Site-specific rate constants for iron acquisition from transferrin by the Aspergillus fumigatus siderophores N′,N′′,N′′′-triacetylfusarinine C and ferricrocin

Abstract

Aspergillus fumigatus is an opportunistic fungal pathogen that causes life-threatening infections in immunocompromised patients. Despite low levels of free iron, A. fumigatus grows in the presence of human serum in part because it produces high concentrations of siderophores. The most abundant siderophores produced by A. fumigatus are N',N'',N'''-triacetylfusarinine C (TAF) and ferricrocin, both of which have thermodynamic iron binding constants that theoretically allow them to remove transferrin (Tf)-bound iron. Urea-polyacrylamide gel electrophoresis was used to measure the change in concentration of Tf species incubated with TAF or ferricrocin. The rate of removal of iron from diferric Tf by both siderophores was measured, as were the individual microscopic rates of iron removal from each Tf species (diferric Tf, N-terminal monoferric Tf and C-terminal monoferric Tf). TAF removed iron from all Tf species at a faster rate than ferricrocin. Both siderophores showed a preference for removing C-terminal iron, evidenced by the fact that k(1C) and k(2C) were much larger than k(1N) and k(2N). Cooperativity in iron binding was observed with TAF, as the C-terminal iron was removed by TAF much faster from monoferric than from diferric Tf. With both siderophores, C-terminal monoferric Tf concentrations remained below measurable levels during incubations. This indicates that k(2C) and k(1C) are much larger than k(1N). TAF and ferricrocin both removed Tf-bound iron with second-order rate constants that were comparable to those of the siderophores of several bacterial pathogens, indicating they may play a role in iron uptake in vivo and thereby contribute to the virulence of A. fumigatus.

Iron – A Key Nexus in the Virulence of Aspergillus fumigatus

“…SidG-deficiency, which eliminates TAFC production with concomitant increase of FsC production, affects neither growth nor virulence, indicating that the structural differences between these two siderophores do not play a role in these settings (Schrettl et al, 2007). Consistent with a role in iron acquisition during infection, A. fumigatus ’ siderophores are able to remove iron from host sources, such as transferrin (Hissen et al, 2004; Hissen and Moore, 2005). …”

Fungal siderophore metabolism with a focus onAspergillus fumigatus

“…23 The fact that A. fumigatus siderophores are able to remove iron from host sources, such as transferrin underlines their crucial role in virulence. 90,91 …”

Hybrid Imaging of Aspergillus fumigatus Pulmonary Infection with Fluorescent, 68Ga-Labelled Siderophores

“…The three amino groups are either acetylated (TAFC) or present as free amines (FsC), that allow chemical modification [14]. A high iron binding affinity of pM = 31.8 enables TAFC trans-chelation of ferric irons from transferrin (pM = 23.6) in the human host [15]. This high ferric iron affinity can also be used to exchange iron by gallium-68, which has the same size and charge as ferric iron, and facilitates the application of [ 68 Ga]Ga-TAFC as a radioactive tracer for the rapid localisation of IPA infections by PET/CT scan [16].…”