6
1.5 Fungal Siderophores and Iron Storage
Apart from contributing to iron uptake in restricted microecosystem, the siderophores play a pivotal role in storing iron in the cytoplasm of the fungi. Fungi principally utilize two distinct approaches for iron storage: (i) deposition of iron in the
vessels and (ii) iron storage facilitated by siderophores. A. fumigatus uses both strategies for iron storage. Unlike bacteria, the fungi infecting the plants and animals do
not have the ferritin-mediated iron storage. The iron storage happens even in the
fungal spore forms. The fungi capable of generating the siderophores have the
potential to extract iron from the proteins present in the host. The siderophores triacetyl fusarinine C and fusarinine secreted by A. fumigatus are more potent and
capable of extracting iron bound to transferrin, a protein present in the host. For
Aspergillus spp., the primary method of acquirement of iron is through siderophore
production because of their inability to get iron from either heme or ferritin or transferrin. In A. fumigatus, iron permease was superfluous and is not essential for pathogenicity, but deletion of siderophore-producing genes results in increased
pathogenicity as evident from increased virulence and formation of conida. In addition, A. nidulans needs siderophores for its existence, and deleting siderophoreproducing genes resulted in abnormal growth and development. After binding with
ferric iron, siderophore is moved to the cytoplasm of A. fumigatus through siderophore iron transporters, and iron is stored in the cytoplasm of vacuoles.
The specific iron storage exists in certain fungal species. The fungi grouped
under Mucorales order have no mechanism to generate siderophores with hydroxamate class. Rhizoferrin, a siderophore belonging to carboxylate class produced by
mucormycetes, has poor affinity to obtain iron from the proteins of the hosts, and
hence rhizoferrin is a poor infecting agent in humans. As mucormycetes cannot use
its own siderophore, they use the iron vehicles that act as exogenous siderophores.
The patients with the risk of iron intoxication are prescribed with defuroximine, a
potent chelating agent. The patients are reported with the episodes of siderophoremediated mucormycosis.
1.6 Chemistry and Biosynthesis
Most of the fungal siderophores are hydroxamates with few exceptions. The biosynthesis of hydroxamate siderophores is regulated by an iron-dependent mechanism in
most of the fungal species including Epichloë festucae, Ustilago maydis, and
Saccharomyces cerevisiae (Holinsworth and Martin 2009; Forester et al. 2018; An
et al. 1997a, b). Genes such as Sid1, Sid2, SidN, and urbs1 are known to be involved
in the biosynthesis pathway (An et al. 1997a, b). The hydroxamates establish a stable ferric iron-binding bidentate. N
5
-Hydroxy-l-ornithine is a nonprotein synthetic
amino acid that contributes to the formation of hydroxamates through acylation.
N
5
-Hydroxy-l-ornithine is generated by the hydroxylation of l-ornithine that has a
variety of functional groups such as acetyl, hydromevalonyl, and many more
S. S. Arputhanantham et al.
1.5 Fungal Siderophores and Iron Storage
Apart from contributing to iron uptake in restricted microecosystem, the siderophores play a pivotal role in storing iron in the cytoplasm of the fungi. Fungi principally utilize two distinct approaches for iron storage: (i) deposition of iron in the
vessels and (ii) iron storage facilitated by siderophores. A. fumigatus uses both strategies for iron storage. Unlike bacteria, the fungi infecting the plants and animals do
not have the ferritin-mediated iron storage. The iron storage happens even in the
fungal spore forms. The fungi capable of generating the siderophores have the
potential to extract iron from the proteins present in the host. The siderophores triacetyl fusarinine C and fusarinine secreted by A. fumigatus are more potent and
capable of extracting iron bound to transferrin, a protein present in the host. For
Aspergillus spp., the primary method of acquirement of iron is through siderophore
production because of their inability to get iron from either heme or ferritin or transferrin. In A. fumigatus, iron permease was superfluous and is not essential for pathogenicity, but deletion of siderophore-producing genes results in increased
pathogenicity as evident from increased virulence and formation of conida. In addition, A. nidulans needs siderophores for its existence, and deleting siderophoreproducing genes resulted in abnormal growth and development. After binding with
ferric iron, siderophore is moved to the cytoplasm of A. fumigatus through siderophore iron transporters, and iron is stored in the cytoplasm of vacuoles.
The specific iron storage exists in certain fungal species. The fungi grouped
under Mucorales order have no mechanism to generate siderophores with hydroxamate class. Rhizoferrin, a siderophore belonging to carboxylate class produced by
mucormycetes, has poor affinity to obtain iron from the proteins of the hosts, and
hence rhizoferrin is a poor infecting agent in humans. As mucormycetes cannot use
its own siderophore, they use the iron vehicles that act as exogenous siderophores.
The patients with the risk of iron intoxication are prescribed with defuroximine, a
potent chelating agent. The patients are reported with the episodes of siderophoremediated mucormycosis.
1.6 Chemistry and Biosynthesis
Most of the fungal siderophores are hydroxamates with few exceptions. The biosynthesis of hydroxamate siderophores is regulated by an iron-dependent mechanism in
most of the fungal species including Epichloë festucae, Ustilago maydis, and
Saccharomyces cerevisiae (Holinsworth and Martin 2009; Forester et al. 2018; An
et al. 1997a, b). Genes such as Sid1, Sid2, SidN, and urbs1 are known to be involved
in the biosynthesis pathway (An et al. 1997a, b). The hydroxamates establish a stable ferric iron-binding bidentate. N
5
-Hydroxy-l-ornithine is a nonprotein synthetic
amino acid that contributes to the formation of hydroxamates through acylation.
N
5
-Hydroxy-l-ornithine is generated by the hydroxylation of l-ornithine that has a
variety of functional groups such as acetyl, hydromevalonyl, and many more
S. S. Arputhanantham et al.