176
11.2.1 Reductive Iron Acquisition
In a reductive pathway, the extracellular ferric (Fe
3+
) iron (either free or ligandbound) is reduced into ferrous (Fe
2+
) iron, and then reoxidized by ferroxidase which
is linked to high-affinity permease. This reduction process usually takes place with
the help of multiple enzymes. The membrane-bound reductases and secreted reductases play an important role in iron reduction (Howard 1999; Saikia et al. 2014;
Schrettl et al. 2004). In addition, fungi are also expressing the high-affinity iron
permeases like CaFtr1, CaFtr2, Cft1 and Cft2; multicopper ferroxidases; a copper
transporter homolog Ccc2; and ferroxidase/permease homologs fetC and ftrA (Eck
et al. 1999; Jung et al. 2008; Weissman et al. 2002). Studies showed that only
Caftr1∆ and cft1∆ mutants displayed reduced virulence whereas the remaining
exhibit either low virulence or no virulence in low iron environment (Jung et al.
2008). This ensures their significance in reductive iron acquisition mechanisms.
However, when the reductive iron acquisition is blocked, fungi are compensating
this loss by upregulating the non-reductive iron acquisition mechanisms to satisfy
their demand for iron. Hence, these enzymes could not be a good choice as drug
targets in antifungal drug design.
11.2.2 Siderophore Biosynthesis
Iron is essential for most of the important biological processes. When this iron is
deficient in its environment, fungus synthesizes siderophores, ferric ion–specific
chelating agents which can capture the iron with high affinity. As mentioned earlier,
most of the fungal siderophores are hydroxamates and these are categorized into
four families: rhodotorulic acid, fusarinines, coprogens and ferrichromes (Garnerin
et al. 2017; Haas 2003).
Siderophore biosynthetic pathway starts with L-Ornithine, followed by the production of hydroxamate prosthetic groups which are linked together to form
siderophores.
The first step in fungal siderophore biosynthesis is N
5
-hydroxylation of
L-Ornithine by L-Ornithine N
5
-oxygenase. In Ustilago maydis, this enzyme is
encoded by Sid1 gene, expressed in an iron deficit condition to produce siderophores. The orthologs of this Sid1 gene are observed in most of the fungus which
shows the importance of this gene in fungal survival in various environmental
conditions.
In the subsequent steps of the biosynthetic pathway, an acyl group is transferred
to N
5
-hydroxyornithine by N
5
-transacetylase, whereas in coprogen and triacetylfusarinine siderophore families, further acetylation at N
2
-amino group also takes place
by N
2
-transacetylase.
The final step is associated with the linking of hydroxamates by non-ribosomal
peptide synthetases (NRPS). The simplest of fungal siderophore family,
A. Shanmugam et al.
11.2.1 Reductive Iron Acquisition
In a reductive pathway, the extracellular ferric (Fe
3+
) iron (either free or ligandbound) is reduced into ferrous (Fe
2+
) iron, and then reoxidized by ferroxidase which
is linked to high-affinity permease. This reduction process usually takes place with
the help of multiple enzymes. The membrane-bound reductases and secreted reductases play an important role in iron reduction (Howard 1999; Saikia et al. 2014;
Schrettl et al. 2004). In addition, fungi are also expressing the high-affinity iron
permeases like CaFtr1, CaFtr2, Cft1 and Cft2; multicopper ferroxidases; a copper
transporter homolog Ccc2; and ferroxidase/permease homologs fetC and ftrA (Eck
et al. 1999; Jung et al. 2008; Weissman et al. 2002). Studies showed that only
Caftr1∆ and cft1∆ mutants displayed reduced virulence whereas the remaining
exhibit either low virulence or no virulence in low iron environment (Jung et al.
2008). This ensures their significance in reductive iron acquisition mechanisms.
However, when the reductive iron acquisition is blocked, fungi are compensating
this loss by upregulating the non-reductive iron acquisition mechanisms to satisfy
their demand for iron. Hence, these enzymes could not be a good choice as drug
targets in antifungal drug design.
11.2.2 Siderophore Biosynthesis
Iron is essential for most of the important biological processes. When this iron is
deficient in its environment, fungus synthesizes siderophores, ferric ion–specific
chelating agents which can capture the iron with high affinity. As mentioned earlier,
most of the fungal siderophores are hydroxamates and these are categorized into
four families: rhodotorulic acid, fusarinines, coprogens and ferrichromes (Garnerin
et al. 2017; Haas 2003).
Siderophore biosynthetic pathway starts with L-Ornithine, followed by the production of hydroxamate prosthetic groups which are linked together to form
siderophores.
The first step in fungal siderophore biosynthesis is N
5
-hydroxylation of
L-Ornithine by L-Ornithine N
5
-oxygenase. In Ustilago maydis, this enzyme is
encoded by Sid1 gene, expressed in an iron deficit condition to produce siderophores. The orthologs of this Sid1 gene are observed in most of the fungus which
shows the importance of this gene in fungal survival in various environmental
conditions.
In the subsequent steps of the biosynthetic pathway, an acyl group is transferred
to N
5
-hydroxyornithine by N
5
-transacetylase, whereas in coprogen and triacetylfusarinine siderophore families, further acetylation at N
2
-amino group also takes place
by N
2
-transacetylase.
The final step is associated with the linking of hydroxamates by non-ribosomal
peptide synthetases (NRPS). The simplest of fungal siderophore family,
A. Shanmugam et al.