Fungal siderophores function as protective agents of LDL oxidation and are promising anti‐atherosclerotic metabolites in functional food

Abstract

Iron-mediated oxidation of low-density lipoprotein has been implicated in the pathogenesis of vascular disorders such as atherosclerosis. The present investigations were performed to test whether hydrophobic fungal siderophores -hexadentate trihydroxamates desferricoprogen, desferrichrome, desferrirubin, and desferrichrysin -might suppress heme-catalyzed LDL oxidation and the toxic effects of heme-treated LDL on vascular endothelium. Indeed, two of these -desferricoprogen and desferrichrome -markedly increased the resistance of LDL to heme-catalyzed oxidation. In similar doseresponse fashion, these siderophores also inhibited the generation of LDL products cytotoxic to human vascular endothelium. When iron-free fungal siderophores were added to LDL/heme oxidation reactions, the product failed to induce heme oxygenase-1, a surrogate marker for the noncytocidal effects of oxidized LDL (not in the case of desferrichrysin). Desferricoprogen also hindered the ironmediated peroxidation of lipids from human atherosclerotic soft plaques in vitro, and was taken up in the gastrointestinal tract of rat. The absorbed siderophore was accumulated in the liver and was secreted in its iron-complexed form in the feces and urine. The consumption of mold-ripened food products such as aged cheeses and the introduction of functional foods and food additives rich in fungal iron chelators in diets may lower the risk of cardiovascular diseases.

Structure-based differences between the metal ion selectivity of two siderophores desferrioxamine B (DFB) and desferricoprogen (DFC): Why DFC is much better Pb(II) sequestering agent than DFB?

“…Because the complex-formation especially with Ca(II) and even with Mg(II) is weak, therefore the interaction between these two metal ions and desferricoprogen is of negligible physiological significance. The normal serum concentrations for Ca(II) and Mg(II) (1.2 and 0.9 mmol l À1 [38,39], respectively) were found two orders of magnitude higher than that for desferricoprogen (12 lmol l À1 ), when this siderophore was introduced orally at 100 mg kg body mass À1 concentration [16]. Therefore, desferricoprogen absorbed from the gastrointestinal tract is unlikely to interfere with the pathogenesis of cardiovascular disorders at the level of Ca(II) homeostasis [18,19] and will not decrease protective Mg(II) concentrations [17] either.…”

“…A poor uptake of this siderophore in the gastrointestinal tract [14] can be assigned mainly to the positively charged terminal ammonium group. This assumption is supported by the fact that the fungal trihydroxamate-type desferricoprogen (DFC) (Scheme 1), which is uncharged under physiological conditions [15], was orally active, accumulated in the liver and was secreted via its iron-complex into the feces and urine in a rat model [16]. Similarly to DFB, DFC was found to increase the resistance of LDL to heme-catalyzed oxidation and attenuate the cytotoxicity of the oxidation products of LDL to human vascular endothelium.…”

“…Moreover, DFC was found also to hinder the heme-mediated oxidation of human atherosclerotic soft plaque lipids. Based on the results, the consumption of traditional mould-ripened foods and the development of functional foods with increased trihydroxamate contents are believed to represent powerful tools in the prevention of cardiovascular disorders [16]. However, the development and introduction of desferricoprogenenriched functional food in anti-atherosclerotic diets need information about the interaction of this siderophore with various metal ions, including essential alkaline earth metals, namely Mg(II), which is protective against various diseases, e.g., hypertension [17], and Ca(II), which has an adverse effect on vascular calcification, a risk factor e.g.…”

Biotechnology of siderophores in high-impact scientific fields

“…Recent reports described the potential use of these two siderophores produced by fungi as anti-atherosclerotic agents (24,25). The researchers based their findings on the fact that iron accumulates in atherosclerotic lesions contributing to iron-dependent lipid oxidation.…”

“…By utilizing siderophores as iron-chelating agents the effects of lipid oxidation can be reduced, representing potential improvement of the disease. Pócsi and coworkers (25) determined that both coprogen (produced by P. chrysogenum and Neurospora crassa) and ferrichrome (produced by P. chrysogenum) reduced the heme-catalyzed low density lipoprotein (LDL) oxidation and its cytotoxic metabolites to human vasculature tissue. The other group studied the stability and antimicrobial and antifungal effects of coprogen produced by Penicillium nalgiovense in cheese and sausage sources (24).…”