Source: http://www.asmscience.org/content/book/10.1128/9781555815523.ch09
Timestamp: 2019-04-21 08:35:50+00:00

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This chapter is a compilation of the current knowledge about Aspergillus fumigatus mechanisms involved in maintaining iron (Fe) and zinc (Zn) homeostasis and their impact on pathogenicity. In filamentous fungi, genes encoding components of common pathways are often organized in gene clusters defined by coregulation, which facilitates molecular analysis of pathways. Consistent with the role of siderophores in virulence, A. fumigatus sidD was found to be the most highly expressed A. fumigatus nonribosomal peptide synthetases (NRPS)-encoding gene following incubation with macrophages, and genes encoding A. fumigatus siderophore biosynthetic enzymes (SidC, SidD, SidF, and SidG) are significantly induced at the level of gene expression at an early stage of infection in neutropenic mice. Fungal requirements for zinc and iron could potentially open up perspectives for the development of novel antifungal treatments. For instance, since humans do not possess a ZafA ortholog, the ZafA protein might constitute a target for the development of chemotherapeutic agents that selectively interfere with fungal zinc homeostasis. Similarly, blocking of siderophore transporters or siderophore biosynthetic enzymes appears to be particularly promising because the involved proteins are not present in mammals.
Schematic representation of proteins putatively involved in maintaining zinc homeostasis in A. fumigatus. Each protein is represented in its more likely subcellular location according to what is currently known about its correspondent yeast ortholog. Zinc transporters of the ZIP and CDF families are represented by gray cylinders and dashed cylinders, respectively. Other proteins that also may be involved in zinc homeostasis are depicted with a dotted pattern. The zinc-responsive transcriptional activator ZafA is represented by a dark gray pentagon in either an active or inactive state (saturated with zinc ions). MP, metalloproteins. Zinc ions are represented by small black circles.
Comparison of systems for uptake and storage in S. cerevisiae and A. fumigatus. CM, cytoplasmic membrane; XS, xenosiderophore.
Structures of TAFC and FC (A) and the proposed biosynthetic pathway (B). Enzymatic activities are boxed, and encoding enzymes are shaded in gray. CoA, coenzyme A.
Phylogenetic analysis of siderophore transporters from A. fumigatus (Afu), A. nidulans (An), and S. cerevisiae (Y). Available gene names and substrate specificities are indicated. CG, coprogen; EB, enterobactin; FCH, ferrichromes; FOX, ferrioxamines. A. terreus ATEG 06291.1 is a major facilitator not belonging to the SIT family and served as an outgroup. S. cerevisiae transporters are boxed. Permeases likely to be involved in transport of TAFC are marked by an open bar.
Schematic comparison of iron regulatory mechanisms of A. nidulans and S. cerevisiae.
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