Iron uptake by fungi: contrasted mechanisms with internal or external reduction.

Almost all iron uptake by fungi involves reduction from Fe(III) to Fe(II) in order to facilitate ligand exchange. This leads to two mechanisms: uptake before reduction, or reduction before uptake. Many fungi secrete specific hydroxamate siderophores when short of iron. The mechanism with uptake before reduction is described in the context of siderophore synthesis and usage, since it applies to many (but not all) siderophores. The hydroxamate functional group is synthesized from ornithine by N5 hydroxylation and acylation. In most fungal siderophores, two or three modified ornithines are joined together by a non-ribosomal peptide synthetase. The transcription of these genes is regulated by an iron activated repressor. There is evidence that the iron-free siderophore may be stored in intracellular vesicles until secretion is required. After loading with iron, re-entry is likely to be via a proton symport. In some fungi, siderophores are used for iron storage. The iron is liberated by an NADPH-linked reductase. The second mechanism starts with Fe(III) reduction. In yeast, this is catalysed by an NADPH-linked transmembrane reductase, which has homology with the NADPH oxidase of neutrophils. There are two closely similar reductases with overlapping roles in Fe(III) and Cu(II) reduction, while the substrates for reduction include Fe(III)-siderophores. External reductants, which may be important in certain fungi, include 3-hydroxyanthranilic acid, melanin, cellobiose dehydrogenase and 2,5-dimethylhydroquinone. In yeast, a high-affinity iron uptake pathway involves reoxidation of Fe(II) to Fe(III), probably to confer specificity for iron. This is catalysed by a copper protein which has homology with ceruloplasmin, and is closely coupled to Fe(III) transport. The transcription of these genes is regulated by an iron-inhibited activator. Because of its copper requirement, the high-affinity pathway is blocked by disruption of genes for copper metabolism. A low-affinity uptake transports Fe(II) directly and is important in anoxic growth. In many fungi, mechanisms with internal or external reduction are both important. The external reduction is applicable to almost any Fe(III) complex, while internal reduction is more efficient at low iron but requires a siderophore permease through which toxins might enter. Both mechanisms require close coupling of Fe(III) reduction and Fe(II) utilization in order to minimize production of active oxygen.