scholar
  118. Manns JM, Mosser DM, Buckley HR (1994) Production of a hemolytic factor by Candida albicans. Infect Immun 62:5154–5156PubMedGoogle Scholar
  119. Marahiel MA (1997) Protein templates for the biosynthesis of peptide antibiotics. Chem Biol 4:561–567PubMedCrossRefGoogle Scholar
  120. Martins LJ, Jensen LT, Simon JR, Keller GL, Winge DR, Simons JR (1998) Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. J Biol Chem 273:23716–23721PubMedCrossRefGoogle Scholar
  121. Matzanke BF (1994) Iron storage in fungi. In: Winkelmann G, Winge DR (eds) Metal ions in fungi. Decker, New York,pp 179–213Google Scholar
  122. Matzanke BF, Bill E, Trautwein AX, Winkelmann G (1987) Role of siderophores in iron storage in spores of Neurospora crassa and Aspergillus ochraceus. J Bacteriol 169:5873–5876PubMedGoogle Scholar
  123. Matzanke BF, Bill E, Trautwein AX, Winkelmann G (1988) Ferricrocin functions as the main intracellular iron-storage compound in mycelia of Neurospora crassa. Biol Met 1:18–25PubMedCrossRefGoogle Scholar
  124. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755–1759PubMedCrossRefGoogle Scholar
  125. Mei B, Budde AD, Leong SA (1993) sid1, a gene initiating siderophore biosynthesis in Ustilago maydis: molecular characterization, regulation by iron, and role in phytopathogenicity. Proc Natl Acad Sci USA 90:903–907PubMedCrossRefGoogle Scholar
  126. Moors MA, Stull TL, Blank KJ, Buckley HR, Mosser DM (1992) A role for complement receptor-like molecules in iron acquisition by Candida albicans. J Exp Med 175:1643–1651PubMedCrossRefGoogle Scholar
  127. Mootz HD, Schörgendorfer K, Marahiel MA (2002) Functional characterization of 4’-phosphopantetheinyl transferase genes of bacterial and fungal origin by complementation of Saccharomyces cerevisiae lys5. FEMS Microbiol Lett 213:51–57PubMedGoogle Scholar
  128. Morrissey JA, Williams PH, Cashmore AM (1996) Candida albicans has a cell-associated ferric-reductase activity which is regulated in response to levels of iron and copper. Microbiology 142:485–492PubMedCrossRefGoogle Scholar
  129. Muhlenhoff U, Richter N, Gerber J, Lill R (2002) Characterization of iron-sulfur protein assembly in isolated mitochondria: a requirement for ATP, NADH and reduced iron. J Biol Chem 13:13Google Scholar
  130. Muller G, Barclay SJ, Raymond KN (1985) The mechanism and specificity of iron transport in Rhodotorula pilimanae probed by synthetic analogs of rhodotorulic acid. J Biol Chem 260:13916–13920PubMedGoogle Scholar
  131. Neilands JB (1995) Siderophores: structure and function of microbial iron transport compounds. J Biol Chem 270:26723–26726PubMedGoogle Scholar
  132. Neilands JB, Konopka K, Schwyn B, Coy M, Francis RT, Paw BH, Bagg A (1987) Comparative biochemistry of microbial iron assimilation. In: Winkelmann G, Winge DR (eds) Iron transport in microbes, plants and animals. Weinheim and VCH, New York, pp 3–34Google Scholar
  133. Nilius AM, Farmer SG (1990) Identification of extracellular siderophores of pathogenic strains of Aspergillus fumigatus. J Med Vet Mycol 28:395–403PubMedCrossRefGoogle Scholar
  134. Nyhus KJ, Jacobson ES (1999) Genetic and physiologic characterization of ferric/cupric reductase constitutive mutants of Cryptococcus neoformans. Infect Immun 67:2357–2365PubMedGoogle Scholar
  135. Oberegger H, Zadra I, Schoeser M, Haas H (2000) Iron starvation leads to increased expression of Cu/Zn-superoxide dismutase in Aspergillus. FEBS Lett 485:113–116PubMedCrossRefGoogle Scholar
  136. Oberegger H, Schoeser M, Zadra I, Abt B, Haas H (2001) SREA is involved in regulation of siderophore biosynthesis, utilization and uptake in Aspergillus nidulans. Mol Microbiol 41:1077–1089PubMedCrossRefGoogle Scholar
  137. Oberegger H, Schoeser M, Zadra I, Schrettl M, Parson W, Haas H (2002a) Regulation of freA, acoA, lysF and cycA expression by iron availability in Aspergillus nidulans. Appl Environ Microbial 68:5769–5772CrossRefGoogle Scholar
  138. Oberegger H, Zadra I, Schoeser M, Abt B, Parson W, Haas H (2002b) Identification of members of the Aspergillus nidulans SREA regulon: genes involved in siderophore biosynthesis and utilization. Biochem Soc T 30:781–783CrossRefGoogle Scholar
  139. Odds FC, Van Nuffel L, Gow NA (2000) Survival in experimental Candida albicans infections depends on inoculum growth conditions as well as animal host. Microbiology 146:1881–1889PubMedGoogle Scholar
  140. Ong DE, Emery TF (1972) Ferrichrome biosynthesis: enzyme catalyzed formation of the hydroxamic acid group. Arch Biochem Biophys 148:77–83PubMedCrossRefGoogle Scholar
  141. Pao SS, Paulsen IT, Saier MH Jr (1998) Major facilitator superfamily. Microbiol Mol Biol Rev 62:1–34PubMedGoogle Scholar
  142. Paronetto MP, Miele R, Maugliani A, Borro M, Bonaccorsi di Patti MC (2001) Cloning of Pichia pastoris Fet3: insights into the high affinity iron uptake system. Arch Biochem Biophys 392:162–167PubMedCrossRefGoogle Scholar
  143. Pelletier B, Beaudoin J, Mukai Y, Labbe S (2002) Fep1, an iron sensor regulating iron transporter gene expression in Schizosaccharomyces pombe. J Biol Chem 277: 22950–22958PubMedCrossRefGoogle Scholar
  144. Pendrak ML, Krutzsch HC, Roberts DD (2000) Structural requirements for hemoglobin to induce fibronectin receptor expression in Candida albicans. Biochemistry 39:16110–16118PubMedCrossRefGoogle Scholar
  145. Perotto S, Bonfante P (1997) Bacterial associations with mycorrhizal fungi: close and distant friends in the rhizosphere. Trends Microbiol 5:496–501PubMedCrossRefGoogle Scholar
  146. Philpott CC, Rashford J, Yamaguchi-Iwai Y, Rouault TA, Dancis A, Klausner RD (1998) Cell-cycle arrest and inhibition of Gl cyclin translation by iron in AFT1–1(up) yeast. EMBO J 17:5026–5036PubMedCrossRefGoogle Scholar
  147. Plattner HJ, Diekmann H (1994) Enzymology of siderophore biosynthesis in fungi. In: Winkelmann G, Winge DR (eds) Metal ions in fungi. Decker, New York, pp 99–117Google Scholar
  148. Portnoy ME, Liu XF, Culotta VC (2000) Saccharomyces cerevisiae expresses three functionally distinct homologues of the Nramp family of metal transporters. Mol Cell Biol 20:7893–7902PubMedCrossRefGoogle Scholar
  149. Portnoy ME, Jensen LT, Culotta VC (2002) The distinct methods by which manganese and iron regulate the Nramp transporters in yeast. Biochem J 362:119–124PubMedCrossRefGoogle Scholar
  150. Protchenko O, Ferea T, Rashford J, Tiedeman J, Brown PO, Botstein D, Philpott CC (2001) Three cell wall manno-proteins facilitate the uptake of iron in Saccharomyces cerevisiae. J Biol Chem 276:49244–49250PubMedCrossRefGoogle Scholar
  151. Raguzzi F, Lesuisse E, Crichton RR (1988) Iron storage in Saccharomyces cerevisiae. FEBS Lett 231:253–258PubMedCrossRefGoogle Scholar
  152. Ramanan N, Wang Y (2000) A high-affinity iron permease essential for Candida albicans virulence. Science 288: 1062–1064PubMedCrossRefGoogle Scholar
  153. Ratledge C, Dover LG (2000) Iron metabolism in pathogenic bacteria. Annu Rev Microbiol 54:881–941PubMedCrossRefGoogle Scholar
  154. Richardson DR, Ponka P (1998) Development of iron chelators to treat iron overload disease and their use as experimental tools to probe intracellular iron metabolism. Am J Hematol 58:299–305PubMedCrossRefGoogle Scholar
  155. Robertson LS, Causton HC, Young RA, Fink GR (2000) The yeast A kinases differentially regulate iron uptake and respiratory function. Proc Natl Acad Sci USA 97: 5984–5988PubMedCrossRefGoogle Scholar
  156. Robinson NJ, Procter CM, Connolly EL, Guerinot ML (1999) A ferric-chelate reductase for iron uptake from soils. Nature 397:694–697PubMedCrossRefGoogle Scholar
  157. Roman DG, Dancis A, Anderson GJ, Klausner RD (1993) The fission yeast ferric reductase gene frpl+ is required for ferric iron uptake and encodes a protein that is homologous to the gp91-phox subunit of the human NADPH phagocyte oxidoreductase. Mol Cell Biol 13:4342–4350PubMedGoogle Scholar
  158. Roosenberg JM, Lin YM, Lu Y, Miller MJ (2000) Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents. Curr Med Chem 7:159–197PubMedCrossRefGoogle Scholar
  159. Rotrosen D, Yeung CL, Leto TL, Malech HL, Kwong CH (1992) Cytochrome b558: the flavin-binding component of the phagocyte NADPH oxidase. Science 256: 1459–1462PubMedCrossRefGoogle Scholar
  160. Rutherford JC, Jaron S, Ray E, Brown PO, Winge DR (2001) A second iron-regulatory system in yeast independent of Aft1p. Proc Natl Acad Sci USA 98:14322–14327PubMedCrossRefGoogle Scholar
  161. Scazzocchio C (2000) The fungal GATA factors. Curr Opin Microbiol 3:126–131PubMedCrossRefGoogle Scholar
  162. Shatwell KP, Dancis A, Cross AR, Klausner RD, Segal AW (1996) The FREI ferric reductase of Saccharomyces cerevisiae is a cytochrome b similar to that of NADPH oxidase. J Biol Chem 271:14240–14244PubMedCrossRefGoogle Scholar
  163. Smith RL, Johnson AD (2000) Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends Biochem Sci 25:325–330PubMedCrossRefGoogle Scholar
  164. Spizzo T, Byersdorfer C, Duesterhoeft S, Eide D (1997) The yeast FET5 gene encodes a FET3-related multicopper oxidase implicated in iron transport. Mol Gen Genet 256:547–556PubMedGoogle Scholar
  165. Stadler JA, Schweyen RJ (2002) The yeast iron regulon is induced upon cobalt stress and crucial for cobalt tolerance. J Biol Chem 9:9Google Scholar
  166. Stearman R, Yuan DS, Yamaguchi-Iwai Y, Klausner RD, Dancis A (1996) A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science 271:1552–1557PubMedCrossRefGoogle Scholar
  167. Straka JG, Emery T (1979) The role of ferrichrome reductase in iron metabolism of Ustilago sphaerogena. Biochim Biophys Acta 569:277–286PubMedCrossRefGoogle Scholar
  168. Supek F, Supekova L, Nelson H, Nelson N (1996) A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc Natl Acad Sci USA 93:5105–5110PubMedCrossRefGoogle Scholar
  169. Szczypka MS, Zhu Z, Silar P, Thiele DJ (1997) Saccharomyces cerevisiae mutants altered in vacuole function are defective in copper detoxification and iron-responsive gene transcription. Yeast 13:1423–1435PubMedCrossRefGoogle Scholar
  170. Ter Linde JJ, Liang H, Davis RW, Steensma HY, van Dijken JP, Pronk JT (1999) Genome-wide transcriptional analysis of aerobic and anaerobic chemostat cultures of Saccharomyces cerevisiae. J Bacteriol 181:7409–7413PubMedGoogle Scholar
  171. Thomine S, Wang R, Ward JM, Crawford NM, Schroeder JI (2000) Cadmium and iron transport by members of a plant metal transporter family in Arabidopsis with homology to Nramp genes. Proc Natl Acad Sci USA 97:4991–4996PubMedCrossRefGoogle Scholar
  172. Timmerman MM, Woods JP (1999) Ferric reduction is a potential iron acquisition mechanism for Histoplasma capsulatum. Infect Immun 67:6403–6408PubMedGoogle Scholar
  173. Timmerman MM, Woods JP (2001) Potential role for extracellular glutathione-dependent ferric reductase in utilization of environmental and host ferric compounds by Histoplasma capsulatum. Infect Immun 69:7671–7678PubMedCrossRefGoogle Scholar
  174. Unz RF, Shuttleworth KL (1996) Microbial mobilization and immobilization of heavy metals. Curr Opin Biotechnol 7:307–310PubMedCrossRefGoogle Scholar
  175. Urbanowski JL, Piper RC (1999) The iron transporter Fth1p forms a complex with the Fet5 iron oxidase and resides on the vacuolar membrane. J Biol Chem 274: 38061–38070PubMedCrossRefGoogle Scholar
  176. Van der Helm D, Winkelmann G (1994) Hydroxamates and polycarbonates as iron transport agents (siderophores) in fungi. In: Winkelmann G, Winge DR (eds) Metal ions in fungi. Decker, New York, pp 39–148Google Scholar
  177. Voisard C, Wang J, McEvoy JL, Xu P, Leong SA (1993) urbs1, a gene regulating siderophore biosynthesis in Ustilago maydis, encodes a protein similar to the erythroid transcription factor GATA-1. Mol Cell Biol 13:7091–7100PubMedGoogle Scholar
  178. Wartmann T, Stephan UW, Bube I, Boer E, Melzer M, Manteuffel R, Stoltenburg R, Guengerich L, Gellissen G, Kunze G (2002) Post-translational modifications of the AFET3 gene product — a component of the iron transport system in budding cells and mycelia of the yeast Arxula adeninivorans. Yeast 19:849–862PubMedCrossRefGoogle Scholar
  179. Watanabe T, Tanaka H, Nakao N, Mikami T, Suzuki M, Matsumoto T (1997) Anti Candida activity of induced transferrin in mice immunized with inactivated Candida albicans. Biol Pharm Bull 20:637–640PubMedCrossRefGoogle Scholar
  180. Waters BM, Eide DJ (2002) Combinatorial control of yeast FET4 gene expression by iron, zinc, and oxygen. J Biol Chem 2:2Google Scholar
  181. Weinberg ED (1993) The development of awareness of iron-withholding defense. Perspect Biol Med 36:215–221PubMedGoogle Scholar
  182. Weinberg ED (1999) The role of iron in protozoan and fungal infectious diseases. J Eukaryot Microbiol 46: 231–238PubMedCrossRefGoogle Scholar
  183. Weissman Z, Shemer R, Kornitzer D (2002) Deletion of the copper transporter CaCCC2 reveals two distinct pathways for iron acquisition in Candida albicans. Mol Microbiol 44:1551–1560PubMedCrossRefGoogle Scholar
  184. Wiest A, Grzegorski D, Xu BW, Goulard C, Rebuffat S, Ebbole DJ, Bodo B, Kenerley C (2002) Identification of peptaibols from Trichoderma virens and cloning of a peptaibol synthetase. J Biol Chem 277:20862–20868PubMedCrossRefGoogle Scholar
  185. Wilhite SE, Lumsden RD, Straney DC (2001) Peptide synthetase gene in Trichoderma virens. App1 Environ Microbiol 67:5055–5062CrossRefGoogle Scholar
  186. Winkelmann G (1993) Kinetics, energetics, and mechanisms of siderophore iron transport in fungi. In: Barton LL, Hemmings BC (eds) Iron chelation in plants and soil microorganisms. Academic Press, New York, pp 219–239Google Scholar
  187. Winkelmann G (2001) Siderophore transport in fungi. In: Winkelmann G (ed) Microbial transport systems. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  188. Yamaguchi-Iwai Y, Dancis A, Klausner RD (1995) AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. EMBO J 14:1231–1239PubMedGoogle Scholar
  189. Yamaguchi-Iwai Y, Stearman R, Dancis A, Klausner RD (1996) Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in yeast. EMBO J15: 3377–3384Google Scholar
  190. Yamaguchi-Iwai Y, Ueta R, Fukunaka A, Sasaki R (2002) Subcellular localization of Aft1 transcription factor responds to iron status in Saccharomyces cerevisiae. J Biol Chem 277:18914–18918PubMedCrossRefGoogle Scholar
  191. Yuan DS, Stearman R, Dancis A, Dunn T, Beeler T, Klausner RD (1995) The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplas-min-like oxidase required for iron uptake. Proc Natl Acad Sci USA 92:2632–2636PubMedCrossRefGoogle Scholar
  192. Yuan WM, Gentil GD, Budde AD, Leong SA (2001) Characterization of the Ustilago maydis sid2 gene, encoding a multidomain peptide synthetase in the ferrichrome biosynthetic gene cluster. J Bacteriol 183:4040–4051PubMedCrossRefGoogle Scholar
  193. Yun CW, Ferea T, Rashford J, Ardon O, Brown PO, Botstein D, Kaplan J, Philpott CC (2000a) Desferrioxamine-mediated iron uptake in Saccharomyces cerevisiae. Evidence for two pathways of iron uptake. J Biol Chem 275:10709–10715PubMedCrossRefGoogle Scholar
  194. Yun CW, Tiedeman JS, Moore RE, Philpott CC (2000b) Siderophore-iron uptake in Saccharomyces cerevisiae. Identification of ferrichrome and fusarinine transporters. J Biol Chem 275:16354–16359PubMedCrossRefGoogle Scholar
  195. Yun CW, Bauler M, Moore RE, Klebba PE, Philpott CC (2001) The role of the FRE family of plasma membrane reductases in the uptake of siderophore-iron in Saccharomyces cerevisiae. J Biol Chem 276:10218–10223PubMedCrossRefGoogle Scholar
  196. Zhao H, Eide D (1996a) The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proc Natl Acad Sci USA 93:2454–2458PubMedCrossRefGoogle Scholar
  197. Zhao H, Eide D (1996b) The ZRT2 gene encodes the low affinity zinc transporter in Saccharomyces cerevisiae. J Biol Chem 271:23203–23210PubMedCrossRefGoogle Scholar
  198. Zhou L, Marzluf GA (1999) Functional analysis of the two zinc fingers of SRE, a GATA-type factor that negatively regulates siderophore synthesis in Neurospora crassa. Biochemistry 38:4335–4341PubMedCrossRefGoogle Scholar
  199. Zhou LW, Haas H, Marzluf GA (1998) 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 259:532–540.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • H. Haas
    • 1
  1. 1.Department of Molecular BiologyUniversity of InnsbruckInnsbruckAustria

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