Structure and Mechanism of the Siderophore-Interacting
Protein from the Fuscachelin Gene Cluster of <i>Thermobifida
fusca</i>
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Abstract
Microbial iron acquisition is a complex
process and frequently
a key and necessary step for survival. Among the several paths for
iron assimilation, small molecule siderophore-mediated transport is
a commonly employed strategy of many microorganisms. The chemistry
and biology of the extraordinary tight and specific binding of siderophores
to metal is also exploited in therapeutic treatments for microbial
virulence and metal toxicity. The intracellular fate of iron acquired
via the siderophore pathway is one of the least understood steps in
the complex process at the molecular level. A common route to cellular
incorporation is the single-electron reduction of ferric to ferrous
iron catalyzed by specific and/or nonspecific reducing agents. The
biosynthetic gene clusters for siderophores often contain representatives
of one or two families of redox-active enzymes: the flavin-containing
“siderophore-interacting protein” and iron–sulfur
ferric siderophore reductases. Here we present the structure and characterization
of the siderophore-interacting protein, FscN, from the fuscachelin
siderophore gene cluster of <i>Thermobifida fusca</i>. The
structure shows a flavoreductase fold with a noncovalently bound FAD
cofactor along with an unexpected metal bound adjacent to the flavin
site. We demonstrated that FscN is redox-active and measured the binding
and reduction of ferric fuscachelin. This work provides a structural
basis for the activity of a siderophore-interacting protein and further
insight into the complex and important process of iron acquisition
and utilization