Appl Microbiol Biotechnol (2003) 62:316–330 DOI 10.1007/s00253-003-1335-2 MINI-REVIEW H. Haas Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage Received: 5 March 2003 / Revised: 11 April 2003 / Accepted: 11 April 2003 / Published online: 21 May 2003  Springer-Verlag 2003 Abstract To acquire iron, all species have to overcome the problems of iron insolubility and toxicity. In response to low iron availability in the environment, most fungi excrete ferric iron-specific chelators—siderophores—to mobilize this metal. Siderophore-bound iron is subse- quently utilized via the reductive iron assimilatory system or uptake of the siderophore-iron complex. Furthermore, most fungi possess intracellular siderophores as iron storage compounds. Molecular analysis of siderophore biosynthesis was initiated by pioneering studies on the basidiomycete Ustilago maydis, and has progressed recently by characterization of the relevant structural and regulatory genes in the ascomycetes Aspergillus nidulans and Neurospora crassa. In addition, significant advances in the understanding of utilization of sidero- phore-bound iron have been made recently in the yeasts Saccharomyces cerevisiae and Candida albicans as well as in the filamentous fungus A. nidulans. The present review summarizes molecular details of fungal sidero- phore biosynthesis and uptake, and the regulatory mech- anisms involved in control of the corresponding genes. Introduction Iron is an essential element for nearly all organisms. As a transition element, iron can reversibly modify its oxida- tion state. Accordingly, this metal is used in a variety of cofactors, e.g., heme moieties and iron-sulfur clusters, making it essential in key metabolic processes, including deoxyribonucleotide synthesis, oxidative phosphorylation and electron transport. However, iron can also catalyze the deleterious oxidation of biomolecules via Haber- Weiss/Fenton chemistry (Halliwell and Gutteridge 1984). Thus, the concentration of iron in biological fluids is tightly regulated by control of its uptake and intracellular storage. Despite its relative abundance in nature, the amount of bioavailable iron is very limited—probably not greater than 10 18 M (Neilands et al. 1987)—because atmospheric oxygen rapidly oxidizes iron to form spar- ingly soluble ferric oxyhydroxids. Under iron starvation, most fungi excrete at least one type of siderophore—low molecular weight, ferric iron-specific chelators—in order to solubilize environmental iron. Siderophores can be divided into three groups based on chemical composition: (1) catechols; (2) carboxylates; (3) hydroxamates. With exception of carboxylates produced by zygomycetes (e.g., rhizoferrin produced by various Mucorales), fungal siderophores are hydroxamates (van der Helm and Winkelmann 1994). Most siderophores possess three bidentate iron chelating groups and all form six coordi- nate complexes with extraordinary affinity for ferric iron. Subsequently, cells recover iron from the ferri-sidero- phore complexes via specific uptake mechanisms (Winkelmann 2001, 2002). Remarkably, numerous fungi possess specific uptake systems not only for native siderophores but also for siderophore-types synthesized exclusively by other fungi; e.g., Aspergillus nidulans can take up various heterologous siderophores (xenosidero- phores) including the hydroxamate-type siderophore fer- rirubin, synthesized by Aspergillus ochraceus, and the catecholate-type siderophore enterobactin, produced by various bacteria of the families Enterobacteriaceae and Streptomycetaceae (Fiedler et al. 2001; Oberegger et al. 2001). Such a strategy might have evolved for competi- tion with other organisms and/or conservation of meta- bolic energy. In addition to iron acquisition, siderophores play a role in intracellular iron storage in most fungi (Matzanke et al. 1987). Moreover, siderophores have often been suggested to function as virulence factors because the acquisition of iron is a key step in any infection process (Weinberg 1999), and the respective pathways for biosynthesis and H. Haas ( ) ) Department of Molecular Biology, University of Innsbruck, Fritz-Pregl-Strasse 3, 6020 Innsbruck, Austria e-mail: hubertus.haas@uibk.ac.at Tel.: +43-512-5073605 Fax: +43-512-5072866