Abstract
Iron is an essential micronutrient for almost all organisms, including fungi. Usually, fungi can uptake iron through receptor-mediated internalization of a siderophore or heme, and/or reductive iron assimilation (RIA). Traditionally, the RIA pathway consists of ferric reductases (Fres), ferroxidase (Fet3) and a high-affinity iron permease (Ftr1). Paracoccidioides spp. genomes do not present an Ftr1 homolog. However, this fungus expresses zinc regulated transporter homologs (Zrts), members of the ZIP family of membrane transporters that are able in some organisms to transport zinc and iron. A 2,3,5-triphenyltetrazolium chloride (TTC)-overlay assay indicates that both Pb01 and Pb18 express a ferric reductase activity; however, 59Fe uptake assays indicate that only in Pb18 is this activity coupled to a reductase-dependent iron uptake pathway. In addition, Zrts are up-regulated in iron deprivation, as indicated by RNAseq and qRT-PCR using Pb01 transcripts. RNAseq strategy also demonstrated that transcripts related to siderophore uptake and biosynthesis are up-regulated in iron-deprived condition. The data suggest that the fungus could use both a non-classical RIA, comprising ferric reductases and Fe/Zn permeases (Zrts), and siderophore uptake pathways under iron-limited conditions. The study of iron metabolism reveals novel surface molecules that could function as accessible targets for drugs to block iron uptake and, consequently, inhibit pathogen's proliferation.
Highlights
Iron is the most common cofactor in biology
It could be observed that all the Paracoccidioides spp. sequences are grouped with H. capsulatum, C. immitis, C. posadasii, and B. dermatitidis sequences
Paracoccidioides spp. presents multiple ferric reductases (Silva et al, 2011). These proteins are very similar to homologs found in H. capsulatum, C. immitis, C. posadasii, and B. dermatitidis, as expected, since all the organisms are classified in the Onygenales order (Sharpton et al, 2009)
Summary
Iron is the most common cofactor in biology. This fact could be explained by the high abundance of the element in nature and by its chemical properties, mainly by its redox ability. Fungi accumulate iron through two different strategies: (1) receptor-mediated internalization of ferric-siderophore complexes and/or heme group; and (2) reductive iron assimilation (RIA), involving iron reduction, followed by a ferroxidase-permeation step (Kosman, 2013). The first strategy has been recently described in Paracoccidioides spp. It has been shown that this fungus is able to utilize siderophores and hemoglobin as iron sources through receptor-mediated pathways (Bailão et al, 2014; Silva-Bailão et al, 2014). The RIA in Paracoccidioides spp. remains elusive
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